[Federal Register Volume 81, Number 156 (Friday, August 12, 2016)]
[Proposed Rules]
[Pages 53767-53845]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-17960]
[[Page 53767]]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Chapter II
[Docket No. DEA-427]
Denial of Petition To Initiate Proceedings To Reschedule
Marijuana
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Denial of petition to initiate proceedings to reschedule
marijuana.
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SUMMARY: By letter dated July 19, 2016 the Drug Enforcement
Administration (DEA) denied a petition to initiate rulemaking
proceedings to reschedule marijuana. Because the DEA believes that this
matter is of particular interest to members of the public, the agency
is publishing below the letter sent to the petitioner which denied the
petition, along with the supporting documentation that was attached to
the letter.
DATES: August 12, 2016.
FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Office of Diversion
Control, Drug Enforcement Administration; Mailing Address: 8701
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812
SUPPLEMENTARY INFORMATION:
July 19, 2016
Dear Mr. Krumm:
On December 17, 2009, you petitioned the Drug Enforcement
Administration (DEA) to initiate rulemaking proceedings under the
rescheduling provisions of the Controlled Substances Act (CSA).
Specifically, you petitioned DEA to have marijuana removed from
schedule I of the CSA and rescheduled in any schedule other than
schedule I of the CSA.
You requested that DEA remove marijuana from schedule I based on
your assertion that:
1. Marijuana has accepted medical use in the United States;
2. Studies have shown that smoked marijuana has proven safety
and efficacy;
3. Marijuana is safe for use under medical supervision; and
4. Marijuana does not have the abuse potential for placement in
schedule I
In accordance with the CSA scheduling provisions, after
gathering the necessary data, DEA requested a scientific and medical
evaluation and scheduling recommendation from the Department of
Health and Human Services (HHS). HHS concluded that marijuana has a
high potential for abuse, has no accepted medical use in the United
States, and lacks an acceptable level of safety for use even under
medical supervision. Therefore, HHS recommended that marijuana
remain in schedule I. The scientific and medical evaluation and
scheduling recommendation that HHS submitted to DEA is attached
hereto.
Based on the HHS evaluation and all other relevant data, DEA has
concluded that there is no substantial evidence that marijuana
should be removed from schedule I. A document prepared by DEA
addressing these materials in detail also is attached hereto. In
short, marijuana continues to meet the criteria for schedule I
control under the CSA because:
(1) Marijuana has a high potential for abuse. The HHS evaluation
and the additional data gathered by DEA show that marijuana has a
high potential for abuse.
(2) Marijuana has no currently accepted medical use in treatment
in the United States. Based on the established five-part test for
making such determination, marijuana has no ``currently accepted
medical use'' because: As detailed in the HHS evaluation, the drug's
chemistry is not known and reproducible; there are no adequate
safety studies; there are no adequate and well-controlled studies
proving efficacy; the drug is not accepted by qualified experts; and
the scientific evidence is not widely available.
(3) Marijuana lacks accepted safety for use under medical
supervision. At present, there are no U.S. Food and Drug
Administration (FDA)-approved marijuana products, nor is marijuana
under a New Drug Application (NDA) evaluation at the FDA for any
indication. The HHS evaluation states that marijuana does not have a
currently accepted medical use in treatment in the United States or
a currently accepted medical use with severe restrictions. At this
time, the known risks of marijuana use have not been shown to be
outweighed by specific benefits in well-controlled clinical trials
that scientifically evaluate safety and efficacy.
The statutory mandate of 21 U.S.C. 812(b) is dispositive.
Congress established only one schedule, schedule I, for drugs of
abuse with ``no currently accepted medical use in treatment in the
United States'' and ``lack of accepted safety for use under medical
supervision.'' 21 U.S.C. 812(b).
Although the HHS evaluation and all other relevant data lead to
the conclusion that marijuana must remain in schedule I, it should
also be noted that, in view of United States obligations under
international drug control treaties, marijuana cannot be placed in a
schedule less restrictive than schedule II. This is explained in
detail in the accompanying document titled ``Preliminary Note
Regarding Treaty Considerations.''
Accordingly, and as set forth in detail in the accompanying HHS
and DEA documents, there is no statutory basis under the CSA for DEA
to grant your petition to initiate rulemaking proceedings to
reschedule marijuana. Your petition is, therefore, hereby denied.
Sincerely,
Chuck Rosenberg,
Acting Administrator
Attachments:
Preliminary Note Regarding Treaty Considerations
Cover Letter from HHS to DEA Summarizing the Scientific and
Medical Evaluation and Scheduling Recommendation for Marijuana.
U.S. Department of Health and Human Services (HHS)--Basis for
the Recommendation for Maintaining Marijuana in Schedule I of the
Controlled Substances Act
U.S. Department of Justice--Drug Enforcement Administration
(DEA), Schedule of Controlled Substances: Maintaining Marijuana in
Schedule I of the Controlled Substances Act, Background, Data, and
Analysis: Eight Factors Determinative of Control and Findings
Pursuant to 21 U.S.C. 812(b)
Dated: July 19, 2016.
Chuck Rosenberg,
Acting Administrator.
Preliminary Note Regarding Treaty Considerations
As the Controlled Substances Act (CSA) recognizes, the United
States is a party to the Single Convention on Narcotic Drugs, 1961
(referred to here as the Single Convention or the treaty). 21 U.S.C.
801(7). Parties to the Single Convention are obligated to maintain
various control provisions related to the drugs that are covered by the
treaty. Many of the provisions of the CSA were enacted by Congress for
the specific purpose of ensuring U.S. compliance with the treaty. Among
these is a scheduling provision, 21 U.S.C. 811(d)(1). Section 811(d)(1)
provides that, where a drug is subject to control under the Single
Convention, the DEA Administrator (by delegation from the Attorney
General) must ``issue an order controlling such drug under the schedule
he deems most appropriate to carry out such [treaty] obligations,
without regard to the findings required by [21 U.S.C. 811(a) or 812(b)]
and without regard to the procedures prescribed by [21 U.S.C. 811(a)
and (b)].''
Marijuana is a drug listed in the Single Convention. The Single
Convention uses the term ``cannabis'' to refer to marijuana.\1\ Thus,
the DEA Administrator is obligated under section 811(d) to control
marijuana in the
[[Page 53768]]
schedule that he deems most appropriate to carry out the U.S.
obligations under the Single Convention. It has been established in
prior marijuana rescheduling proceedings that placement of marijuana in
either schedule I or schedule II of the CSA is ``necessary as well as
sufficient to satisfy our international obligations'' under the Single
Convention. NORML v. DEA, 559 F.2d 735, 751 (D.C. Cir. 1977). As the
United States Court of Appeals for the D.C. Circuit has stated,
``several requirements imposed by the Single Convention would not be
met if cannabis and cannabis resin were placed in CSA schedule III, IV,
or V.'' \2\ Id. Therefore, in accordance with section 811(d)(1), DEA
must place marijuana in either schedule I or schedule II.
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\1\ Under the Single Convention, ``'cannabis plant' means any
plant of the genus Cannabis.'' Article 1(c). The Single Convention
defines ``cannabis'' to include ``the flowering or fruiting tops of
the cannabis plant (excluding the seeds and leaves when not
accompanied by the tops) from which the resin has not been
extracted, by whatever name they may be designated.'' Article 1(b).
This definition of ``cannabis'' under the Single Convention is
slightly less inclusive than the CSA definition of ``marihuana,''
which includes all parts of the cannabis plant except for the mature
stalks, sterilized seeds, oil from the seeds, and certain
derivatives thereof. See 21 U.S.C. 802(16). Cannabis and cannabis
resin are included in the list of drugs in Schedule I and Schedule
IV of the Single Convention. In contrast to the CSA, the drugs
listed in Schedule IV of the Single Convention are also listed in
Schedule I of the Single Convention and are subject to the same
controls as Schedule I drugs as well as additional controls. Article
2, par. 5
\2\ The Court further stated: ``For example, [article 31
paragraph 4 of the Single Convention] requires import and export
permits that would not be obtained if the substances were placed in
CSA schedules III through V. In addition, the quota and
[recordkeeping] requirements of Articles 19 through 21 of the Single
Convention would be satisfied only by placing the substances in CSA
schedule I or II.'' Id. n. 71 (internal citations omitted).
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Because schedules I and II are the only possible schedules in which
marijuana may be placed, for purposes of evaluating this scheduling
petition, it is essential to understand the differences between the
criteria for placement of a substance in schedule I and those for
placement in schedule II. These criteria are set forth in 21 U.S.C.
812(b)(1) and (b)(2), respectively. As indicated therein, substances in
both schedule I and schedule II share the characteristic of ``a high
potential for abuse.'' Where the distinction lies is that schedule I
drugs have ``no currently accepted medical use in treatment in the
United States'' and ``a lack of accepted safety for use of the drug . .
. under medical supervision,'' while schedule II drugs do have ``a
currently accepted medical use in treatment in the United States.'' \3\
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\3\ As DEA has stated in evaluating prior marijuana rescheduling
petitions, ``Congress established only one schedule, schedule I, for
drugs of abuse with `no currently accepted medical use in treatment
in the United States' and `lack of accepted safety for use . . .
under medical supervision.' 21 U.S.C. 812(b).'' 76 FR 40552 (2011);
66 FR 20038 (2001).
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Accordingly, in view of section 811(d)(1), this scheduling petition
turns on whether marijuana has a currently accepted medical use in
treatment in the United States. If it does not, DEA must, pursuant to
section 811(d), deny the petition and keep marijuana in schedule I.
As indicated, where section 811(d)(1) applies to a drug that is the
subject of a rescheduling petition, the DEA Administrator must issue an
order controlling the drug under the schedule he deems most appropriate
to carry out United States obligations under the Single Convention,
without regard to the findings required by sections 811(a) or 812(b)
and without regard to the procedures prescribed by sections 811(a) and
(b). Thus, since the only determinative issue in evaluating the present
scheduling petition is whether marijuana has a currently accepted
medical use in treatment in the United States, DEA need not consider
the findings of sections 811(a) or 812(b) that have no bearing on that
determination, and DEA likewise need not follow the procedures
prescribed by sections 811(a) and (b) with respect to such irrelevant
findings. Specifically, DEA need not evaluate the relative abuse
potential of marijuana or the relative extent to which abuse of
marijuana may lead to physical or psychological dependence.
As explained below, the medical and scientific evaluation and
scheduling recommendation issued by the Secretary of Health and Human
Services concludes that marijuana has no currently accepted medical use
in treatment in the United States, and the DEA Administrator likewise
so concludes. For the reasons just indicated, no further analysis
beyond this consideration is required. Nonetheless, because of the
widespread public interest in understanding all the facts relating to
the harms associated with marijuana, DEA is publishing here the entire
medical and scientific analysis and scheduling evaluation issued by the
Secretary, as well as DEA's additional analysis.
Department of Health and Human Services,
Office of the Secretary Assistant Secretary for Health, Office of
Public Health and Science
Washington DC 20201.
June 25, 2015.
The Honorable Chuck Rosenberg
Acting Administrator, Drug Enforcement Administration, U.S.
Department of Justice, 8701 Morrissette Drive, Springfield, VA 22152
Dear Mr. Rosenberg:
Pursuant to the Controlled Substances Act (CSA, 21 U.S.C.
811(b), (c), and (f)), the Department of Health and Human Services
(HHS) is recommending that marijuana continue to be maintained in
Schedule I of the CSA.
The Food and Drug Administration (FDA) has considered the abuse
potential and dependence-producing characteristics of marijuana.
Marijuana meets the three criteria for placing a substance in
Schedule I of the CSA under 21 U.S.C. 812(b)(1). As discussed in the
enclosed analyses, marijuana has a high potential for abuse, no
currently accepted medical use in treatment in the United States,
and a lack of accepted safety for use under medical supervision.
Accordingly, HHS recommends that marijuana be maintained in Schedule
I of the CSA. Enclosed are two documents prepared by FDA's
Controlled Substance Staff (in response to petitions filed in 2009
by Mr. Bryan Krumm and in 2011 by Governors Lincoln D. Chafee and
Christine O. Gregoire) that form the basis for the recommendation.
Pursuant to the requests in the petitions, FDA broadly evaluated
marijuana, and did not focus its evaluation on particular strains of
marijuana or components or derivatives of marijuana.
FDA's Center for Drug Evaluation and Research's current review
of the available evidence and the published clinical studies on
marijuana demonstrated that since our 2006 scientific and medical
evaluation and scheduling recommendation responding to a previous
DEA petition, research with marijuana has progressed. However, the
available evidence is not sufficient to determine that marijuana has
an accepted medical use. Therefore, more research is needed into
marijuana's effects, including potential medical uses for marijuana
and its derivatives. Based on the current review, we identified
several methodological challenges in the marijuana studies published
in the literature. We recommend they be addressed in future clinical
studies with marijuana to ensure that valid scientific data are
generated in studies evaluating marijuana's safety and efficacy for
therapeutic use. For example, we recommend that studies need to
focus on consistent administration and reproducible dosing of
marijuana, potentially through the use of administration methods
other than smoking. A summary of our review of the published
literature on the clinical uses of marijuana, including
recommendations for future studies, is attached to this document.
FDA and the National Institutes of Health's National Institute
on Drug Abuse (NIDA) also believe that work continues to be needed
to ensure support by the federal government for the efficient
conduct of clinical research using marijuana. Concerns have been
raised about whether the existing federal regulatory system is
flexible enough to respond to increased interest in research into
the potential therapeutic uses of marijuana and marijuana-derived
drugs. HHS welcomes an opportunity to continue to explore these
concerns with DEA.
Should you have any questions regarding theses recommendations,
please contact Corinne P. Moody, Science Policy Analyst, Controlled
Substances Staff, Center for Drug Evaluation and Research, FDA, at
(301) 796-3152.
Sincerely yours,
Karen B. DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health
Enclosure:
Basis for the Recommendation for Maintaining Marijuana in Schedule I
of the Controlled Substances Act
[[Page 53769]]
Basis for the Recommendation for Maintaining Marijuana in Schedule I of
the Controlled Substances Act
On December 17, 2009, Mr. Bryan Krumm submitted a petition to the
Drug Enforcement Administration (DEA) requesting that proceedings be
initiated to repeal the rules and regulations that place marijuana \4\
in Schedule I of the Controlled Substances Act (CSA). The petitioner
contends that marijuana has an accepted medical use in the United
States, has proven safety and efficacy, is safe for use under medical
supervision, and does not have the abuse potential for placement in
Schedule I. The petitioner requests that marijuana be rescheduled to
any schedule other than Schedule I of the CSA. In May 2011, the DEA
Administrator requested that the U.S. Department of Health and Human
Services (HHS) provide a sdentific and medical evaluation of the
available information and a scheduling recommendation for marijuana, in
accordance with the provisions of 21 U.S.C. 811(b).
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\4\ Note that ``marihuana'' is the spelling originally used in
the Controlled Substances Act (CSA). This document uses the spelling
that is more common in current usage, ``marijuana.''
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In accordance with 21 U.S.C. 811(b), the DEA has gathered
information related to the control of marijuana (Cannabis sativa) \5\
under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary of HHS is
required to consider in a scientific and medical evaluation eight
factors determinative of control under the CSA. Following consideration
of the eight factors, if it is appropriate, the Secretary must make
three findings to recommend scheduling a substance in the CSA or
transferring a substance from one schedule to another. The findings
relate to a substance's abuse potential, legitimate medical use, and
safety or dependence liability. Administrative responsibilities for
evaluating a substance for control under the CSA are performed by the
Food and Drug Administration (FDA), with the concurrence of the
National Institute on Drug Abuse (NIDA), as described in the Memorandum
of Understanding (MOU) of March 8, 1985 (50 FR 9518-20).
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\5\ The CSA defines marihuana (marijuana) as the following:
All parts of the plant Cannabis sativa L., whether growing or
not; the seeds thereof; the resin extracted from any part of such
plant; and every compound, manufacture, salt, derivative, mixture,
or preparation of such plant, its seeds or resin. Such term does not
include the mature stalks of such plant, fiber produced from such
stalks, oil or cake made from the seeds of such plant, any other
compound, manufacture, salt, derivative, mixture, or preparation of
such mature stalks (except the resin extracted therefrom), fiber,
oil, or cake, or the sterilized seed of such plant which is
incapable of germination (21 U.S.C. 802(16)).
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In this document, FDA recommends continued control of marijuana in
Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c), the eight factors
pertaining to the scheduling of marijuana are considered below.
1. Its Actual or Relative Potential for Abuse
Under the first factor the Secretary must consider marijuana's
actual or relative potential for abuse. The CSA does not define the
term ``abuse.'' However, the CSA's legislative history suggests the
following in determining whether a particular drug or substance has a
potential for abuse: \6\
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\6\ Comprehensive Drug Abuse Prevention and Control Act of 1970,
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in
U.S.C.C.A.N. 4566, 4603.
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a. There is evidence that individuals are taking the drug or drugs
containing such a substance in amounts sufficient to create a hazard to
their health or to the safety of other individuals or to the community.
b. There is a significant diversion of the drug or drugs containing
such a substance from legitimate drug channels.
c. Individuals are taking the drug or drugs containing such a
substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice.
d. The drug or drugs containing such a substance are new drugs so
related in their action to a drug or drugs already listed as having a
potential for abuse to make it likely that the drug will have the same
potentiality for abuse as such drugs, thus making it reasonable to
assume that there may be significant diversions from legitimate
channels, significant use contrary to or without medical advice, or
that it has a substantial capability of creating hazards to the health
of the user or to the safety of the community.
In the development of this scientific and medical evaluation for
the purpose of scheduling, the Secretary analyzed considerable data
related to the substance's abuse potential. The data include a
discussion of the prevalence and frequency of use, the amount of the
substance available for illicit use, the ease of obtaining or
manufacturing the substance, the reputation or status of the substance
``on the street,'' and evidence relevant to at-risk populations.
Importantly, the petitioners define marijuana as including all Cannabis
cultivated strains. Different marijuana samples derived from various
cultivated strains may have very differernt chemical consituents, thus
the analysis is based on what is known about the range of these
constituents across all cultivated strains.
Determining the abuse potential of a substance is complex with many
dimensions, and no single test or assessment provides a complete
characterization. Thus, no single measure of abuse potential is ideal.
Scientifically, a comprehensive evaluation of the relative abuse
potential of a substance can include consideration of the following
elements: Receptor binding affinity, preclinical pharmacology,
reinforcing effects, discriminative stimulus effects, dependence
producing potential, pharmacokinetics, route of administration,
toxicity, data on actual abuse, clinical abuse potential studies, and
public health risks. Importantly, abuse can exist independently from
tolerance or physical dependence because individuals may abuse drugs in
doses or patterns that don not induce these phenomena. Additionally
evidence of clandestine population and illicit trafficking of a
substance can shed light on both the demand for a substance as well as
the ease of obtaining a substance. Animal and human laboratory data and
epidemiological data are all used in determining a substance's abuse
potential. Moreover, epidemiological data can indicate actual abuse.
The petitioner compares the effects of marijuana to currently
controlled Schedule II substances and make repeated claims about their
comparative effects. Comparisons between marijuana and the diverse
array of Schedule II substances is difficult, because of the
pharmacologically dissimilar actions of substances of Schedule II of
the CSA. For example, Schedule II substances include stimulant-like
drugs (e.g., cocaine, methylphenidate, and amphetamine), opioids (e.g.,
oxycodone, fentanyl), sedatives (e.g., pentobarbital, amobarbital),
dissociative anesthetics (e.g., PCP), and naturally occurring plant
components (e.g., coca leaves and poppy straw). The mechanism(s) of
action of the above Schedule II substances are wholly different from on
another, and they are different from tetrahydrocannabinol (THC) and
marijuana as well. For example, Schedule II stimulants typically
function by increasing monoaminergic tone via an increase in dopamine
and norepinephrine (Schmitt et al., 2013). In contrast, opioid
analgesics function via mu-opioid receptor agonist effects.
[[Page 53770]]
These differing mechanism(s) of action result in vastly different
behavioral and adverse effect profiles, making comparisons across the
range of pharmacologically diverse C-II substances inappropriate.
In addition, many substances scheduled under the CSA are reviewed
and evaluated within the context of commercial drug development, using
data submitted in the form of a new drug application (NDA). A new
analgesic drug might be compared to a currently scheduled analgesic
drug as part of the assessment of its relative abuse potential.
However, because the petitioners have not identified a specific
indication for the use of marijuana, identifying an appropriate
comparator based on indication cannot be done.
a. There is evidence that individuals are taking the substance in
amounts sufficient to create a hazard to their health or to the safety
of other individuals or to the community.
Evidence shows that some individuals are taking marijuana in
amounts sufficient to create a hazard to their health and to the safety
of other individuals and the community. A large number of individuals
use marijuana. HHS provides data on the extent of marijuana abuse
through NIDA and the Substance Abuse and Mental Health Services
Administration (SAMHSA). According to the most recent data from
SAMHSA's 2012 National Survey on Drug Use and Health (NSDUH), which
estimates the number of individuals who have use a substance within a
month prior to the study (described as ``current use''), marijuana is
the most commonly used illicit drug among American aged 12 years and
older, with an estimated 18.9 million Americans having used marijuana
within the month prior to the 2012 NSDUH. Compared to 2004, when an
estimated 14.6 million individuals reported using marijuana within the
month prior to the study, the estimated rates in 2012 show an increase
of approximately 4.3 million individuals. The 2013 Monitoring the
Future (MTF) survey of 8th, 10th, and 12th grade students also
indicates that marijuana is the most widely used illicit substance in
this age group. Specifically, current month use was at 7.0 percent of
8th graders, 18.0 percent of 10th, graders and 22.7 percent of 12th
graders. Additionally, the 2011 Treatment Episode Data Set (TEDS)
reported that primary marijuana abuse accounted for 18.1 percent of
non-private substance-abuse treatment facility admissions, with 24.3
percent of those admitted reporting daily use. However, of these
admissions for primary marijuana abuse, the criminal justice system
referred 51.6 percent to treatment. SAMHSA's Drug Abuse Warning Network
(DAWN) was a national probability survey of U.S. hospitals with
emergency departments (EDs) and was designed to obtain information on
ED visits in which marijuana was mentioned, accounting for 36.4 percent
of illicit drug related ED visits. There are some limitations related
to DAWN data on ED visits, which are discussed in detail in Factor 4,
``Its History and Current Pattern of Abuse;'' Factor 5, ``The Scope,
Duration, and Significance of Abuse;'' and Factor 6, ``What, if an,
Risk There is to the Public Health.'' These factors contain detailed
discussions of these data.
A number of risks can occur with both acute and chronic use of
marijuana. Detailed discussions of the risks are addressed in Factor 2,
``Scientific Evidence of its Pharmacological Effect, if Known,'' and
Factor 6, ``What, if any, Risk There is to the Public Health.''
b. There is significant diversion of the substance from legitimate
drug channels.
There is a lack of evidence of significant diversion of marijuana
from legitimate drug channels, but this is likely due to the fact that
marijuana is more widely available from illicit sources rather than
through legitimate channels. Marijuana is not an FDA-approved drug
product, as an NDA or biologics license application (BLA) has not been
approved for marketing in the United States. Numerous states and the
District of Columbia have state-level medical marijuana laws that allow
for marijuana use within that state. These state-level drug channels do
not have sufficient collection of data related to medical treatment,
including efficacy and safety.
Marijuana is used by researchers for nonclinical research as well
as clinical research under investigational new drug (IND) applications;
this represents the only legitimate drug channel in the United States.
However, marijuana used for research reporesents a very small
contribution of the total amount of marijuana available in the United
States, and thus provides limited information about diversion. In
addition, the lack of significant diversion of investigation supplies
is likely because of the widespread availability of illicit marijuana
of equal or greater amounts of delta\9\-THC. The data originating from
the DEA on seizure statistics demonstrate the magnitude of the
availability for illicit marijuana. DEA's System to Retrieve
Information from Drug Evidence (STRIDE) provides information on total
domestic drug seizures, STRIDE reports a total domestic seizure of
573,195 kg of marijuana in 2011, the most recent year with complete
data that is currently publically available (DEA Domestic Drug
Seizures, n.d.).
c. Individuals are taking the substance on their own initiative
rather than on the basis of medical advice from a practitioner licensed
by law to administer such substances.
Because the FDA has not approved an NDA or BLA for a marijuana drug
product for any therapeutic indication, the only way an individual can
take marijuana on the basis of medical advice through legitimate
channels at the federal level is by participating in research under an
IND application. That said, numerous states and the District of
Columbia have passed state-level medical marijuana laws allowing for
individuals to use marijuana under certain cicrumstances. However, data
are not yet available to determine the number of individuals using
marijuana under these state-level medical marijuana laws. Regardless,
according to the 2012 NSDUH data, 18.9 million American adults
currently use marijuana (SAMHSA, 2013). Based on the large number of
individuals reporting current use of marijuana and the lack of an FDA-
approved drug product in the United States, one can assume that it is
likely that the majority of individuals using marijuana do so on their
own initiative rather than on the basis of medical advice from a
licensed practitioner.
d. The substance is so related in its action to a substance already
listed as having a potential for abuse to make it likely that it will
have the same potential for abuse as such substance, thus making it
reasonable to assume that there may be significant diversions from
legitimate channels, significant use contrary to or without medical
advice, or that it has a substantial capability of creating hazards to
the health of the user or to the safety of the community.
FDA has approved two drug products containing cannabinoid compounds
that are structurally related to the active components in marijuana.
These two marketed products are controlled under the CSA. Once a
specific drug product containing cannabinoids becomes approved, that
specific drug product may be moved from Schedule I to a different
Schedule (II-V) under the CSA. Firstly, Marinol--generically known as
dronabinol--is a Schedule III drug product containing synthetic
delta\9\-THC. Marinol, which is formulated in sesame oil in soft
gelatin capsules, was first placed in Schedule II under the CSA
following its approval by the FDA. Marinol was later rescheduled
[[Page 53771]]
to Schedule III under the CSA because of low numbers of reports of
abuse relative to marijuana. Dronabinol is listed in Schedule I under
the CSA. FDA approved Marinol in 1985 for the treatment of nausea and
vomiting associated with cancer chemotherapy in patients who failed to
respond adequately to conventional anti-emetic treatments. In 1992, FDA
approved Marional for anorexia associated with weight loss in patients
with acquired immunodeficiency syndrome (AIDS). Secondly, in 1985, FDA
approved Cesamet, a drug product containing the Schedule II substance
nabilone, for the treatment of nausea and vomiting associated with
cancer chemotherapy. Besides the two cannabinoid-containing drug
products FDA approved for marketing, other naturally occurring
cannabinoids and their derivatives (from Cannabis) and their synthetic
equivalents with similar chemical structure and pharmacological
activity are included in the CSA as Schedule I substances.
2. Scientific Evidence of Its Pharmacological Effects, if Known
Under the second factor, the Secretary must consider the scientific
evidence of marijuana's pharmacological effects. Abundant scientific
data are available on the neurochemistry, toxicology, and pharmacology
of marijuana. This section includes a scientific evaluation of
marijuana's neurochemistry; pharmacology; and human and animal
behavioral, central nervous system, cognitive, cardiovascular,
autonomic, endocrinological, and immunological system effects. The
overview presented below relies upon the most current research
literature on cannabinoids.
Neurochemistry and Pharmacology of Marijuana
Marijuana is a plant that contains numerous natural constituents,
such as cannabinoids, that have a variety of pharmacological actions.
The petition defines marijuana as including all Cannabis cultivated
strains. Different marijuana samples derived from various cultivated
strains may have very different chemical constituents including
delta\9\-THC and other cannabinoids (Appendino et al., 2011). As a
consequence, marijuana products from different strains will have
different biological and pharmacological profiles.
According to ElSohly and Slade (2005) and Appendino et al. (2011),
marijuana contains approximately 525 identified natural constituents,
including approximately 100 compounds classified as cannabinoids.
Cannabinoids primarily exist in Cannabis, and published data suggests
that most major cannabinoid compounds occurring naturally have been
identified chemically. New and minor cannabinoids and other new
compounds are continuously being characterized (Pollastro et al.,
2011). So far, only two cannabinoids (cannabigerol and its
corresponding acid) have been obtained from a non-Cannabis source. A
South African Helichrysum (H. umbraculigerum) accumulates these
compounds (Appendino et al., 2011). The chemistry of marijuana is
described in more detail in Factor 3, ``The State of Current Scientific
Knowledge Regarding the Drug or Other Substance.''
The site of cannabinoid action is at the cannabinoid receptors.
Cloning of cannabinoid receptors, first from rat brain tissue (Matsuda
et al., 1990) and then from human brain tissue (Gerard et al., 1991),
has verified the site of action. Two cannabinoid receptors,
CB1 and CB2, were characterized (Battista et al.,
2012; Piomelli, 2005). Evidence of a third cannabinoid receptor exists,
but it has not been identified (Battista et al., 2012).
The cannabinoid receptors, CB1 and CB2,
belong to the family of G-protein-coupled receptors, and present a
typical seven transmembrane-spanning domain structure. Cannabinoid
receptors link to an inhibitory G-protein (Gi), such that
adenylate cyclase activity is inhibited when a ligand binds to the
receptor. This, in tum, prevents the conversion of ATP to the second
messenger, cyclic AMP (cAMP). Examples of inhibitory coupled receptors
include opioid, muscarinic cholinergic, alpha2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).
Cannabinoid receptor activation inhibits N- and P/Q-type calcium
channels and activates inwardly rectifying potassium channels (Mackie
et al., 1995; Twitchell et al., 1997). N-type calcium channel
inhibition decreases neurotransmitter release from several tissues.
Thus, calcium channel inhibition may be the mechanism by which
cannabinoids inhibit acetylcholine, norepinephrine, and glutamate
release from specific areas of the brain. These effects may represent a
potential cellular mechanism underlying cannabinoids' antinociceptive
and psychoactive effects (Ameri, 1999).
CB1 receptors are found primarily in the central nervous
system, but are also present in peripheral tissues. CB1
receptors are located mainly in the basal ganglia, hippocarnpus, and
cerebellum of the brain (Howlett et al., 2004). The localization of
these receptors may explain cannabinoid interference with movement
coordination and effects on memory and cognition. Additionally,
CB1 receptors are found in the immune system and numerous
other peripheral tissues (Petrocellis and Di Marzo, 2009). However, the
concentration of CB1 receptors is considerably lower in
peripheral tissues than in the central nervous system (Herkenharn et
al., 1990 and 1992).
CB2 receptors are found primarily in the immune system,
but are also present in the central nervous system and other peripheral
tissues. In the immune system, CB2 receptors are found
predominantly in B lymphocytes and natural killer cells (Bouaboula et
al., 1993). CB2 receptors may mediate cannabinoids'
immunological effects (Galiegue et al., 1995). Additionally,
CB2 receptors have been localized in the brain, primarily in
the cerebellum and hippocampus (Gong et al., 2006). The distribution of
CB2 receptors throughout the body is less extensive than the
distribution of CB1 receptors (Petrocellis and Di Marzo,
2009). However, both CB1 and CB2 receptors are
present in numerous tissues of the body.
Cannabinoid receptors have endogenous ligands. In 1992 and 1995,
two endogenous cannabinoid receptor agonists, anandamide and
arachidonyl glycerol (2-AG), respectively, were identified (Di Marzo,
2006). Anandamide is a low efficacy agonist (Breivogel and Childers,
2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000).
Cannabinoid endogenous ligands are present in central as well as
peripheral tissues. A combination of uptake and hydrolysis terminate
the action of the endogenous ligands. The endogenous cannabinoid system
is a locally active signaling system that, to help restore homeostasis,
is activated ``on demand'' in response to changes to the local
homeostasis (Petrocellis and Di Marzo, 2009). The endogenous
cannabinoid system, including the endogenous cannabinoids and the
cannabinoid receptors, demonstrate substantial plasticity in response
to several physiological and pathological stimuli (Petrocellis and Di
Marzo, 2009). This plasticity is particularly evident in the central
nervous system.
Delta\9\-THC and cannabidiol (CBD) are two abundant cannabinoids
present in marijuana. Marijuana's major psychoactive cannabinoid is
delta\9\-THC (Wachtel et al., 2002). In 1964, Gaoni and Mechoularn
first described delta\9\-THC's structure and function. In 1963,
Mechoularn and Shvo first described CBD's structure. The
pharmacological actions of CBD have not been fully studied in humans.
[[Page 53772]]
Delta\9\-THC and CBD have varying affinity and effects at the
cannabinoid receptors. Delta\9\-THC displays similar affinity for
CB1 and CB2 receptors, but behaves as a weak
agonist for CB2 receptors. The identification of synthetic
cannabinoid ligands that selectively bind to CB2 receptors
but do not have the typical delta\9\-THC-like psychoactive properties
suggests that the activation of CB1-receptors mediates
cannabinoids' psychotropic effects (Hanus et al., 1999). CBD has low
affinity for both CB1 and CB2 receptors
(Mechoulam et al., 2007). According to Mechoulam et al. (2007), CBD has
antagonistic effects at CB1 receptors and some inverse
agonistic properties at CB2 receptors. When cannabinoids are
given subacutely to rats, CB1 receptors down-regulate and
the binding of the second messenger system coupled to CB1
receptors, GTPgarnmaS, decreases (Breivogel et al., 2001).
Animal Behavioral Effects
Self-Administration
Self-administration is a method that assesses the ability of a drug
to produce rewarding effects. The presence of rewarding effects
increases the likelihood of behavioral responses to obtain additional
drug. Animal self-administration of a drug is often useful in
predicting rewarding effects in humans, and is indicative of abuse
liability. A good correlation is often observed between those drugs
that rhesus monkeys self-administer and those drugs that humans abuse
(Balster and Bigelow, 2003). Initially, researchers could not establish
self-administration of cannabinoids, including delta\9\-THC, in animal
models. However, self-administration of delta\9\-THC can now be
established in a variety of animal models under specific training
paradigms (Justinova et al., 2003, 2004, 2005).
Squirrel monkeys, with and without prior exposure to other drugs of
abuse, self-administer delta\9\-THC under specific conditions. For
instance, Tanda et al. (2000) observed that when squirrel monkeys are
initially trained to self-administer intravenous cocaine, they will
continue to bar-press delta\9\-THC at the same rate as they would with
cocaine. The doses were notably comparable to those doses used by
humans who smoke marijuana. SR141716, a CB1 cannabinoid
receptor agonist-antagonist, can block this rewarding effect. Other
studies show that na[iuml]ve squirrel monkeys can be successfully
trained to self-administer delta\9\-THC intravenously (Justinova et
al., 2003). The maximal responding rate is 4 [mu]g/kg per injection,
which is 2-3 times greater than observed in previous studies using
cocaine-experienced monkeys. Naltrexone, a mu-opioid antagonist,
partially antagonizes these rewarding effects of delta\9\-THC
(Justinova et al., 2004).
Additionally, data demonstrate that under specific conditions,
rodents self-administer cannabinoids. Rats will self-administer
delta\9\-THC when applied intracerebroventricularly (i.c.v.), but only
at the lowest doses tested (0.01-0.02 [mu]g/infusion) (Braida et al.,
2004). SR141716 and the opioid antagonist naloxone can antagonize this
effect. However, most studies involve rodents self-administrating the
synthetic cannabinoid WIN 55212, a CB1 receptor agonist with
a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007;
Martellotta et al., 1998; Mendizabal et al., 2006).
Aversive effects, rather than reinforcing effects, occur in rats
that received high doses of WIN 55212 (Chaperon et al., 1998) or
delta\9\-THC (Sanudo-Pena et al., 1997), indicating a possible critical
dose-dependent effect. In both studies, SR141716 reversed these
aversive effects.
Conditioned Place Preference
Conditioned place preference (CPP) is a less rigorous method than
self-administration for determining whether or not a drug has rewarding
properties. In this behavioral test, animals spend time in two distinct
environments: One where they previously received a drug and one where
they received a placebo. If the drug is reinforcing, animals will
choose to spend more time in the environment paired with the drug,
rather than with the placebo, when presented with both options
s.imultaneously.
Animals show CPP to delta\9\-THC, but only at the lowest doses
tested (0.075-1.0 mg/kg, intraperitoneal (i.p.)) (Braida et al., 2004).
SR141716 and naloxone antagonize this effect (Braida et al., 2004). As
a partial agonist, SR141716 can induce CPP at doses of 0.25, 0.5, 2 and
3 mg/kg (Cheer et al., 2000). In knockout mice, those without [mu]-
opioid receptors do not develop CPP to delta\9\-THC (Ghozland et al.,
2002).
Drug Discrimination Studies
Drug discrimination is a method where animals indicate whether a
test drug produces physical or psychic perceptions similar to those
produced by a known drug of abuse. In this test, an animal learns to
press one bar when it receives the known drug of abuse and another bar
when it receives placebo. To determine whether the test drug is like
the known drug of abuse, a challenge session with the test drug
demonstrates which of the two bars the animal presses more often.
In addition to humans (Lile et al., 2009; Lile et al., 2011), it
has been noted that animals, including monkeys (McMahon, 2009), mice
(McMahon et al., 2008), and rats (Gold et al., 1992), are able to
discriminate cannabinoids from other drugs or placebo. Moreover, the
major active metabolite of delta\9\-THC, 11-hydroxy-delta\9\-THC, also
generalizes (following oral administration) to the stimulus cues
elicited by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other
cannabinoids found in marijuana also fully substitute for delta\9\-THC.
However, CBD does not substitute for delta\9\-THC in rats (Vann et al.,
2008).
Discriminative stimulus effects of delta\9\-THC are
pharmacologically specific for marijuana containing cannabinoids
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al.,
1993, 1995). The discriminative stimulus effects of the cannabinoid
group appear to provide unique effects because stimulants,
hallucinogens, opioids, benzodiazepines, barbiturates, NMDA
antagonists, and antipsychotics do not fully substitute for delta\9\-
THC.
Central Nervous System Effects
Human Physiological and Psychological Effects
Psychoactive Effects
Below is a list of the common subjective responses to cannabinoids
(Adams and Martin, 1996; Gonzalez, 2007; Hollister 1986, 1988;
Institute of Medicine, 1982). According to Maldonado (2002), these
responses to marijuana are pleasurable to many humans and are often
associated with drug-seeking and drug-taking. High levels of positive
psychoactive effects are associated with increased marijuana use,
abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010).
(1) Disinhibition, relaxation, increased sociability, and
talkativeness.
(2) Increased merriment and appetite, and even exhilaration at high
doses.
(3) Enhanced sensory perception, which can generate an increased
appreciation of music, art, and touch.
(4) Heightened imagination, which can lead to a subjective sense of
increased creativity.
(5) Initial dizziness, nausea, tachycardia, facial flushing, dry
mouth, and tremor.
(6) Disorganized thinking, inability to converse logically, time
distortions, and short-term memory impairment.
[[Page 53773]]
(7) Ataxia and impaired judgment, which can impede driving ability
or lead to an increase in risk-tasking behavior.
(8) Illusions, delusions, and hallucinations that intensify with
higher doses.
(9) Emotional lability, incongruity of affect, dysphoria,
agitation, paranoia, confusion, drowsiness, and panic attacks, which
are more common in inexperienced or high-dosed users.
As with many psychoactive drugs, a person's medical, psychiatric,
and drug-taking history can influence the individual's response to
marijuana. Dose preferences to marijuana occur in that marijuana users
prefer higher concentrations of the principal psychoactive substance
(1.95 percent delta\9\-THC) over lower concentrations (0.63 percent
delta\9\-THC) (Chait and Burke, 1994). Nonetheless, frequent marijuana
users (>100 times of use) were able to identify a drug effect from low-
dose delta\9\-THC better than occasional users (<10 times of use) while
also experiencing fewer sedative effects from marijuana (Kirk and de
Wit, 1999).
The petitioners contend that many of marijuana's naturally
occurring cannabinoids mitigate the psychoactive effects of delta\9\-
THC, and therefore that marijuana lacks sufficient abuse potential to
warrant Schedule I placement, because Marinol, which is in Schedule
III, contains only delta\9\-THC. This theory has not been demonstrated
in controlled studies. Moreover, the concept of abuse potential
encompasses all properties of a substance, including its chemistry,
pharmacology, and pharmacokinetics, as well as usage patterns and
diversion history. The abuse potential of a substance is associated
with the repeated or sporadic use of a substance in nonmedical
situations for the psychoactive effects the substance produces. These
psychoactive effects include euphoria, perceptual and other cognitive
distortions, hallucinations, and mood changes. However, as stated
above, the abuse potential not only includes the psychoactive effects,
but also includes other aspects related to a substance.
DEA's final published rule entitled ``Rescheduling of the Food and
Drug Administration Approved Product Containing Synthetic Dronabinol
[(-)-delta\9\-(trans)-Tetrahydrocannabinol] in Sesame Oil and
Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule
III'' (64 FR 35928, July 2, 1999) rescheduled Marinol from Schedule II
to Schedule III. The HHS assessment of the abuse potential and
subsequent scheduling recommendation compared Marinol to marijuana on
different aspects related to abuse potential. Major differences in
formulation, availability, and usage between marijuana and the drug
product, Marinol, contribute to their differing abuse potentials.
Hollister and Gillespie (1973) estimated that delta\9\-THC by
smoking is 2.6 to 3 times more potent than delta\9\-THC ingested
orally. The intense psychoactive drug effect achieved, rapidly by
smoking is generally considered to produce the effect desired by the
abuser. This effect explains why abusers often prefer to administer
certain drugs by inhalation, intravenously, or intranasally rather than
orally. Such is the case with cocaine, opium, heroin, phencyclidine,
methamphetamine, and delta\9\-THC from marijuana (0.1-9.5 percent
delta\9\-THC range) or hashish (10-30 percent delta\9\-THC range)
(Wesson and Washburn, 1990). Thus, the delayed onset and longer
duration of action for Marinol may be contributing factors limiting the
abuse or appeal of Marinol as a drug of abuse relative to marijuana.
The formulation of Marinol is a factor that contributes to
differential scheduling of Marinol and marijuana. For example,
extraction and purification of dronabinol from the encapsulated sesame
oil mixture of Marinol is highly complex and difficult. Additionally,
the presence of sesame oil mixture in the formulation may preclude the
smoking of Marinol-laced cigarettes.
Additionally, there is a dramatic difference between actual abuse
and illicit trafficking of Marinol and marijuana. Despite Marinol's
availability in the United States, there have been no significant
reports of abuse, diversion, or public health problems due to Marinol.
By comparison, 18.9 million American adults report currently using
marijuana (SAMHSA, 2013).
In addition, FDA's approval of an NDA for Marinol allowed for
Marinol to be rescheduled to Schedule II, and subsequently to Schedule
III of the CSA. In conclusion, marijuana and Marinol differ on a wide
variety of factors that contribute to each substance's abuse potential.
These differences are major reasons distinguishing the higher abuse
potential for marijuana and the different scheduling determinations of
marijuana and Marinol.
In terms of the petitioners' claim that different cannabinoids
present in marijuana mitigate the psychoactive effects of delta\9\-THC,
only three of the cannabinoids present in marijuana were simultaneously
administered with delta\9\-THC to examine how the combinations of these
cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN)
influence delta\9\-THC's psychoactive effects. Dalton et al. (1976)
observed that smoked administration of placebo marijuana cigarettes
containing injections of 0.15 mg/kg CBD combined with 0.025mg/kg of
delta\9\-THC, in a 7:1 ratio of CBD to delta\9\-THC, significantly
decreased ratings of acute subjective effects and ``high'' when
compared to smoking delta\9\-THC alone. In contrast, Ilan et al. (2005)
calculated the naturally occurring concentrations of CBC and CBD in a
batch of marijuana cigarettes with either 1.8 percent or 3.6 percent
delta\9\-THC concentration by weight. For each strength of delta\9\-THC
in marijuana cigarettes, the concentrations of CBC and CBD were
classified in groups of either low or high. The study varied the amount
of CBC and CBD within each strength of delta\9\-THC marijuana
cigarettes, with administrations consisting of either low CBC (between
0.1-0.2 percent CBC concentration by weight) and low CBD (between 0.1-
0.4 percent CBD concentration by weight), high CBC (>0.5 percent CBC
concentration by weight) and low CBD, or low CBC and high CBD (>1.0
percent CBD concentration by weight). Overall, all combinations scored
significantly greater than placebo on ratings of subjective effects,
and there was no significant difference between any combinations.
The oral administration of a combination of either 15, 30, or 60 mg
CBD with 30 mg delta\9\-THC dissolved in liquid (in a ratio of at least
1:2 CBD to delta\9\-THC) reduced the subjective effects produced by
delta\9\-THC alone (Karniol et al., 1974). Additionally, orally
administering a liquid mixture combining 1 mg/kg CBD with 0.5 mg/kg of
delta\9\-THC (ratio of 2:1 CBD to delta\9\-THC) decreased scores of
anxiety and marijuana drug effect on the Addiction Research Center
Inventory (ARCI) compared to delta\9\-THC alone (Zuardi et al., 1982).
Lastly, oral administration of either 12.5, 25, or 50 mg CBN combined
with 25 mg delta\9\-THC dissolved in liquid (ratio of at least 1:2 CBN
to delta\9\-THC) significantly increased subjective ratings of
``drugged,'' ``drowsy,'' ``dizzy,'' and ``drunk,'' compared to
delta\9\-THC alone (Karniol et al., 1975).
Even though some studies suggest that CBD may decrease some of
delta\9\-THC's psychoactive effects, the ratios of CBD to delta\9\-THC
administered in these studies are not present in marijuana used by most
people. For example, in one study, researchers used smoked
[[Page 53774]]
marijuana with ratios of CBD to delta\9\-THC naturally present in
marijuana plant material and they found out that varying the amount of
CBD actually had no effect on delta\9\-THC's psychoactive effects (Ilan
et al., 2005). Because most marijuana currently available on the street
has high amounts of delta\9\-THC with low amounts of CBD and other
cannabinoids, most individuals use marijuana with low levels of CBD
present (Mehmedic et al., 2010). Thus, any possible mitigation of
delta\9\-THC's psychoactive effects by CBD will not occur for most
marijuana users. In contrast, one study indicated that another
cannabinoid present in marijuana, CBN, may enhance delta\9\-THC's
psychoactive effects (Karniol et al., 1975).
Behavioral Impairment
Marijuana induces various psychoactive effects that can lead to
behavioral impairment. Marijuana's acute effects can significantly
interfere with a person's ability to learn in the classroom or to
operate motor vehicles. Acute administration of smoked marijuana
impairs performance on learning, associative processes, and psychomotor
behavioral tests (Block et al., 1992). Ramaekers et al. (2006a) showed
that acute administration of 250 [mu]g/kg and 500 [mu]g/kg of delta\9\-
THC in smoked marijuana dose-dependently impairs cognition and motor
control, including motor impulsivity and tracking impairments
(Ramaekers et al., 2006b). Similarly, administration of 290 [mu]g/kg
delta\9\-THC in a smoked marijuana cigarette resulted in impaired
perceptual motor speed and accuracy: Two skills which are critical to
driving ability (Kurzthaler et al., 1999). Lastly, administration of
3.95 percent delta\9\-THC in a smoked marijuana cigarette not only
increased disequilibrium measures, but also increased the latency in a
task of simulated vehicle braking at a rate comparable to an increase
in stopping distance of five feet at 60 mph (Liguori et al., 1998).
However, acute administration of marijuana containing 2.1 percent
delta\9\-THC does not produce ``hangover effects'' (Chait, 1990).
In addition to measuring the acute effects immediately following
marijuana administration, researchers have conducted studies to
determine how long behavioral impairments last after abstinence. Some
of marijuana's acute effects may not fully resolve until at least one
day after the acute psychoactive effects have subsided. Heishman et al.
(1990) showed that impairment on memory tasks persists for 24 hours
after smoking marijuana cigarettes containing 2.57 percent delta\9\-
THC. However, Fant et al. (1998) showed that the morning after exposure
to 1.8 percent or 3.6 percent smoked delta\9\-THC, subjects had minimal
residual alterations in subjective or performance measures.
A number of factors may influence marijuana's behavioral effects
including the duration of use (chronic or short term), frequency of use
(daily, weekly, or occasionally), and amount of use (heavy or
moderate). Researchers also have examined how long behavioral
impairments last following chronic marijuana use. These studies used
self-reported histories of past duration, frequency, and amount of past
marijuana use, and administered a variety of performance and cognitive
measures at different time points following marijuana abstinence. In
chronic marijuana users, behavioral impairments may persist for up to
28 days of abstinence. Solowij et al. (2002) demonstrated that after 17
hours of abstinence, 51 adult heavy chronic marijuana users performed
worse on memory and attention tasks than 33 non-using controls or 51
heavy, short-term users. Another study noted that heavy, frequent
marijuana users, abstinent for at least 24 hours, performed
significantly worse than the controls on verbal memory and psychomotor
speed tests (Messinis et al., 2006). Additionally, after at least 1
week of abstinence, young adult frequent marijuana users, aged 18-28,
showed deficits in psychomotor speed, sustained attention, and
cognitive inhibition (Lisdahl and Price, 2012). Adult heavy, chronic
marijuana users showed deficits on memory tests after 7 days of
supervised abstinence (Pope et al., 2002). However, when these same
individuals were again tested after 28 days of abstinence, they did not
show significant memory deficits. The authors concluded, ``cannabis-
associated cognitive deficits are reversible and related to recent
cannabis exposure, rather than irreversible and related to cumulative
lifetime use.'' \7\ However, other researchers reported
neuropsychological deficits in memory, executive functioning,
psychomotor speed and manual dexterity in heavy marijuana users
abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up
study of heavy marijuana users noted decision-making deficits after 25
days of supervised abstinence. (Bolla et al., 2005). However, moderate
marijuana users did not show decision-making deficits after 25 days of
abstinence, suggesting the amount of marijuana use may impact the
duration of residual impairment.
---------------------------------------------------------------------------
\7\ In this quotation the term Cannabis is used interchangeably
for marijuana.
---------------------------------------------------------------------------
The effects of chronic marijuana use do not seem to persist after
more than 1 to 3 months of abstinence. After 3 months of abstinence,
any deficits observed in IQ, immediate memory, delayed memory, and
information-processing speeds following heavy marijuana use compared to
pre-drug use scores were no longer apparent (Fried et al., 2005).
Marijuana did not appear to have lasting effects on performance of a
comprehensive neuropsychological battery when 54 monozygotic male twins
(one of whom used marijuana, one of whom did not) were compared 1-20
years after cessation of marijuana use (Lyons et al., 2004). Similarly,
following abstinence for a year or more, both light and heavy adult
marijuana users did not show deficits on scores of verbal memory
compared to non-using controls (Tait et al., 2011). According to a
recent meta-analysis looking at non-acute and long-lasting effects of
marijuana use on neurocognitive performance, any deficits seen within
the first month following abstinence are generally not present after
about 1 month of abstinence (Schreiner and Dunn, 2012).
Another aspect that may be a critical factor in the intensity and
persistence of impairment resulting from chronic marijuana use is the
age of first use. Individuals with a diagnosis of marijuana misuse or
dependence who were seeking treatment for substance use, who initiated
marijuana use before the age of 15 years, showed deficits in
performance on tasks assessing sustained attention, impulse control,
and general executive functioning compared to non-using controls. These
deficits were not seen in individuals who initiated marijuana use after
the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic
marijuana users who began using marijuana before the age of 16 years
had greater decrements in executive functioning tasks than heavy,
chronic marijuana users who started using after the age of 16 years and
non-using controls (Gruber et al., 2012). Additionally, in a
prospective longitudinal birth cohort study of 1,037 individuals,
marijuana dependence or chronic marijuana use was associated with a
decrease in IQ and general neuropsychological performance compared to
pre-marijuana exposure levels in adolescent onset users (Meier et al.,
2012). The decline in adolescent-onset user's IQ persisted even after
reduction or abstinence of marijuana use for at least 1 year. In
contrast, the adult-onset chronic marijuana users showed no significant
[[Page 53775]]
changes in IQ compared to pre-exposure levels whether they were current
users or abstinent for at least 1 year (Meier et al., 2012).
In addition to the age of onset of use, some evidence suggests that
the amount of marijuana used may relate to the intensity of
impairments. In the above study by Gruber et al. (2012), where early-
onset users had greater deficits than late-onset users, the early-onset
users reported using marijuana twice as often and using three times as
much marijuana per week than the late-onset users. Meier et al. (2012)
showed that the deficits in IQ seen in adolescent-onset users increased
with the amount of marijuana used. Moreover, when comparing scores for
measures of IQ, immediate memory, delayed memory, and information-
processing speeds to pre-drug-use levels, the current, heavy, chronic
marijuana users showed deficits in all three measures while current,
occasional marijuana users did not (Fried et al., 2005).
Behavioral Effects of Prenatal Exposure
Studies with children at different stages of development are used
to examine the impact of prenatal marijuana exposure on performance in
a series of cognitive tasks. However, many pregnant women who reported
marijuana use were more likely to also report use of alcohol, tobacco,
and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure
to multiple drugs, it is difficult to determine the specific impact of
prenatal marijuana exposure.
Most studies assessing the behavioral effects of prenatal marijuana
exposure included women who, in addition to using marijuana, also
reported using alcohol and tobacco. However, some evidence suggests an
association between heavy prenatal marijuana exposure and deficits in
some cognitive domains. In both 4-year-old and 6-year-old children,
heavy prenatal marijuana use is negatively associated with performance
on tasks assessing memory, verbal reasoning, and quantitative reasoning
(Fried and Watkinson, 1987; Goldschmidt et al., 2008). Additionally,
heavy prenatal marijuana use is associated with deficits in measures of
sustained attention in children at the ages of 6 years and 13-16 years
(Fried et al., 1992; Fried, 2002). In 9- to 12-year-old children,
prenatal marijuana exposure is negatively associated with executive
functioning tasks that require impulse control, visual analysis, and
hypothesis (Fried et al., 1998).
Association of Marijuana Use With Psychosis
This analysis evaluates only the evidence for a direct link between
prior marijuana use and the subsequent development of psychosis. Thus,
this discussion does not consider issues such as whether marijuana's
transient effects are similar to psychotic symptoms in healthy
individuals or exacerbate psychotic symptoms in individuals already
diagnosed with schizophrenia.
Extensive research has been conducted to investigate whether
exposure to marijuana is associated with the development of
schizophrenia or other psychoses. Although many studies are small and
inferential, other studies in the literature use hundreds to thousands
of subjects. At present, the available data do not suggest a causative
link between marijuana use and the development of psychosis (Minozzi et
al., 2010). Numerous large, longitudinal studies show that subjects who
used marijuana do not have a greater incidence of psychotic diagnoses
compared to those who do not use marijuana (Fergusson et al., 2005;
Kuepper et al., 2011; Van Os et al., 2002).
When analyzing the available evidence of the connection between
psychosis and marijuana, it is critical to determine whether the
subjects in the studies are patients who are already diagnosed with
psychosis or individuals who demonstrate a limited number of symptoms
associated with psychosis without qualifying for a diagnosis of the
disorder. For example, instead of using a diagnosis of psychosis, some
researchers relied on non-standard methods of representing symptoms of
psychosis including ``schizophrenic cluster'' (Maremmani et al., 2004),
``subclinical psychotic symptoms'' (Van Gastel et al., 2012), ``pre-
psychotic clinical high risk'' (Van der Meer et al., 2012), and
symptoms related to ``psychosis vulnerability'' (Griffith-Lendering et
al., 2012). These groupings do not conform to the criteria in the
Diagnostic and Statistical Manual (DSM-5) or the International
Classification of Diseases (ICD-10) for a diagnosis of psychosis. Thus,
these groupings are not appropriate for use in evaluating marijuana's
impact on the development of actual psychosis. Accordingly, this
analysis includes only those studies that use subjects diagnosed with a
psychotic disorder.
In the largest study evaluating the link between psychosis and drug
use, 274 of the approximately 45,500 Swedish conscripts in the study
population (<0.01 percent) received a diagnosis of schizophrenia within
the 14-year period following military induction from 1969 to 1983
(Andreasson et al., 1987). Of the conscripts diagnosed with psychosis,
7.7 percent (21 of the 274 conscripts with psychosis) had used
marijuana more than 50 times at induction, while 72 percent (197 of the
274 conscripts with psychosis) had never used marijuana. Although high
marijuana use increased the relative risk for schizophrenia to 6.0, the
authors note that substantial marijuana use history ``accounts for only
a minority of all cases'' of psychosis (Andreasson et al., 1987).
Instead, the best predictor for whether a conscript would develop
psychosis was a non-psychotic psychiatric diagnosis upon induction. The
authors concluded that marijuana use increased the risk for psychosis
only among individuals predisposed to develop the disorder. In
addition, a 35-year follow up to this study reported very similar
results (Manrique-Garcia et al., 2012). In this follow up study, 354
conscripts developed schizophrenia; of these 354 conscripts, 32 used
marijuana more than 50 times at induction (9 percent, an odds ratio of
6.3), while 255 had never used marijuana (72 percent).
Additionally, the conclusion that the impact of marijuana may
manifest only in individuals likely to develop psychotic disorders has
been shown in many other types of studies. For example, although
evidence shows that marijuana use may precede the presentation of
symptoms in individuals later diagnosed with psychosis (Schimmelmann et
al., 2011), most reports conclude that prodromal symptoms of
schizophrenia appear prior to marijuana use (Schiffman et al., 2005).
Similarly, a review of the gene-environment interaction model for
marijuana and psychosis concluded that some evidence supports marijuana
use as a factor that may influence the development of psychosis, but
only in those individuals with psychotic liability (Pelayo-Teran et
al., 2012).
A similar conclusion was drawn when the prevalence of schizophrenia
was modeled against marijuana use across eight birth cohorts in
Australia in individuals born between the years 1940 to 1979
(Degenhardt et al., 2003). Although marijuana use increased over time
in adults born during the four-decade period, there was not a
corresponding increase in diagnoses for psychosis in these individuals.
The authors conclude that marijuana may precipitate schizophrenic
disorders only in those individuals who are vulnerable to developing
psychosis. Thus, marijuana per se does not appear to
[[Page 53776]]
induce schizophrenia in the majority of individuals who have tried or
continue to use marijuana. However, in individuals with a genetic
vulnerability for psychosis, marijuana use may influence the
development of psychosis.
Cardiovascular and Autonomic Effects
Single smoked or oral doses of delta\9\-THC produce tachycardia and
may increase blood pressure (Capriotti et al., 1988; Benowitz and
Jones, 1975). Some evidence associates the tachycardia produced by
delta\9\-THC with excitation of the sympathetic and depression of the
parasympathetic nervous systems (Malinowska et al., 2012). During
chronic marijuana ingestion, a tolerance to tachycardia develops
(Malinowska et al., 2012).
However, prolonged delta\9\-THC ingestion produces bradycardia and
hypotension (Benowitz and Jones, 1975). Plant-derived cannabinoids and
endocannabinoids elicit hypotension and bradycardia via activation of
peripherally-located CB1 receptors (Wagner et al., 1998).
Specifically, the mechanism of this effect is through presynaptic CB1
receptor-mediated inhibition of norepinephrine release from peripheral
sympathetic nerve terminals, with possible additional direct
vasodilation via activation of vascular cannabinoid receptors (Pacher
et al., 2006). In humans, tolerance can develop to orthostatic
hypotension (Jones, 2002; Sidney, 2002) possibly related to plasma
volume expansion, but tolerance does not develop to the supine
hypotensive effects (Benowitz and Jones, 1975). Additionally,
electrocardiographic changes are minimal, even after large cumulative
doses of delta\9\-THC are administered. (Benowitz and Jones, 1975).
Marijuana smoking by individuals, particularly those with some
degree of coronary artery or cerebrovascular disease, poses risks such
as increased cardiac work, catecholamines and carboxyhemoglobin,
myocardial infarction, and postural hypotension (Benowitz and Jones,
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al.,
2012).
Respiratory Effects
After acute exposure to marijuana, transient bronchodilation is the
most typical respiratory effect (Gong et al., 1984). A recent 20-year
longitudinal study with over 5,000 individuals collected information on
the amount of marijuana use and pulmonary function data at years 0, 2,
5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000
individuals who participated in the study, almost 800 of them reported
current marijuana use but not tobacco use at the time of assessment.
Pletcher et al. (2012) found that the occasional use of marijuana is
not associated with decreased pulmonary function. However, some
preliminary evidence suggests that heavy marijuana use may be
associated with negative pulmonary effects (Pletcher et al., 2012).
Long-term use of marijuana can lead to chronic cough and increased
sputum, as well as an increased frequency of chronic bronchitis and
pharyngitis. In addition, pulmonary function tests reveal that large-
airway obstruction can occur with chronic marijuana smoking, as can
cellular inflammatory histopathological abnormalities in bronchial
epithelium (Adams and Martin 1996; Hollister 1986).
Evidence regarding marijuana smoking leading to cancer is
inconsistent, as some studies suggest a positive correlation while
others do not (Lee and Hancox, 2011; Tashkin, 2005). Several lung
cancer cases have been reported in young marijuana users with no
tobacco smoking history or other significant risk factors (Fung et al.,
1999). Marijuana use may dose-dependently interact with mutagenic
sensitivity, cigarette smoking, and alcohol use to increase the risk of
head and neck cancer (Zhang et al., 1999). However, in a large study
with 1,650 subjects, a positive association was not found between
marijuana and lung cancer (Tashkin et al., 2006). This finding remained
true, regardless of the extent of marijuana use, when controlling for
tobacco use and other potential confounding variables. Overall, new
evidence suggests that the effects of marijuana smoking on respiratory
function and carcinogenicity differ from those of tobacco smoking (Lee
and Hancox, 2011).
Endocrine System
Experimental marijuana administration to humans does not
consistently alter many endocrine parameters. In an early study, male
subjects who experimentally received smoked marijuana showed a
significant depression in luteinizing hormone and a significant
increase in cortisol (Cone et al., 1986). However, two later studies
showed no changes in hormones. Male subjects experimentally exposed to
smoked delta\9\-THC (18 mg/marijuana cigarette) or oral delta\9\-THC
(10 mg three times per day for 3 days and on the morning of the fourth
day) showed no changes in plasma adrenocorticotropic hormone (ACTH),
cortisol, prolactin, luteinizing hormone, or testosterone levels (Dax
et al., 1989). Similarly, a study with 93 men and 56 women showed that
chronic marijuana use did not significantly alter concentrations of
testosterone, luteinizing hormone, follicle stimulating hormone,
prolactin, or cortisol (Block et al., 1991). Additionally, chronic
marijuana use did not affect serum levels of thyrotropin, thyroxine,
and triiodothyronine (Bonnet, 2013). However, in a double-blind,
placebo-controlled, randomized clinical trial of HIV-positive men,
smoking marijuana dose-dependently increased plasma levels of ghrelin
and leptin, and decreased plasma levels of peptide YY (Riggs et al.,
2012).
The effects of marijuana on female reproductive system
functionality differ between humans and animals. In monkeys, delta\9\-
THC administration suppressed ovulation (Asch et al., 1981) and reduced
progesterone levels (Almirez et al., 1983). However, in women, smoked
marijuana did not alter hormone levels or the menstrual cycle
(Mendelson and Mello, 1984). Brown and Dobs (2002) suggest that the
development of tolerance in humans may be the cause of the
discrepancies between animal and human hormonal response to
cannabinoids.
The presence of in vitro delta\9\-THC reduces binding of the
corticosteroid, dexamethasone, in hippocampal tissue from
adrenalectomized rats, suggesting an interaction with the
glucocorticoid receptor (Eldridge et al., 1991). Although acute
delta\9\-THC presence releases corticosterone, tolerance develops in
rats with chronic administration (Eldridge et al., 1991).
Some studies support a possible association between frequent, long-
term marijuana use and increased risk of testicular germ cell tumors
(Trabert et al., 2011). On the other hand, recent data suggest that
cannabinoid agonists may have therapeutic value in the treatment of
prostate cancer, a type of carcinoma in which growth is stimulated by
androgens. Research with prostate cancer cells shows that the mixed
CB1/CB2 agonist, WIN-55212-2, induces apoptosis
in prostate cancer cells, as well as decreases the expression of
androgen receptors and prostate-specific antigens (Sarfaraz et al.,
2005).
Immune System
Cannabinoids affect the immune system in many different ways.
Synthetic, natural, and endogenous cannabinoids often cause different
effects in a dose-dependent biphasic manner (Croxford and Yamamura,
2005; Tanasescu and Constantinescu, 2010).
Studies in humans and animals give conflicting results about
cannabinoid
[[Page 53777]]
effects on immune functioning in subjects with compromised immune
systems. Abrams et al. (2003) investigated marijuana's effect on
immunological functioning in 62 AIDS patients taking protease
inhibitors. Subjects received one of the following three times a day: A
smoked marijuana cigarette containing 3.95 percent delta\9\-THC, an
oral tablet containing delta\9\-THC (2.5 mg oral dronabinol), or an
oral placebo. The results showed no changes in CD4+ and CD8+ cell
counts, HIV RNA levels, or protease inhibitor levels between groups.
Thus, the use of cannabinoids showed no short-term adverse virologic
effects in individuals with compromised immune systems. However, these
human data contrast with data generated in immunodeficient mice, which
demonstrated that exposure to delta\9\-THC in vivo suppresses immune
function, increases HIV co-receptor expression, and acts as a cofactor
to enhance HIV replication (Roth et al., 2005).
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance
Under the third factor, the Secretary must consider the state of
current scientific knowledge regarding marijuana. Thus, this section
discusses the chemistry, human pharmacokinetics, and medical uses of
marijuana.
Chemistry
Marijuana is one of the common names of Cannabis sativa L. in the
family Cannabaceae. Cannabis is one of the oldest cultivated crops,
providing a source of fiber, food, oil, and drug. Botanists still
debate whether Cannabis should be considered as a single (The Plant
List, 2010) or three species, i.e., C. sativa, C. indica, and C.
ruderalis (Hillig, 2005). Specifically, marijuana is developed as
sativa and indica cultivated varieties (strains) or various hybrids.
The petition defines marijuana as including all Cannabis cultivated
strains. Different marijuana samples derived from various cultivated
strains may have very different chemical constituents including
delta\9\ -THC and other cannabinoids (Appendino et al., 2011). As a
consequence, marijuana products from different strains will have
different safety, biological, pharmacological, and toxicological
profiles. Thus, all Cannabis strains cannot be considered together
because of the varying chemical constituents between strains.
Marijuana contains numerous naturally occurring constituents
including cannabinoids. Overall, various Cannabis strains contain more
than 525 identified natural constituents. Among those constituents, the
most important ones are the 21 (or 22) carbon terpenoids found in the
plant, as well as their carboxylic acids, analogues, and transformation
products, known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam,
1973; Appendino et al., 2011). Thus far, more than 100 compounds
classified as cannabinoids have been characterized (ElSohly and Slade,
2005; Radwan, ElSohly et al., 2009; Appendino et al. 2011).
Cannabinoids primarily exist in Cannabis, and published data
suggest that most major cannabinoid compounds occurring naturally have
been chemically identified. New and minor cannabinoids and other new
compounds are continuously being characterized (Pollastro et al.,
2011). So far, only two cannabinoids (cannabigerol and its
corresponding acid) have been obtained from a non-Cannabis source. A
South African Helichrysum (H umbraculigerum) accumulates these
compounds (Appendino et al. 2011).
Among the cannabinoids found in marijuana, delta\9\-THC (alternate
name delta\1\-THC) and delta-8-tetrahydrocannibinol (delta\8\-THC,
alternate name delta\6\-THC) produce marijuana's characteristic
psychoactive effects. Because delta\9\-THC is more abundant than
delta\8\-THC, marijuana's psychoactivity is largely attributed to the
former. Only a few varieties of marijuana analyzed contain delta\8\-THC
at significant amounts (Hively et al., 1966). Delta\9\-THC is an
optically active resinous substance, insoluble in water, and extremely
lipid soluble. Chemically, delta\9\-THC is (6aR-trans)-6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-l-ol, or (-)-
delta\9\-(trans)-tetrahydrocannabinol. The (-)-trans isomer of
delta\9\-THC is pharmacologically 6-100 times more potent than the (+)-
trans isomer (Dewey et al., 1984).
Other cannabinoids present in marijuana include CBD, CBC, and CBN.
CBD, a major cannabinoid of marijuana, is insoluble in water and lipid-
soluble. Chemically, CBD is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-
ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD does not have
cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al.,
1984, 1986; Hollister, 1986). CBC is another major cannabinoid in
marijuana. Chemically, CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-
pentyl-5-chromenol. CBN, a major metabolite of delta\9\-THC, is also a
minor naturally-occurring cannabinoid with weak psychoactivity.
Chemically, CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
Different marijuana samples derived from various cultivated strains
may differ in chemical constituents including delta\9\-THC and other
cannabinoids (Appendino et al. 2011). As a consequence, marijuana
products from different strains may have different safety, biological,
pharmacological, and toxicological profiles. In addition to differences
between cultivated strains, the concentration of delta\9\-THC and other
cannabinoids in marijuana may vary with growing conditions and
processing after harvest. In addition to genetic differences among
Cannabis species, the plant parts collected--for example, flowers,
leaves, and stems--can influence marijuana's potency, quality, and
purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973).
All these variations produce marijuana with potencies, as indicated by
cannabinoid content, on average from as low as 1-2 percent to as high
as 17 percent.
Overall, these variations in the concentrations of cannabinoids and
other chemical constituents in marijuana complicate the interpretation
of clinical data using marijuana. The lack of consistent concentrations
of delta\9\-THC and other substances in marijuana from diverse sources
makes interpreting the effect of different marijuana constituents
difficult. In addition to different cannabinoid concentrations having
different pharmacological and toxicological [middot]profiles, the non-
cannabinoid components in marijuana, such as other terpenoids and
flavonoids, might also contribute to the overall pharmacological and
toxicological profiles of various marijuana strains and products
derived from those strains.
The term marijuana is often used to refer to a mixture of the dried
flowering tops and leaves from Cannabis. Marijuana in this limiting
definition is one of three major derivatives sold as separate illicit
products, which also include hashish and hash oil. According to the
DEA, Cannabis saliva is the primary species of Cannabis currently
marketed illegally in the United States.
Marijuana can vary in cannabinoid content and potency (Agurell et
al., 1984, 1986; Mechoulam 1973, Cascini et al., 2012). In the usual
mixture of leaves and stems distributed as marijuana, the concentration
of delta\9\-THC averages over 12 percent by weight. However, specially
grown and selected marijuana can contain 15 percent or greater
delta\9\-THC (Appendino et al. 2011). Thus, a 1-gram marijuana
cigarette might contain
[[Page 53778]]
delta\9\-THC in a range from as little as 3 milligrams to as much as
150 milligrams or more. Additionally, a recent systematic review and
meta-analysis found that marijuana's delta\9\-THC content has increased
significantly from 1979-2009 (Cascini et al., 2012). In addition to
smoking marijuana, individuals ingest marijuana through food made with
butter or oil infused with marijuana and its extracts. These marijuana
butters are generally made by adding marijuana to butter and heating
it. The resultant butter is then used to cook a variety of foods. There
are no published studies measuring the concentrations of cannabinoids
in these marijuana food products.
Hashish consists of the dried and compressed cannabinoid-rich
resinous material of Cannabis and comes in a variety of forms (e.g.
balls and cakes). Individuals may break off pieces, place it into a
pipe and smoke it. DEA reports that cannabinoid content in hashish
averages six percent (DEA, 2005). With the development and cultivation
of more high potency Cannabis strains, the average cannabinoid content
in hashish will likely increase.
Hash oil is produced by solvent extraction of the cannabinoids from
plant material. The extract's color and odor vary, depending on the
solvent type used. Hash oil is a viscous brown- or amber-colored liquid
containing approximately 50 percent cannabinoids. One or two drops of
the liquid placed on a cigarette purportedly produce the equivalent of
a single[middot] marijuana cigarette (DEA, 2005).
In conclusion, marijuana has hundreds of cultivars containing
variable concentrations of delta\9\-THC, cannabinoids, and other
compounds. Thus, marijuana is not a single chemical with a consistent
and reproducible chemical profile or predictable and consistent
clinical effects. A guidance for industry, entitled Botanical Drug
Products,\8\ provides information on the approval of botanical drug
products. To investigate marijuana for medical use in a manner
acceptable as support for marketing approval under an NDA, clinical
studies under an IND of consistent batches of a particular marijuana
product for particular disease indications should be conducted. In
addition, information and data regarding the marijuana product's
chemistry, manufacturing and control, pharmacology, and animal
toxicology data, among others must be provided and meet the
requirements for new drug approval (See 21 CFR 314.50).
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\8\ This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
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Human Pharmacokinetics
Marijuana can be taken in a variety of formulations by multiple
routes of administration. Individuals smoke marijuana as a cigarette,
weighing between 0.5 and 1.0 gram, or in a pipe. Additionally,
individuals take marijuana orally in foods or as an extract in ethanol
or other solvents. More recently, access to vaporizers provides another
means for abusers to inhale marijuana,
The absorption, metabolism, and pharmacokinetic profile of
delta\9\-THC, cannabinoids, and drug products containing delta\9\-THC
vary with route of administratfon and formulation (Adams and Martin,
1996; Agurell et al., 1984, 1986).
Pharmacokinetics of Smoked Administration of Cannabinoids
Characterization of the pharmacokinetics of delta\9\-THC and other
cannabinoids from smoked marijuana is difficult because a subject's
smoking behavior during an experiment varies (Agurell et al., 1986;
Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a
discrete dose of delta\9\-THC. An experienced marijuana smoker can
titrate and regulate the dose to obtain the desired acute psychological
effects and minimize undesired effects. For example, under naturalistic
conditions, users hold marijuana smoke in their lungs for an extended
period of time which causes prolonged absorption and increases
psychoactive effects. The effect of experience in the psychological
response may explain why delta\9\-THC venous blood levels correlate
poorly with intensity of effects and intoxication level (Agurell et al.
1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation
volumes should be recorded in studies as the concentration (dose) of
cannabinoids administered can vary at different stages of smoking.
Smoked marijuana results in absorption of delta\9\-THC in the form
of an aerosol within seconds. Psychoactive effects occur immediately
following absorption, with mental and behavioral effects measurable for
up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988). Delta\9\-THC
is delivered to the brain rapidly and efficiently as expected of a very
lipid soluble drug.
The bioavailability of the delta\9\ -THC, from marijuana in a
cigarette or pipe, can range from 1 to 24 percent with the fraction
absorbed rarely exceeding 10 to 20 percent (Agurell et al.,1986;
Hollister, 1988). The relatively low and variable bioavailability
results from significant loss of delta\9\-THC in side-stream smoke,
variation in individual smoking behaviors, cannabinoid pyrolysis,
incomplete absorption of inhaled smoke, and metabolism in the lungs. An
individual's experience and technique with smoking marijuana also
determines the dose absorbed (Heming et al., 1986; Johansson et al.,
1989). After smoking, delta\9\-THC venous levels decline precipitously
within minutes, and continue to go down to about 5 to 10 percent of the
peak level within an hour (Agurell et al., 1986, Huestis et al.,1992a,
1992b).
Pharmacokinetics for Oral Administration of Cannabinoids
After oral administration of delta\9\-THC or marijuana, the onset
of effects starts within 30 to 90 minutes, reaches its peak after 2 to
3 hours and then remains for 4 to 12 hours (Grotenhermen, 2003; Adams
and Martin, 1996; Agurell et al., 1984, 1986). Due to the delay in
onset of effects, users have difficulty in titrating oral delta\9\-THC
doses compared to smoking marijuana. Oral bioavailability of delta\9\-
THC, whether pure or in marijuana, is low and extremely variable,
ranging between 5 and 20 percent (Agurell et al., 1984, 1986).
Following oral administration of radioactive-labeled delta\9\-THC,
delta\9\-THC plasma levels are low relative to plasma levels after
smoking or intravenous administration. Inter- and intra-subject
variability occurs even with repeated dosing under controlled
conditions. The low and variable oral bioavailability of delta\9\-THC
is a consequence of its first-pass hepatic elimination from blood and
erratic absorption from stomach and bowel.
Cannabinoid Metabolism and Excretion
Cannabinoid metabolism is complex. Delta\9\-THC is metabolized via
microsomal hydroxylation to both active and inactive metabolites
(Lemberger et al., 1970, 1972a, 1972b; Agurell et al., 1986; Hollister,
1988). The primary active metabolite of delta\9\-THC following oral
ingestion is 11-hydroxy-delta\9\-THC. This metabolite is approximately
equipotent to delta\9\-THC in producing marijuana-like subjective
effects (Agurell et al., 1986, Lemberger and Rubin, 1975). After oral
administration, metabolite levels may exceed that of delta\9\-THC and
thus contribute greatly to the pharmacological effects of oral
delta\9\-THC or marijuana.
Plasma clearance of delta\9\-THC approximates hepatic blood flow at
about 950 ml/min or greater. The rapid disappearance of delta\9\-THC
from blood
[[Page 53779]]
is largely due to redistribution to other tissues in the body, rather
than to metabolism (Agurell et al., 1984, 1986). Metabolism in most
tissues is relatively slow or absent. Slow release of delta\9\-THC and
other cannabinoids from tissues and subsequent metabolism results in a
long elimination half-life. The terminal half-life of delta\9\-THC
ranges from approximately 20 hours to as long as 10 to13 days, though
reported estimates vary as expected with any slowly cleared substance
and the use of assays with variable sensitivities (Hunt and Jones,
1980). Lemberger et al. (1970) determined the half-life of delta\9\-THC
to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours
in naive users. In addition to 11-hydroxy-delta\9\-THC, some inactive
carboxy metabolites have terminal half-lives of 50 hours to 6 days or
more. The latter substances serve as long-term markers in urine tests
for earlier marijuana use.
The majority of the absorbed delta\9\-THC dose is eliminated in
feces, and about 33 percent in urine. Delta\9\-THC enters enterohepatic
circulation and undergoes hydroxylation and oxidation to 11-nor-9-
carboxy-delta\9\-THC. The glucuronide is excreted as the major urine
metabolite along with about 18 non-conjugated metabolites. Frequent and
infrequent marijuana users metabolize delta\9\-THC similarly (Agurell
et al., 1986).
Status of Research Into the Medical Uses for Marijuana
State-level public initiatives, including laws and referenda in
support of the medical use of marijuana, have generated interest in the
medical community and the need for high quality clinical investigation
as well as comprehensive safety and effectiveness data. In order to
address the need for high quality clinical investigations, the state of
California established the Center for Medicinal Cannabis Research
(CMCR, www.cmcr.ucsd.edu) in 2000 ``in response to scientific evidence
for therapeutic possibilities of cannabis \9\ and local legislative
initiatives in favor of compassionate use'' (Grant, 2005). State
legislation establishing the CMCR called for high quality medical
research that would ``enhance understanding of the efficacy and adverse
effects of marijuana as a pharmacological agent,'' but stressed the
project ``should not be construed as encouraging or sanctioning the
social or recreational use of marijuana.'' The CMCR funded many of the
published studies on marijuana's potential use for treating multiple
sclerosis, neuropathic pain, appetite suppression and cachexia.
However, aside from the data produced by CMCR, no state-level medical
marijuana laws have produced scientific data on marijuana's safety and
effectiveness.
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\9\ In this quotation the term cannabis is interchangeable with
marijuana.
---------------------------------------------------------------------------
FDA approves medical use of a drug following a submission and
review of an NDA or BLA. The FDA has not approved any drug product
containing marijuana for marketing. Even so, results of small clinical
exploratory studies have been published in the current medical
literature. Many studies describe human research with marijuana in the
United States under FDA-regulated IND applications.
However, FDA approval of an NDA is not the only means through which
a drug can have a currently accepted medical use in treatment in the
United States. In general, a drug may have a ``currently accepted
medical use'' in treatment in the United States if the drug meets a
five-part test. Established case law (Alliance for Cannabis
Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the
Administrator of DEA's application of the five-part test to determine
whether a drug has a ``currently accepted medical use.'' The following
describes the five elements that characterize ``currently accepted
medical use'' for a drug: \10\
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\10\ 57 FR I 0499, 10504-06 (March 26, 1992).
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i. the drug's chemistry must be known and reproducible
``The substance's chemistry must be scientifically established to
permit it to be reproduced into dosages which can be standardized. The
listing of the substance in a current edition of one of the official
compendia, as defined by section 201 G) of the Food, Drug and Cosmetic
Act, 21 U.S.C. 321G), is sufficient to meet this requirement.''
ii. there must be adequate safety studies
``There must be adequate pharmacological and toxicological studies,
done by all methods reasonably applicable, on the basis of which it
could fairly and responsibly be concluded, by experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, that the substance is safe for treating a
specific, recognized disorder.''
iii. there must be adequate and well-controlled studies proving
efficacy
``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical
investigations, by experts qualified by scientific training and
experience to evaluate the safety and effectiveness of drugs, on the
basis of which it could be fairly and responsibly concluded by such
experts that the substance will have the intended effect in treating a
specific, recognized disorder.''
iv. the drug must be accepted by qualified experts
``The drug has a New Drug Application (NDA) approved by the Food
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act,
21 U.S.C. 355. Or, a consensus of the national community of experts,
qualified by scientific training and experience to evaluate the safety
and effectiveness of drugs, accepts the safety and effectiveness of the
substance for use in treating a specific, recognized disorder. A
material conflict of opinion among experts precludes a finding of
consensus.'' and
v. the scientific evidence must be widely available
``In the absence of NDA approval, information concerning the
chemistry, pharmacology, toxicology, and effectiveness of the substance
must be reported, published, or otherwise widely available, in
sufficient detail to permit experts, qualified by scientific training
and experience to evaluate the safety and effectiveness of drugs, to
fairly and responsibly conclude the substance is safe and effective for
use in treating a specific, recognized disorder.''
Marijuana does not meet any of the five elements necessary for a
drug to have a ``currently accepted medical use.''
Firstly, the chemistry of marijuana, as defined in the petition, is
not reproducible in terms of creating a standardized dose. The petition
defines marijuana as including all Cannabis cultivated strains.
Different marijuana samples derived from various cultivated strains may
have very different chemical constituents including delta9-THC and
other cannabinoids (Appendino et al., 2011). As a consequence,
marijuana products from different strains will have different safety,
biological, pharmacological, and toxicological profiles. Thus, when
considering all Cannabis strains together, because of the varying
chemical constituents, reproducing consistent standardized doses is not
possible. Additionally, smoking marijuana currently has not been shown
to allow delivery of consistent and reproducible doses. However, if a
specific Cannabis strain is grown and processed under strictly
controlled conditions, the plant chemistry may be kept consistent
enough to produce reproducible and standardized doses.
[[Page 53780]]
As to the second and third criteria; there are neither adequate
safety studies nor adequate and well-controlled studies proving
marijuana's efficacy. To support the petitioners' assertion that
marijuana has accepted medical use, the petitioners cite the American
Medical Association's (AMA) 2009 report entitled ``Use of Cannabis for
Medicinal Purposes.'' The petitioners claim the AMA report is evidence
the AMA accepts marijuana's safety and efficacy. However, the 2009 AMA
report clarifies that the report ``should not be viewed as an
endorsement of state-based medical cannabis programs, the legalization
of marijuana, or that scientific evidence on the therapeutic use of
cannabis meets the same and current standards for a prescription drug
product.'' \11\
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\11\ In this quotation the term cannabis is used interchangeably
for marijuana.
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Currently, no published studies conducted with marijuana meet the
criteria of an adequate and well-controlled efficacy study. The
criteria for an adequate and well-controlled study for purposes of
determining the safety and efficacy of a human drug are defined under
the Code of Federal Regulations (CFR) in 21 CFR 314.126. In order to
assess this element, FDA conducted a review of clinical studies
published and available in the public domain before February, 2013.
Studies were identified through a search of PubMed \12\ for articles
published from inception to February 2013, for randomized controlled
trials using marijuana to assess marijuana's efficacy in any
therapeutic indication. Additionally, the review included studies
identified through a search of bibliographic references in relevant
systematic reviews and identified studies presenting original research
in any language. Selected studies needed to be placebo-controlled and
double-blinded. Additionally, studies needed to encompass administered
marijuana plant material. There was no requirement for any specific
route of administration, nor any age limits on study subjects. Studies
were excluded that used placebo marijuana supplemented by the addition
of specific amounts of THC or other cannabinoids. Additionally, studies
administering marijuana plant extracts were excluded.
---------------------------------------------------------------------------
\12\ The following search strategy was used, ``(cannabis OR
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized
controlled trial OR ``systematic review'' OR clinical trial OR
clinical trials) NOT (``marijuana abuse''[Mesh] OR addictive
behavior OR substance related disorders).''
---------------------------------------------------------------------------
The PubMed search yielded a total of 566 abstracts of scientific
articles. Of these abstracts, a full-text review was conducted with 85
papers to assess eligibility. Of the studies identified through the
search of the references and the 566 abstracts from the PubMed search,
only 11 studies met all the criteria for selection (Abrams et al.,
2007; Corey-Bloom et al., 2012; Crawford and Merritt, 1979; Ellis et
al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt et al.,
1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008;
Wilsey et al., 2013). These 11 studies were published between 197 4 and
2013. Ten of these studies were conducted in the United States and one
study was conducted in Canada. The identified studies examine the
effects of smoked and vaporized marijuana for the indications of
chronic neuropathic pain, spasticity related to Multiple Sclerosis
(MS), appetite stimulation in human immunodeficiency virus (HIV)
patients, glaucoma, and asthma. All studies used adult subjects.
The 11 identified studies were individually evaluated to determine
if they successfully meet accepted scientific standards. Specifically,
they were evaluated on study design including subject selection
criteria, sample size, blinding techniques, dosing paradigms, outcome
measures, and the statistical analysis of the results. The analysis
relied on published studies, thus information available about
protocols, procedures, and results were limited to documents published
and widely available in the public domain. The review found that all 11
studies that examined effects of inhaled marijuana do not currently
prove efficacy of marijuana in any therapeutic indication based on a
number of limitations in their study design; however, they may be
considered proof of concept studies. Proof of concept studies provide
preliminary evidence on a proposed hypothesis involving a drug's
effect. For drugs under development, the effect often relates to a
short-term clinical outcome being investigated. Proof of concept
studies often serve as the link between preclinical studies and dose
ranging clinical studies. Thus, proof of concept studies generally are
not sufficient to prove efficacy of a drug because they provide only
preliminary information about the effects of a drug.
In addition to the lack of published adequate and well-controlled
efficacy studies proving efficacy, the criteria for adequate safety
studies has also not been met. Importantly, in its discussion of the
five-part test used to determine whether a drug has a ``currently
accepted medical use,'' DEA said, ``No drug can be considered safe in
the abstract. Safety has meaning only when judged against the intended
use of the drug, its known effectiveness, its known and potential
risks, the severity of the illness to be treated, and the availability
of alternative remedies'' (57 FR 10504). When determining whether a
drug product is safe and effective for any indication, FDA performs an
extensive risk-benefit analysis to determine whether the risks posed by
the drug product's side effects are outweighed by the drug product's
potential benefits for a particular indication. Thus, contrary to the
petitioner's assertion that marijuana has accepted safety, in the
absence of an accepted therapeutic indication which can be weighed
against marijuana's risks, marijuana does not satisfy the element for
having adequate safety studies such that experts may conclude that it
is safe for treating a specific, recognized disorder.
The fourth of the five elements for determining ``currently
accepted medical use'' requires that the national community of experts,
qualified by scientific training and experience to evaluate the safety
and effectiveness of drugs, accepts the safety and effectiveness of the
substance for use in treating a specific, recognized disorder. A
material conflict of opinion among experts precludes a finding of
consensus. Medical practitioners who are not experts in evaluating
drugs are not qualified to determine whether a drug is generally
recognized as safe and effective or meets NDA requirements (57 FR
10499-10505).
There is no evidence that there is a consensus among qualified
experts that marijuana is safe and effective for use in treating a
specific, recognized disorder. As discussed above, there are not
adequate scientific studies that show marijuana is safe and effective
in treating a specific, recognized disorder. In addition, there is no
evidence that a consensus of qualified experts have accepted the safety
and effectiveness of marijuana for use in treating a specific,
recognized disorder. Although medical practitioners are not qualified
by scientific training and experience to evaluate the safety and
effectiveness of drugs, we also note that the AMA's report, entitled
``Use of Cannabis for Medicinal Purposes,'' does not accept that
marijuana currently has accepted medical use. Furthermore, based on the
above definition of a ``qualified expert'', who is an individual
qualified by scientific training and experience to evaluate the safety
and effectiveness of a drug, state-level medical marijuana laws do not
provide evidence of a consensus among qualified experts that marijuana
is safe and effective for use in treating a specific, recognized
disorder.
[[Page 53781]]
As to the fifth part of the test, which requires that information
concerning the chemistry, pharmacology, toxicology, and effectiveness
of marijuana to be reported in sufficient detail, the scientific
evidence regarding all of these aspects is not available in sufficient
detail to allow adequate scientific scrutiny. Specifically, the
scientific evidence regarding marijuana's chemistry in terms of a
specific Cannabis strain that could produce standardized and
reproducible doses is not currently available.
Alternately, a drug can be considered to have a ``currently
accepted medical use with severe restrictions'' (21 U.S.C.
812(b)(2)(B)), as allowed under the stipulations for a Schedule II
drug. Yet, as stated above, currently marijuana does not have any
accepted medical use, even under conditions where its use is severely
restricted.
In conclusion, to date, research on marijuana's medical use has not
progressed to the point where marijuana is considered to have a
``currently accepted medical use'' or a ``currently accepted medical
use with severe restrictions.''
4. Its History and Current Pattern of Abuse
Under the fourth factor, the Secretary must consider the history
and current pattern of marijuana abuse. A variety of sources provide
data necessary to assess abuse patterns and trends of marijuana. The
data indicators of marijuana use include the NSDUH, MTF, DAWN, and
TEDS. The following briefly describes each data source, and summarizes
the data from each source.
National Survey on Drug Use and Health (NSDUH) 13
---------------------------------------------------------------------------
\13\ NSDUH provides national estimates of the prevalence and
incidence of illicit drug, alcohol and tobacco use in the United
States. NSDUH is an annual study conducted by SAMHSA. Prior to 2002,
the database was known as the National Household Survey on Drug
Abuse (NHSDA). NSDUH utilizes a nationally representative sample of
United States civilian, non-institutionalized population aged 12
years and older. The survey excludes homeless people who do not use
shelters, active military personnel, and residents of institutional
group quarters such as jails and hospitals. The survey identifies
whether an individual used a drug within a specific time period, but
does not identify the amount of the drug used on each occasion.
NSDUH defines ``current use'' as having used the substance within
the month prior to the study.
---------------------------------------------------------------------------
According to 2012 NSDUH \14\ data, the most recent year with
complete data, the use of illicit drugs, including marijuana, is
increasing. The 2012 NSDUH estimates that 23.9 million individuals over
12 years of age (9.2 percent of the U.S. population) currently use
illicit drugs, which is an increase of 4.8 million individuals from
2004 when 19.1 million individuals (7.9 percent of the U.S. population)
were current illicit drug users. NSDUH reports marijuana as the most
commonly used illicit drug, with 18.9 million individuals (7.3 percent
of the U.S. population) currently using marijuana in 2012. This
represents an increase of 4.3 million individuals from 2004, when 14.6
million individuals (6.1 percent of the U.S. population) were current
marijuana users.
---------------------------------------------------------------------------
\14\ 2013; http://www.samhsa.gov/data/NSDUH.aspx.
---------------------------------------------------------------------------
The majority of individuals who try marijuana at least once in
their lifetime do not currently use marijuana. The 2012 NSDUH estimates
that 111.2 million individuals (42.8 percent of the U.S. population)
have used marijuana at least once in their lifetime. Based on this
estimate and the estimate for the number of individuals currently using
marijuana, approximately 16.9 percent of those who have tried marijuana
at least once in their lifetime currently use marijuana; conversely,
83.1 percent do not currently use marijuana. In terms of the frequency
of marijuana use, an estimated 40.3 percent of individuals who used
marijuana in the past month used marijuana on 20 or more days within
the past month. This amount corresponds to an estimated 7.6 million
individuals who used marijuana on a daily or almost daily basis.
Some characteristics of marijuana users are related to age, gender,
and criminal justice system involvement. In observing use among
different age cohorts, the majority of individuals who currently use
marijuana are shown to be between the ages of 18-25, with 18.7 percent
of this age group currently using marijuana. In the 26 and older age
group, 5.3 percent of individuals currently use marijuana.
Additionally, in individuals aged 12 years and older, males reported
more current marijuana use than females.
NSDUH includes a series of questions aimed at assessing the
prevalence of dependence and abuse of different substances in the past
12 months.\15\ In 2012, marijuana was the most common illicit drug
reported by individuals with past year dependence or abuse. An
estimated 4.3 million individuals meet the NSDUH criteria for marijuana
dependence or abuse in 2012. The estimated rates and number of
individuals with marijuana dependence or abuse has remained similar
from 2002 to 2012. In addition to data on dependence and abuse, NSDUH
includes questions aimed at assessing treatment for a substance use
problem.\16\ In 2012, an estimated 957,000 persons received treatment
for marijuana use during their most recent treatment in the year prior
to the survey.
---------------------------------------------------------------------------
\15\ ``These questions are used to classify persons as dependent
on or abusing specific substances based on criteria specified in the
Diagnostic and Statistical Manual of Mental Disorder, 4th edition
(DSM-IV). The questions related to dependence ask about health and
emotional problems associated with substance use, unsuccessful
attempts to cut down on use, tolerance, withdrawal, reducing other
activities to use substances, spending a lot time engaging in
activities related to substance use, or using the substance in
greater quantities or for longer time than intended. The questions
on abuse ask about problems at work, home, and school; problems with
family or friends; physical danger; and trouble with the law due to
substance use. Dependence is considered to be a more severe
substance use problem than abuse because it involves the
psychological and physiological effects of tolerance and
withdrawal.'' (NSDUH, 2013).
\16\ ``Estimates . . . refer to treatment received for illicit
drug or alcohol use, or for medical problems associated with the use
of illicit drugs or alcohol. This includes treatment received in the
past year at any location, such as a hospital (inpatient),
rehabilitation facility (outpatient or inpatient), mental health
center, emergency room, private doctor's office, prison or jail, or
a self-help group, such as Alcoholics Anonymous or Narcotics
Anonymous.'' (NSDUH, 2013).
---------------------------------------------------------------------------
Monitoring the Future (MTF) 17
---------------------------------------------------------------------------
\17\ Monitoring the Future is a national survey that tracks drug
use prevalence and trends among adolescents in the United States.
MTF is reported annually by the Institute for Social Research at the
University of Michigan under a grant from NIDA. Every spring, MTF
surveys 8th, 10th, and 12th graders in randomly selected U.S.
schools. MTF has been conducted since 1975 for 12th graders and
since 1991 for 8th and 10th graders. The MTF survey presents data in
terms of prevalence among the sample interviewed. For 2012, the
latest year with complete data, the sample sizes were 15,200--8th
graders; 13,300--10th graders; and 13,200--12th graders. In all, a
total of about 41,700 students of 389 schools participated in the
2013 MTF.
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According to MTF,\18\ rates of marijuana and illicit drug use
declined for all three grades from 2005 through 2007. However, starting
around 2008, rates of annual use of illicit drugs and marijuana
increased through 2013 for all three grades. Marijuana remained the
most widely used illicit drug during all time periods. The prevalence
of annual and past month marijuana use in 10th and 12th graders in 2013
is greater than in 2005. Table 1 lists the lifetime, annual, and
monthly prevalence rates of various drugs for 8th, 10th, and 12th
graders in 2013.
---------------------------------------------------------------------------
\18\ 2013; http://www.monitoringthefuture.org/index.html.
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[[Page 53782]]
[GRAPHIC] [TIFF OMITTED] TP12AU16.005
''-->Drug Abuse Warning Network (DAWN) \19\
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\19\ DAWN is a national probability survey of the U.S. hospitals
with ED designed to obtain information on drug related ED visits.
DAWN is sponsored by SAMHSA. The DAWN system provides information on
the health consequences of drug use in the United States, as
manifested by drug-related visits to ED. The ED data from a
representative sample of hospital emergency departments are weighted
to produce national estimates. Importantly, DAWN data and estimates,
starting in 2004, are not comparable to those for prior years
because of vast changes in the methodology used to collect the data.
Furthermore, estimates for 2004 are the first to be based on a
redesigned sample of hospitals, which ended in 2011.
---------------------------------------------------------------------------
Importantly, many factors can influence the estimates of ED visits,
including trends in overall use of a substance as well as trends in the
reasons for ED usage. For instance, some drug users may visit EDs for
life-threatening issues while others may visit to seek care for
detoxification because they needed certification before entering
treatment. Additionally, DAWN data do not distinguish the drug
responsible for the ED visit from other drugs that may have been used
concomitantly. As stated in a DAWN report, ``Since marijuana/hashish is
frequently present in combination with other drugs, the reason for the
ED visit may be more relevant to the other drug(s) involved in the
episode.''
For 2011, DAWN \20\ estimates a total of 5,067,374 (95 percent
confidence interval [CI]: 4,616,753 to 5,517,995) drug-related ED
visits from the entire United States. Of these, approximately 2,462,948
([CI]: 2,112,868 to 2,813,028) visits involved drug misuse or abuse.
---------------------------------------------------------------------------
\20\ 2011; http://www.samhsa.gov/data/dawn.aspx.
---------------------------------------------------------------------------
During the same period, DAWN estimates that 1,252,500 (CI: 976,169
to 1,528,831) drug related ED visits involved illicit drugs. Thus, over
half of all drug-related ED visits associated with drug misuse or abuse
involved an illicit drug. For ED visits involving illicit drugs, 56.3
percent involved multiple drugs while 43.7 percent involved a single
drug.
Marijuana was involved in 455,668 ED visits (CI: 370,995 to
540,340), while cocaine was involved in 505,224 (CI: 324,262 to
686,185) ED visits, heroin was involved in 258,482 (CI: 205,046 to
311,918) ED visits and stimulants including amphetamine and
methamphetamine were involved in 159,840 (CI: 100,199 to 219,481) ED
visits. Other illicit drugs, such as PCP, MDMA, GHB and LSD were much
less frequently associated with ED visits. The number of ED visits
involving marijuana has increased by 62 percent since 2004.
Marijuana-related ED visits were most frequent among young adults
and minors. Individuals under the age of 18 accounted for 13.2 percent
of these marijuana-related visits, whereas this age group accounted for
approximately 1.2 percent of ED visits involving cocaine, and less than
1 percent of ED visits involving heroin. However, the age group with
the most marijuana-related ED visits was between 25 and 29 years old.
Yet, because populations differ between age groups, a standardized
measure for population size is useful to make comparisons. For
marijuana, the rates of ED visits per 100,000 population were highest
for patients aged 18 to 20 (443.8 ED visits per 100,000) and for
patients aged 21 to 24 (446.9 ED visits per 100,000).
While DAWN provides estimates for ED visits associated with the use
of medical marijuana for 2009-2011, the validity of these estimates is
questionable. Because the drug is not approved by the FDA, reporting
medical marijuana may be inconsistent and reliant on a number of
factors including whether the patient self-reports the marijuana use as
medicinal, how the treating health care provider records the marijuana
use, and lastly how the SAMHSA coder interprets the report. All of
these aspects will vary greatly between states with medical marijuana
laws and states without medical marijuana laws. Thus, even though
estimates are reported for medical marijuana related ED visits, medical
marijuana estimates cannot be assessed with any acceptable accuracy at
this time, as FDA has not approved marijuana treatment of any medical
condition. These data show the difficulty in evaluating abuse of a
product that is not currently approved by FDA, but authorized for
medical use, albeit inconsistently, at the state level. Thus, we
believe the likelihood of the treating health care provider or SAMHSA
coder attributing the ED visit to ``medical marijuana'' versus
``marijuana'' to be very low. Overall, the available data are
inadequate to
[[Page 53783]]
characterize its abuse at the community level.
Treatment Episode Data Set (TEDS) \21\
---------------------------------------------------------------------------
\21\ The TEDS system is part of SAMHSA's Drug and Alcohol
Services Information System (Office of Applied Science, SAMHSA). The
TEDS report presents information on the demographic and substance
use characteristics of the 1.8 million annual admissions to
treatment for alcohol and drug abuse in facilities that report to
individual state administrative data systems. Specifically, TEDS
includes facilities licensed or certified by the states to provide
substance abuse treatment and is required by the states to provide
TEDS client-level data. Facilities that report TEDS data are those
receiving State alcohol and drug agency funds for the provision of
alcohol and drug treatment services. Since TEDS is based only on
reports from these facilities, TEDS data do not represent the total
national demand for substance abuse treatment or the prevalence of
substance abuse in the general population. The primary goal for TEDS
is to monitor the characteristics of treatment episodes for
substance abusers. Importantly, TEDS is an admissions-based system,
where admittance to treatment is counted as an anonymous tally. For
instance, a given individual who is admitted to treatment twice
within a given year would be counted as two admissions. The most
recent year with complete data is 2011.
---------------------------------------------------------------------------
Primary marijuana abuse accounted for 18.1 percent of all 2011 TEDS
\22\ admissions. Individuals admitted for primary marijuana abuse were
nearly three-quarters (73.4 percent) male, and almost half (45.2
percent) were white. The average age at admission was 24 years old, and
31.1 percent of individuals admitted for primary marijuana abuse were
under the age of 18. The reported frequency of marijuana use was 24.3
percent reporting daily use. Almost all (96.8 percent) primary
marijuana users utilized the substance by smoking. Additionally, 92.9
percent reported using marijuana for the first time before the age of
18.
---------------------------------------------------------------------------
\22\ 2011; http://www.samhsa.gov/data/DASIS.aspx?qr=t#TEDS.
---------------------------------------------------------------------------
An important aspect of TEDS admission data for marijuana is of the
referral source for treatment. Specifically, primary marijuana
admissions were less likely than all other admissions to either be
self-referred or referred by an individual for treatment. Instead, the
criminal justice system referred more than half (51.6 percent) of
primary marijuana admissions.
Since 2003, the percent of admissions for primary marijuana abuse
increased from 15.5 percent of all admissions in 2003 to 18.l percent
in 2011. This increase is less than the increase seen for admissions
for primary opioids other than heroin, which increased from 2.8 percent
in 2003 to 7.3 percent in 2011. In contrast, the admissions for primary
cocaine abuse declined from 9.8 percent in 2003 to 2.0 percent in 2011.
5. The Scope, Duration, and Significance of Abuse
Under the fifth factor, the Secretary must consider the scope,
duration, and significance of marijuana abuse. According to 2012 data
from NSDUH and 2013 data from MTF, marijuana remains the most
extensively used illegal drug in the United States, with 42.8 percent
of U.S. individuals over age 12 (111.2 million) and 45.5 percent of
12th graders having used marijuana at least once in their lifetime.
Although the majority of individuals over age 12 (83.1 percent) who
have ever used marijuana in their lifetime do not use the drug monthly,
18.9 million individuals (7.3 percent of the U.S. population) report
that they used marijuana within the past 30 days. An examination of use
among various age cohorts through NSDUH demonstrates that monthly use
occurs primarily among college-aged individuals, with use dropping off
sharply after age 25. Additionally, NSDUH data show the number of
individuals reporting past-month use of marijuana has increased by 4.3
million individuals since 2004. Data from MTF shows that annual
prevalence of marijuana use declined for all three grades from 2005
through 2007, then began to rise through 2013. Additionally, in 2013,
1.1 percent of 8th graders, 4.0 percent of 10th graders, and 6.5
percent of 12th graders reported daily use of marijuana, defined as use
on 20 or more days within the past 30 days.
The 2011 DAWN data show that marijuana use was mentioned in 455,668
ED visits, which amounts to approximately 36.4 percent of all illicit
drug-related ED visits.\23\
---------------------------------------------------------------------------
\23\ Many factors can influence the estimates of ED visits,
including trends in the reasons for ED usage. For instance, some
drug users may visit EDs for life-threatening issues while others
may visit to seek care for detoxification because they needed
certification before entering treatment. Additionally, DAWN data do
not distinguish the drug responsible for the ED visit from other
drugs that may have been used concomitantly. As stated in a DAWN
report, ``Since marijuana/hashish is frequently present in
combination with other drugs, the reason for the ED visit may be
more relevant to the other drug(s) involved in the episode.''
---------------------------------------------------------------------------
TEDS data for 2011 show that 18.1 percent of all admissions were
for primary marijuana abuse.\24\ Between 2003 and 2011, there was a 2.6
percent increase in the number of TEDS admissions for primary marijuana
use. Approximately 61.5 percent of primary marijuana admissions in 2011
were for individuals under the age of 25 years.
---------------------------------------------------------------------------
\24\ An important aspect of TEDS admission data for marijuana is
of the referral source for treatment. Specifically, primary
marijuana admissions were less likely than all other admissions to
either be self-referred or referred by an individual for treatment.
Instead, the criminal justice system referred more than half (51.6
percent) of primary marijuana admissions.
---------------------------------------------------------------------------
6. What, if Any, Risk There Is to the Public Health
Under the sixth factor, the Secretary must consider the risks posed
to the public health by marijuana. Factors 1, 4, and 5 include a.
discussion of the risk to the public health as measured by emergency
room episodes and drug treatment admissions. Additionally, Factor 2
includes a discussion of marijuana's central nervous system, cognitive,
cardiovascular, autonomic, respiratory, and immune system effects.
Factor 6 focuses on the health risks to the individual user in terms of
the risks from acute and chronic use of marijuana, as well as the
``gateway hypothesis.''
Risks From Acute Use of Marijuana
Acute use of marijuana impairs psychomotor performance, including
complex task performance, which makes operating motor vehicles or heavy
equipment after using marijuana inadvisable (Ramaekers et al., 2004;
Ramaekers et al., 2006a). A meta-analysis conducted by Li et al. (2011)
showed an association between marijuana use by the driver and a
significantly increased risk of involvement in a car accident.
Additionally, in a minority of individuals who use marijuana, some
potential responses include dysphoria and psychological distress,
including prolonged anxiety reactions (Haney et al., 1999).
Risks From Chronic Use of Marijuana
A distinctive marijuana withdrawal syndrome following long term or
chronic use has been identified. The withdrawal syndrome indicates that
marijuana produces physical dependence that is mild, short-lived, and
comparable to tobacco withdrawal (Budney et al., 2008). Marijuana
withdrawal syndrome is described in detail below under Factor 7.
The following states how the DSM-V (2013) of the American
Psychiatric Association describes the consequences of Cannabis \25\
abuse:
---------------------------------------------------------------------------
\25\ Cannabis is the term used in the DSM-V to refer to
marijuana. In the following excerpt the term Cannabis is
interchangeable for the term marijuana.
---------------------------------------------------------------------------
Individuals with cannabis use disorder may use cannabis throughout
the day over a period of months or years, and thus may spend many hours
a day under the influence. Others may use less frequently, but their
use causes recurrent problems related to family,
[[Page 53784]]
school, work, or other important activities (e.g., repeated absences at
work; neglect of family obligations). Periodic cannabis use and
intoxication can negatively affect behavioral and cognitive functioning
and thus interfere with optimal performance at work or school, or place
the individual at increased physical risk when performing activities
that could be physically hazardous (e.g:, driving a car; playing
certain sports; performing manual work activities, including operating
machinery). Arguments with spouses or parents over the use of cannabis
in the home, or its use in the presence of children, can adversely
impact family functioning and are common features of those with
cannabis use disorder. Last, individuals with cannabis use disorder may
continue using marijuana despite knowledge of physical problems (e.g.,
chronic cough related to smoking) or psychological problems (e.g.,
excessive sedation or exacerbation of other mental health problems)
associated with its use.
Marijuana as a ``Gateway Drug''
Kandel (1975) proposed nearly 40 years ago the hypothesis that
marijuana is a ``gateway drug'' that leads to the use or abuse of other
illicit drugs. Since that time, epidemiological research explored this
premise. Overall, research does not support a direct causal
relationship between regular marijuana use and other illicit drug use.
The studies examining the gateway hypothesis are limited. First, in
general, studies recruit individuals influenced by a myriad of social,
biological, and economic factors that contribute to extensive drug
abuse (Hall & Lynskey, 2005). Second, most studies that test the
hypothesis that marijuana use causes abuse of illicit drugs use the
determinative measure any use of an illicit drug, rather than DSM-5
criteria for drug abuse or dependence on an illicit drug (DSM-5, 2013).
Consequently, although an individual who used marijuana may try other
illicit drugs, the individual may not regularly use drugs, or have a
diagnosis of drug abuse or dependence.
Little evidence supports the hypothesis that initiation of
marijuana use leads to an abuse disorder with other illicit substances.
For example, one longitudinal study of 708 adolescents demonstrated
that early onset marijuana use did not lead to problematic drug use
(Kandel & Chen, 2000). Similarly, Nace et al. (1975) examined Vietnam-
era soldiers who extensively abused marijuana and heroin while they
were in the military, and found a lack of correlation of a causal
relationship demonstrating marijuana use leading to heroin addiction.
Additionally, in another longitudinal study of 2,446 adolescents,
marijuana dependence was uncommon but when it did occur, the common
predictors of marijuana dependence were the following: parental death,
deprived socio-economic status, and baseline illicit drug use other
than marijuana (von Sydow et al., 2002).
When examining the association between marijuana and illicit drugs,
focusing on drug use versus abuse or dependence, different patterns
emerge. For example, a study examining the possible causal relationship
of the gateway hypothesis found a correlation between marijuana use in
adolescents and other illicit drug use in early adulthood and,
adjusting for age-linked experiences, did not effect this correlation
(Van Gundy and Rebellon, 2010). However, when examining the association
in terms of development of drug abuse; age-linked stressors and social
roles moderated the correlation between marijuana use in adolescents
and other illicit drug abuse. Similarly, Degenhardt et al. (2009)
examined the development of drug dependence and found an association
that did not support the gateway hypothesis. Specifically, drug
dependence was significantly associated with the use of other illicit
drugs prior to marijuana use.
Interestingly, the order of initiation of drug use seems to depend
on the prevalence of use of each drug, which varies by country. Based
on the World Health Organization (WHO) World Mental Health Survey that
includes data from 17 different countries, the order of drug use
initiation varies by country and relates to prevalence of drug use in
each country (Degenhardt et al., 2010). Specifically, in the countries
with the lowest prevalence of marijuana use, use of other illicit drugs
before marijuana was common. This sequence of initiation is less common
in countries with higher prevalence of marijuana use. A study of
9,282[middot]households in the United States found that marijuana use
often preceded the use of other illicit drugs; however, prior non-
marijuana drug dependence was also frequently correlated with higher
levels of illicit drug abuse (Degenhardt et al., 2009). Additionally,
in a large 25-year longitudinal study of 1,256 New Zealand children,
the author concluded that marijuana use correlated to an increased risk
of abuse of other drugs, including cocaine and heroin (Fergusson et
al., 2005).
Although many individuals with a drug abuse disorder may have used
marijuana as one of their first illicit drugs, this fact does not
correctly lead to the reverse inference that most individuals who used
marijuana will inherently go on to try or become regular users of other
illicit drugs. Specifically, data from the 2011 NSDUH survey
illustrates this issue (SAMHSA, 2012). NSDUH data estimates 107.8
million individuals have a lifetime history of marijuana use, which
indicates use on at least one occasion, compared to approximately 36
million individuals having a lifetime history of cocaine use and
approximately 4 million individuals having a lifetime history of heroin
use. NSDUH data do not provide information about each individual's
specific drug history. However, even if one posits that every cocaine
and heroin user previously used marijuana, the NSDUH data show that
marijuana use at least once in a lifetime does not predict that an
individual will also use another illicit drug at least once.
Finally, a review of the gateway hypothesis by Vanyukov et al.
(2012) notes that because the gateway hypothesis only addresses the
order of drug use initiation, the gateway hypothesis does not specify
any mechanistic connections between drug ``stages'' following exposure
to marijuana and does not extend to the risks for addiction. This
concept contrasts with the concept of a common liability to addiction
that involves mechanisms and biobehavioral characteristics pertaining
to the entire course of drug abuse risk and disorders.
7. Its Psychic or Physiologic Dependence Liability
Under the seventh factor, the Secretary must consider marijuana's
psychic or physiological dependence liability.
Psychic or psychological dependence has been shown in response to
marijuana's psychoactive effects. Psychoactive responses to marijuana
are pleasurable to many humans and are associated with drug-seeking and
drug-taking (Maldonado, 2002). Moreover, high levels of psychoactive
effects, notably positive reinforcement, are associated with increased
marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et
al., 2010). Epidemiological data support these findings through 2012
NSDUH statistics that show that of individuals years 12 or older who
used marijuana in the past month, an estimated 40.3 percent used
marijuana on 20 or more days within the past month. This equates to
approximately 7.6 million individuals aged 12 or older who used
marijuana on a daily or almost daily basis.
[[Page 53785]]
Additionally, the 2013 MTF data report the prevalence of daily
marijuana use, defined as use on 20 or more days within the past 30
days, in 8th, 10th, and 12th graders is 1.1 percent, 4.0 percent, and
6.5 percent, respectively.
Tolerance is a state of adaptation where exposure to a drug induces
changes that result in a diminution of one or more of the drug's
effects over time (American Academy of Pain Medicine, American Pain
Society and American Society of Addiction Medicine consensus document,
2001). Tolerance can develop to some, but not all, of marijuana's
effects. Specifically, tolerance does not seem to develop in response
to many of marijuana's psychoactive effects. This lack of tolerance may
relate to electrophysiological data demonstrating that chronic
delta\9\-THC administration does not affect increased neuronal firing
in the ventral tegmental area, a region known to play a critical role
in drug reinforcement and reward (Wu and French, 2000). In the absence
of other abuse indicators, such as rewarding properties, the presence
of tolerance or physical dependence does not determine whether a drug
has abuse potential.
However, humans can develop tolerance to marijuana's
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981).
Tolerance to some of marijuana's behavioral effects seems to develop
after heavy marijuana use, but not after occasional marijuana use. For
instance, following acute administration of marijuana, heavy marijuana
users did not exhibit impairments in tracking and attention tasks, as
were seen in occasional marijuana users (Ramaekers et al., 2009).
Furthermore, a neurophysiological assessment administered through an
electroencephalograph (EEG) which measures event-related potentials
(ERP) conducted in the same subjects as the previous study, found a
corresponding effect in the P100 \26\ component of ERPs. Specifically,
corresponding to performance on tracking and attention tasks, heavy
marijuana users showed no changes in P100 amplitudes following acute
marijuana administration, although occasional users showed a decrease
in P100 amplitudes (Theunissen et al., 2012). A possible mechanism
underlying tolerance to marijuana's effects may be the down-regulation
of cannabinoid receptors (Hirvonen et al., 2012; Gonzalez et al., 2005;
Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993).
---------------------------------------------------------------------------
\26\ The P100 component of ERPs is thought to relate to the
visual processing of stimuli and can be modulated by attention.
---------------------------------------------------------------------------
Importantly, pharmacological tolerance alone does not indicate a
drug's physical dependence liability. In order for physical dependence
to exist, evidence of a withdrawal syndrome is needed. Physical
dependence is a state of adaptation, manifested by a drug-class
specific withdrawal syndrome produced by abrupt cessation, rapid dose
reduction, decreasing blood level of the drug, and/or administration of
an antagonist (ibid). Many medications not associated with abuse or
addiction can produce physical dependence and withdrawal symptoms after
chronic use.
Discontinuation of heavy, chronic marijuana use has been shown to
lead to physical dependence and withdrawal symptoms (American
Psychiatric Association DSM-V, 2013; Budney and Hughes, 2006; Haney et
al., 1999). In heavy, chronic marijuana users, the most commonly
reported withdrawal symptoms are sleep difficulties, decreased appetite
or weight loss, irritability, anger, anxiety or nervousness, and
restlessness. Some less commonly reported withdrawal symptoms are
depressed mood, sweating, shakiness, physical discomfort, and chills
(Budney and Hughes, 2006; Haney et al., 1999). The occurrence of
marijuana withdrawal symptoms in light or non-daily marijuana users has
not been established. The American Psychiatric Association's DSM-V
(2013) includes a list of symptoms of ``cannabis withdrawal.'' Most
marijuana withdrawal symptoms begin within 24-48 hours of
discontinuation, peak within 4-6 days, and last for 1-3 weeks.
Marijuana withdrawal syndrome has been reported in adolescents and
adults admitted for substance abuse treatment.
Based on clinical descriptions, this syndrome appears to be mild
compared to classical alcohol and barbiturate withdrawal syndromes,
which can include more serious symptoms such as agitation, paranoia,
and seizures. Multiple studies comparing marijuana and tobacco
withdrawal symptoms in humans demonstrate that the magnitude and time
course of the two withdrawal syndromes are similar (Budney et al.,
2008; Vandrey et al., 2005, 2008).
8. Whether the Substance is an Immediate Precursor of a Substance
Already Controlled Under This Article
Under the eight factor analysis, the Secretary must consider
whether marijuana is an immediate precursor of a controlled substance.
Marijuana is not an immediate precursor of another controlled
substance.
Recommendation
After consideration of the eight factors discussed above, FDA
recommends that marijuana remain in Schedule I of the CSA. NIDA concurs
with this scheduling recommendation.Marijuana meets the three criteria
for placing a substance in Schedule I of the CSA under 21 U.S.C.
812(b)(l):
(1) Marijuana has a high potential for abuse:
A number of factors indicate marijuana's high abuse potential,
including the large number of individuals regularly using marijuana,
marijuana's widespread use, and the vast amount of marijuana available
for illicit use. Approximately 18.9 million individuals in the United
States (7.3 percent of the U.S. population) used marijuana monthly in
2012. Additionally, approximately 4.3 million individuals met
diagnostic criteria for marijuana dependence or abuse in the year prior
to the 2012 NSDUH survey. A 2013 survey indicates that by 12th grade,
36.4 percent of students report using marijuana within the past year,
and 22.7 percent report using marijuana monthly. In 2011, 455,668 ED
visits were marijuana-related, representing 36.4 percent of all illicit
drug-related episodes. Primary marijuana use accounted for 18.1 percent
of admissions to drug treatment programs in 2011. Additionally,
marijuana has dose-dependent reinforcing effects, as demonstrated by
data showing that humans prefer relatively higher doses to lower doses.
Furthermore, marijuana use can result in psychological dependence.
(2) Marijuana has no currently accepted medical use in treatment in
the United States:
FDA has not approved a marketing application for a marijuana drug
product for any indication. The opportunity for scientists to conduct
clinical research with marijuana exists, and there are active INDs for
marijuana; however, marijuana does not have a currently accepted
medical use for treatment in the United States, nor does marijuana have
an accepted medical use with severe restrictions.
A drug has a ``currently accepted medical use'' if all of the
following five elements have been satisfied:
a. The drug's chemistry is known and reproducible;
b. there are adequate safety studies;
c. there are adequate and well-controlled studies proving efficacy;
d. the drug is accepted by qualified experts; and
e. the scientific evidence is widely available.
[[Page 53786]]
[57 FR 10499, March 26, 1992]
Marijuana does not meet any of the elements for having a
``currently accepted medical use.'' First, FDA broadly evaluated
marijuana, and did not focus its evaluation on particular strains of
marijuana or components or derivatives of marijuana. Since different
strains may have different chemical constituents, marijuana, as
identified in this petition, does not have a known and reproducible
chemistry, which would be needed to provide standardized doses. Second,
there are not adequate safety studies on marijuana in the medical
literature in relation to a specific, recognized disorder. Third, there
are no published adequate and well controlled studies proving efficacy
of marijuana. Fourth, there is no evidence that qualified experts
accept marijuana for use in treating a specific, recognized disorder.
Lastly, the scientific evidence regarding marijuana's chemistry in
terms of a specific Cannabis strain that could produce standardized and
reproducible doses is not currently available, so the scientific
evidence on marijuana is not widely available.
Alternately, a Schedule II drug can be considered to have a
``currently accepted medical use with severe restrictions'' (21 U.S.C.
812(b)(2)(B)). Yet as stated above, the lack of accepted medical use
for a specific, recognized disorder precludes the use of marijuana even
under conditions where its use is severely restricted.
In conclusion, to date, research on marijuana's medical use has not
developed to the point where marijuana is considered to have a
``currently accepted medical use'' or a ``currently accepted medical
use with severe restrictions.''
(3) There is a lack of accepted safety for use of marijuana under
medical supervision:
There are currently no FDA-approved marijuana drug products.
Marijuana does not have a currently accepted medical use in treatment
in the United States or a currently accepted medical use with severe
restrictions. Thus, FDA has not determined that marijuana is safe for
use under medical supervision.
In addition, FDA cannot conclude that marijuana has an acceptable
level of safety relative to its effectiveness in treating a specific,
recognized disorder without evidence that the substance is
contamination free, and assurance of a consistent and predictable dose.
Investigations into the medical use of marijuana should include
information and data regarding the chemistry, manufacturing, and
specifications of marijuana. Additionally, a procedure for delivering a
consistent dose of marijuana should also be developed. Therefore, FDA
concludes marijuana does not currently have an accepted level of safety
for use under medical supervision.
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The Medical Application of Marijuana: A Review of Published Clinical
Studies
March 19, 2015
Prepared by:
U.S. Food and Drug Administration
Center for Drug Evaluation and Research (FDA/CDER)
Controlled Substance Staff (CSS)
Table of Contents
1. Introduction.............................................. 71
2. Methods................................................... 73
2.1 Define the Objective of the Review................... 73
2.2 Define ``Marijuana''................................. 74
2.3 Define ``Adequate and Well-Controlled Clinical 74
Studies''...............................................
2.4 Search Medical Literature Databases and Identify 75
Relevant Studies........................................
2.5 Review and Analyze Qualifying Clinical Studies....... 77
3. Results and Discussion.................................... 77
3.1 Neuropathic Pain..................................... 77
3.1.1 Neuropathic Pain Associated with HIV-Sensory 77
Neuropathy..........................................
3.1.2 Central and Peripheral Neuropathic Pain........ 81
3.2 Appetite Stimulation in HIV.......................... 86
3.3 Spasticity in Multiple Sclerosis..................... 89
3.4 Asthma............................................... 90
3.5 Glaucoma............................................. 91
3.6 Conclusions.......................................... 91
3.6.1 Conclusions for Chronic Neuropathic Pain....... 92
3.6.2 Conclusions for Appetite Stimulation in HIV.... 92
3.6.3 Conclusions for Spasticity in MS............... 92
3.6.4 Conclusions for Asthma......................... 93
3.6.5 Conclusions for Glaucoma....................... 93
3.7 Design Challenges for Future Studies................. 93
3.7.1 Sample Size.................................... 93
3.7.2 Marijuana Dose Standardization................. 94
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use.... 96
3.7.4 Smoking as a Route of Administration........... 96
3.7.5 Difficulty in Blinding of Drug Conditions...... 96
3.7.6 Prior Marijuana Experience..................... 97
3.7.7 Inclusion and Exclusion Criteria............... 98
3.7.8 Number of Female Subjects...................... 99
Appendix (Tables)............................................ 103
List of Figure
Figure 1: Identification of Studies From PubMed Search....... 76
List of Tables
Table 1: Randomized, controlled, double-blind trials 103
examining smoked marijuana in treatment of neuropathic pain.
Table 2: Randomized, controlled, double-blind trials 109
examining smoked marijuana in treatment of appetite
stimulation in HIV/AIDS.....................................
Table 3: Randomized, controlled, double-blind trails 112
examining smoked marijuana in treatment of spasticity in
Multiple Sclerosis..........................................
Table 4: Randomized, controlled, double-blind trails 114
examining smoked marijuana in treatment of intraocular
pressure in Glaucoma........................................
Table 5: Randomized, controlled, double-blind trails 116
examining smoked marijuana in treatment of asthma...........
Executive Summary
Marijuana is a Schedule I substance under the Controlled Substances
Act (CSA). Schedule I indicates a high potential for abuse, no
currently accepted medical use in the United States, and a lack of
accepted safety for use under medical supervision. To date, marijuana
has not been subject to an approved new drug application (NDA) that
demonstrates its safety and efficacy for a specific indication under
the Food Drug and Cosmetic Act (FDCA).
Nevertheless, as of October 2014, twenty-three states and the
District of
[[Page 53792]]
Columbia have passed state-level medical marijuana laws that allow for
marijuana use within that state; similar bills are pending in other
states.
The present review was undertaken by the Food and Drug
Administration (FDA) to analyze the clinical studies published in the
medical literature investigating the use of marijuana in any
therapeutic areas. First, we discuss the context for this scientific
review. Next, we describe the methods used in this review to identify
adequate and well-controlled studies evaluating the safety and efficacy
of marijuana for particular therapeutic uses.
The FDA conducted a systematic search for published studies in the
medical literature that meet the described criteria for study design
and outcome measures prior to February 2013. While not part of our
systematic review, we have continued to routinely follow the literature
beyond that date for subsequent studies. Studies were considered to be
relevant to this review if the investigators administered marijuana to
patients with a diagnosed medical condition in a well-controlled,
double-blind, placebo-controlled clinical trial. Of the eleven studies
that met the criteria for review, five different therapeutic areas were
investigated:
Five studies examined chronic neuropathic pain
Two studies examined appetite stimulation in human
immunodeficiency virus (HIV) patients
Two studies examined glaucoma
One study examined spasticity and pain in multiple sclerosis
(MS)
One study examined asthma.
For each of these eleven clinical studies, information is provided
regarding the subjects studied, the drug conditions tested (including
dose and method of administration), other drugs used by subjects during
the study, the physiological and subjective measures collected, the
outcome of these measures comparing treatment with marijuana to
placebo, and the reported and observed adverse events. The conclusions
drawn by the investigators are then described, along with potential
limitations of these conclusions based on the study design. A brief
summary of each study's findings and limitations is provided at the end
of the section.
The eleven clinical studies that met the criteria and were
evaluated in this review showed positive signals that marijuana may
produce a desirable therapeutic outcome, under the specific
experimental conditions tested. Notably, it is beyond the scope of this
review to determine whether these data demonstrate that marijuana has a
currently accepted medical use in the United States. However, this
review concludes that these eleven clinical studies serve as proof-of-
concept studies, based on the limitations of their study designs, as
described in the study summaries. Proof-of-concept studies provide
preliminary evidence on a proposed hypothesis regarding a drug's
effect. For drugs under development, the effect often relates to a
short-term clinical outcome being investigated. Proof-of-concept
studies serve as the link between preclinical studies and dose ranging
clinical studies. Therefore, proof-of-concept studies are not
sufficient to demonstrate efficacy of a drug because they provide only
preliminary information about the effects of a drug. However, the
studies reviewed produced positive results, suggesting marijuana should
be further evaluated as an adjunct treatment for neuropathic pain,
appetite stimulation in HIV patients, and spasticity in MS patients.
The main limitations identified in the eleven studies testing the
medical applications of marijuana are listed below:
The small numbers of subjects enrolled in the studies,
which limits the statistical analyses of safety and efficacy.
The evaluation of marijuana only after acute
administration in the studies, which limits the ability to determine
efficacy following chronic administration.
The administration of marijuana typically through smoking,
which exposes ill patients to combusted material and introduces
problems with determining the doses delivered.
The potential for subjects to identify whether they
received marijuana or placebo, which breaks the blind of the studies.
The small number of cannabinoid na[iuml]ve subjects, which
limits the ability to determine safety and tolerability in these
subjects.
The low number of female subjects, which makes it
difficult to generalize the study findings to subjects of both genders.
Thus, this review discusses the following methodological changes
that may be made in order to resolve these limitations and improve the
design of future studies which examine the safety and efficacy of
marijuana for specific therapeutic indications:
Determine the appropriate number of subjects studied based
on recommendations in various FDA Guidances for Industry regarding the
conduct of clinical trials for specific medical indications.
Administer consistent and reproducible doses of marijuana
based on recommendations in the FDA Guidance for Industry: Botanical
Drug Products (2004).\27\
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\27\ This Guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
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Evaluate the effects of marijuana under therapeutic
conditions following both acute and chronic administration.
Consider alternatives to smoked marijuana (e.g.,
vaporization).
Address and improve whenever possible the difficulty in
blinding of marijuana and placebo treatments in clinical studies.
Evaluate the effect of prior experience with marijuana
with regard to the safety and tolerability of marijuana.
Strive for gender balance in the subjects used in studies.
In conclusion, the eleven clinical studies conducted to date do not
meet the criteria required by the FDA to determine if marijuana is safe
and effective in specific therapeutic areas. However, the studies can
serve as proof-of-concept studies and support further research into the
use of marijuana in these therapeutic indications. Additionally, the
clinical outcome data and adverse event profiles reported in these
published studies can beneficially inform how future research in this
area is conducted. Finally, application of the recommendations listed
above by investigators when designing future studies could greatly
improve the available clinical data that can be used to determine if
marijuana has validated and reliable medical applications.
1. Introduction
In response to citizen petitions submitted to the Drug Enforcement
Administration (DEA) requesting DEA to reschedule marijuana, the DEA
Administrator requested that the U.S. Department of Health and Human
Services (HHS) provide a scientific and medical evaluation of the
available information and a scheduling recommendation for marijuana, in
accordance with 21 U.S.C. 811(b). The Secretary of HHS is required to
consider in a scientific and medical evaluation eight factors
determinative of control under the Controlled Substance Act (CSA).
Administrative responsibilities for evaluating a substance for control
under the CSA are performed by the Food and Drug Administration (FDA),
with the concurrence of the National Institute on Drug Abuse (NIDA).
Part of
[[Page 53793]]
this evaluation includes an assessment of whether marijuana has a
currently accepted medical use in the United States. This assessment
necessitated a review of the available data from published clinical
studies to determine whether there is adequate scientific evidence of
marijuana's effectiveness.
Under Section 202 of the CSA, marijuana is currently controlled as
a Schedule I substance (21 U.S.C. 812). Schedule I includes those
substances that have a high potential for abuse, have no currently
accepted medical use in treatment in the United States, and lack
accepted safety for use under medical supervision (21 U.S.C.
812(b)(1)(A)-(C)).
A drug product which has been approved by FDA for marketing in the
United States is considered to have a ``currently accepted medical
use.'' Marijuana is not an FDA-approved drug product, as a New Drug
Application (NDA) or Biologics License application (BLA) for marijuana
has not been approved by FDA. However, FDA approval of an NDA is not
the only means through which a drug can have a currently accepted
medical use in the United States.
In general, a drug may have a ``currently accepted medical use'' in
the United States if the drug meets a five-part test. Established case
law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135
(D.C. Cir. 1994)) upheld the Administrator of DEA's application of the
five-part test to determine whether a drug has a ``currently accepted
medical use.'' The following describes the five elements that
characterize ``currently accepted medical use'' for a drug: \28\
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\28\ 57 FR 10499, 10504-06 (March 26, 1992).
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i. The drug's chemistry must be known and reproducible
``The substance's chemistry must be scientifically established to
permit it to be reproduced into dosages which can be standardized. The
listing of the substance in a current edition of one of the official
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic
Act, 21 U.S.C. 321(j), is sufficient to meet this requirement.''
ii. there must be adequate safety studies
``There must be adequate pharmacological and toxicological studies,
done by all methods reasonably applicable, on the basis of which it
could fairly and responsibly be concluded, by experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, that the substance is safe for treating a
specific, recognized disorder.''
iii. there must be adequate and well-controlled studies proving
efficacy
``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical
investigations, by experts qualified by scientific training and
experience to evaluate the safety and effectiveness of drugs, on the
basis of which it could be fairly and responsibly concluded by such
experts that the substance will have the intended effect in treating a
specific, recognized disorder.''
iv. the drug must be accepted by qualified experts
``The drug has a New Drug Application (NDA) approved by the Food
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act,
21 U.S.C. 355. Or, a consensus of the national community of experts,
qualified by scientific training and experience to evaluate the safety
and effectiveness of drugs, accepts the safety and effectiveness of the
substance for use in treating a specific, recognized disorder. A
material conflict of opinion among experts precludes a finding of
consensus.'' and
v. the scientific evidence must be widely available.
``In the absence of NDA approval, information concerning the
chemistry, pharmacology, toxicology, and effectiveness of the substance
must be reported, published, or otherwise widely available, in
sufficient detail to permit experts, qualified by scientific training
and experience to evaluate the safety and effectiveness of drugs, to
fairly and responsibly conclude the substance is safe and effective for
use in treating a specific, recognized disorder.''
One way to pass the five-part test for having ``currently accepted
medical use'' is through submission of an NDA or BLA which is approved
by FDA. However, FDA approval of an NDA or BLA is not required for a
drug to pass the five-part test.
This review focuses on FDA's analysis of one element of the five-
part test for determining whether a drug has ``currently accepted
medical use''. Specifically, the present review assesses the 3rd
criterion that addresses whether marijuana has ``adequate and well-
controlled studies proving efficacy''. Thus, this review evaluates
published clinical studies that have been conducted using marijuana in
subjects who have a variety of medical conditions by assessing the
adequacy of the summarized study designs and the study data. The
methodology for selecting the studies that were evaluated is delineated
below.
FDA's evaluation and conclusions regarding the remaining four
criteria for whether marijuana has a ``currently accepted medical
use,'' as well as the eight factors pertaining to the scheduling of
marijuana, are outside the scope of this review. A detailed discussion
of these factors is contained in FDA's scientific and medical
evaluation of marijuana.
2. Methods
The methods for selecting the studies to include in this review
involved the following steps, which are described in detail in the
subsections below:
1. Define the objective of the review.
2. Define ``marijuana'' in order to facilitate the medical
literature search for studies that administered the substance,
3. Define ``adequate and well-controlled studies'' in order to
facilitate the search for relevant data and literature,
4. Search medical literature databases and identify relevant
adequate and well-controlled studies, and
5. Review and analyze the adequate and well-controlled clinical
studies to determine if they demonstrate efficacy of marijuana for any
therapeutic indication.
2.1 Define the Objective of the Review
The objective of this review is to assess the study designs and
resulting data from clinical studies published in the medical
literature that were conducted with marijuana (as defined below) as a
treatment for any therapeutic indication, in order to determine if they
meet the criteria of ``adequate and well-controlled studies proving
efficacy''.
2.2 Define ``Marijuana''
In this review, the term ``marijuana'' refers to the flowering tops
or leaves of the Cannabis plant. There were no restrictions on the
route of administration used for marijuana in the studies.
Studies which administered individual cannabinoids (whether
experimental substances or marketed drug products) or marijuana
extracts were excluded from this review. Additionally, studies of
administered neutral plant material or placebo marijuana (marijuana
with all cannabinoids extracted) that had subsequently been
supplemented by the addition of specific amounts of THC or other
cannabinoids were also excluded (Chang et al., 1979).
[[Page 53794]]
2.3 Define ``Adequate and Well-Controlled Clinical Studies''
The criteria for an ``adequate and well-controlled study'' for
purposes of determining the safety and efficacy of a human drug is
defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126.
The elements of an adequate and well-controlled study as described in
21 CFR 314.126 can be summarized as follows:
1. The main objective must be to assess a therapeutically relevant
outcome.
2. The study must be placebo-controlled.
3. The subjects must qualify as having the medical condition being
studied.
4. The study design permits a valid comparison with an appropriate
control condition.
5. The assignment of subjects to treatment and control groups must
be randomized.
6. There is minimization of bias through the use of a double-blind
study design.
7. The study report contains a full protocol and primary data.
8. Analysis of the study data is appropriately conducted.
As noted above, the current review examines only those data
available in the public domain and thus relies on clinical studies
published in the medical literature. Published studies by their nature
are summaries that do not include the level of detail required by
studies submitted to FDA in an NDA.
While the majority of the elements defining an adequate and well-
controlled study can be satisfied through a published paper (elements
#1-6), there are two elements that cannot be met by a study published
in the medical literature: element #7 (availability of a study report
with full protocol and primary data) and element #8 (a determination of
whether the data analysis was appropriate). Thus, for purposes of this
review, only elements #1-6 will be used to qualify a study as being
adequate and well-controlled.
2.4 Search Medical Literature Databases and Identify Relevant Studies
We identified randomized, double-blind, placebo-controlled clinical
studies conducted with marijuana to assess marijuana's efficacy in any
therapeutic indication. Two primary medical literature databases were
searched for all studies posted to the databases prior to February
2013: \29\
---------------------------------------------------------------------------
\29\ While not a systematic review, we have followed the recent
published literature on marijuana use for possible therapeutic
purposes and, as of January 2015, we found only one new study that
would meet our criteria (Naftali et al., 2013). This study examined
the effects of smoked marijuana on Crohn's disease.
---------------------------------------------------------------------------
PubMed: PubMed is a database of published medical and
scientific studies that is maintained by the U.S. National Library of
Medicine (NLM) at NIH as a part of the Entrez system of information
retrieval. PubMed comprises more than 24 million citations for
biomedical literature from MEDLINE, life science journals, and online
books (http://www.ncbi.nlm.nih.gov/pubmed).
ClinicalTrials.gov: ClinicalTrials.gov is a database of
publicly and privately supported clinical studies that is maintained by
the NLM. Information about the clinical studies is provided by the
Sponsor or Principal Investigator of the study. Information about the
studies is submitted to the Web site (``registered'') when the studies
begin, and is updated throughout the study. In some cases, results of
the study or resulting publication citations are submitted to the Web
site after the study ends (https://clinicaltrials.gov/ct2/about-site/background).
ClinicalTrials.gov was searched for all studies administering
marijuana. The results of this search were used to confirm that no
completed studies with published data were missed in the literature
search. During the literature search, references found in relevant
studies and systematic reviews were evaluated for additional relevant
citations. All languages were included in the search. The PubMed search
yielded a total of 566 abstracts.\30\ Of these abstracts, a full-text
review was conducted with 85 papers to assess eligibility. From this
evaluation, only eleven of 85 studies met the 6 CFR elements for
inclusion as adequate and well-controlled studies.
---------------------------------------------------------------------------
\30\ The following search strategy was used, ``(cannabis OR
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized
controlled trial OR ``systematic review'' OR clinical trial OR
clinical trials) NOT (``marijuana abuse''[Mesh] OR addictive
behavior OR substance related disorders)''.
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Figure 1 (below) provides an overview of the process used to
identify studies from the PubMed search. The eleven studies reviewed
were published between 1974 and 2013. Ten of these studies were
conducted in the United States and one study was conducted in Canada.
These eleven studies examined the effects of smoked and vaporized
marijuana for the indications of chronic neuropathic pain, spasticity
related to multiple sclerosis (MS), appetite stimulation in patients
with human immunodeficiency virus (HIV), glaucoma, and asthma. All
included studies used adult patients as subjects. All studies conducted
in the United States were conducted under an IND as Phase 2
investigations.
[[Page 53795]]
[GRAPHIC] [TIFF OMITTED] TP12AU16.025
Two qualifying studies, which assessed marijuana for glaucoma, were
previously reviewed in the 1999 Institute of Medicine (IOM) report
entitled ``Marijuana and Medicine: Assessing the Science Base''.\31\ We
did our own analysis of these two studies and concurred with the
conclusions in the IOM report. Thus, a detailed discussion of the two
glaucoma studies is not included in the present review. The present
review only discusses 9 of the identified 11 studies. For a summary of
the study design for all eleven qualifying studies, see Tables 1-5
(located in the Appendix).
---------------------------------------------------------------------------
\31\ In January 1997, the White House Office of National Drug
Control Policy (ONDCP) requested that the IOM conduct a review of
the scientific evidence to assess the potential health benefits and
risks of marijuana and its constituent cannabinoids. Information for
this study was gathered through scientific workshops, site visits to
cannabis buyers' clubs and HIV/Acquired Immunodeficiency Syndrome
(AIDS) clinics, analysis of the relevant scientific literature, and
extensive consultation with biomedical and social scientists. The
report was finalized and published in 1999.
---------------------------------------------------------------------------
Based on the selection criteria for relevant studies described in
Section 2.3 (Define Adequate and Well-Controlled Clinical Studies), a
number of clinical studies that investigated marijuana, as defined in
this review, were excluded from this review. Studies that examined the
effects of marijuana in healthy subjects were excluded because they did
not test a patient population with a medical condition (Flom et al.,
1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al., 1974;
Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001;
Wallace et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by
Tashkin et al. was excluded because it had a single-blind, rather than
double-blind, study design. Two other studies were excluded because the
primary outcome measure assessed safety rather than a therapeutic
outcome (Greenberg et al., 1994; Abrams et al., 2003).
2.5 Review and Analyze Qualifying Clinical Studies
Qualified clinical studies that evaluated marijuana for therapeutic
purposes were examined in terms of adequacy of study design including
method of drug administration, study size, and subject inclusion and
exclusion criteria. Additionally, the measures and methods of analysis
used in the studies to assess the treatment effect were examined.
3. Results and Discussion
The eleven qualifying studies in this review assessed a variety of
therapeutic indications. In order to better facilitate analysis and
discussion of the studies, the following sections group the studies by
therapeutic area. Within each section, each individual study is
summarized in terms of its design, outcome data and important
limitations. This information is also provided in the Appendix in
tabular form for each study.
3.1 Neuropathic Pain
Five randomized, double-blind, placebo-controlled Phase 2 clinical
studies have been conducted to examine the effects of inhaled marijuana
smoke on neuropathic pain associated with HIV-sensory neuropathy
(Abrams et al., 2007; Ellis et al., 2009) and chronic neuropathic pain
from multiple causes
[[Page 53796]]
(Wilsey et al., 2008; Ware et al., 2010; Wilsey et al., 2013). Table 1
of the Appendix summarizes these studies.
3.1.1 Neuropathic Pain Associated With HIV-Sensory Neuropathy
Two studies examined the effect of marijuana to reduce the pain
induced by HIV-sensory neuropathy.
Abrams et al. (2007) conducted the first study entitled, ``Cannabis
in painful HIV-associated sensory neuropathy: A randomized placebo-
controlled trial''. The subjects were 50 adult patients with
uncontrolled HIV-associated sensory neuropathy, who had at least 6
experiences with smoking marijuana. The subjects were split into two
parallel groups of 25 subjects each. More than 68% of subjects were
current marijuana users, but all individuals were required to
discontinue using marijuana prior to the study. Most subjects were
taking medication for pain during the study, with the most common
medications being opioids and gabapentin. Upon entry into the study,
subjects had an average daily pain score of at least 30 on a 0-100
visual analog scale (VAS).
Subjects were randomized to receive either smoked marijuana (3.56%
THC \32\) or smoked placebo cigarettes three times per day for 5 days,
using a standardized cued smoking procedure: (1) 5 second inhale, (2)
10 second holding smoke in the lungs, (3) 40 second exhale and
breathing normally between puffs. The authors did not specify how many
puffs the subjects smoked at each smoking session, but they stated that
one cigarette was smoked per smoking session.
---------------------------------------------------------------------------
\32\ The drug dose is reported as percentage of THC present in
the marijuana rather than milligrams of THC present in each
cigarette because of the difficulty in determining the amount of THC
delivered by inhalation (see discussion in the section entitled
``3.7.2 Marijuana Dose Standardization'').
---------------------------------------------------------------------------
Primary outcome measures included daily VAS ratings of chronic pain
and the percentage of subjects who reported a result of more than 30%
reduction in pain intensity. The ability of smoked marijuana to induce
acute analgesia was assessed using both thermal heat model and
capsaicin sensitization model, while anti-hyperalgesia was assessed
with brush and von Frey hair stimuli. The immediate analgesic effects
of smoked marijuana was assessed using a 0-100 point VAS at 40-minute
intervals three times before and three times after the first and last
smoking sessions, which was done to correspond to the time of peak
plasma cannabinoid levels. Notably, not all subjects completed the
induced pain portion of the study (n = 11 in marijuana group, 9 in
placebo group) because of their inability to tolerate the stimuli.
Throughout the study, subjects also completed the Profile of Mood
States (POMS) questionnaire, as well as subjective VAS measures of
anxiety, sedation, disorientation, paranoia, confusion, dizziness, and
nausea.
As a result, the median daily pain was reduced 34% by smoked
marijuana compared to 17% by placebo (p = 0.03). Fifty-two percent of
subjects who smoked marijuana reported a >30% reduction in pain
compared to 24% in the placebo group (p = 0.04). Although marijuana
reduced experimentally-induced hyperalgesia (p <= 0.05) during the
first smoking sessions, marijuana did not alter responses to acutely
painful stimuli.
There were no serious AEs and no episodes of hypertension,
hypotension, or tachycardia requiring medical intervention. No subjects
withdrew from the study for drug related reasons. Subjects in the
marijuana group reported higher ratings on the subjective measures of
anxiety, sedation, disorientation, confusion, and dizziness compared to
the placebo group. There was one case of severe dizziness in a
marijuana-treated subject. By the end of the study, subjects treated
with marijuana and placebo reported a reduction in total mood
disturbance as measured by POMS.
The authors conclude that smoked marijuana effectively reduced
chronic neuropathic pain from HIV-associated sensory neuropathy with
tolerable side effects. However, limitations of this study include:
Maintenance of subjects on other analgesic medication while being
tested with marijuana and a lack of information about the number of
puffs during each inhalation of smoke. These limitations make it
difficult to conclude that marijuana has analgesic properties on its
own and that the actual AEs experienced during the study in response to
marijuana are tolerable. However, the study produced positive results
suggesting that marijuana should be studied further as an adjunct
treatment for uncontrolled HIV-associated sensory neuropathy.
Ellis et al. (2009) conducted a more recent study entitled ``Smoked
medicinal cannabis for neuropathic pain in HIV: a randomized, crossover
clinical trial''. The subjects were 28 HIV-positive adult male patients
with intractable neuropathic pain that was refractory to the effects of
at least two drugs taken for analgesic purposes. Upon entry into the
study, subjects had a mean score of >5 on the Pain Intensity subscale
of the Descriptor Differential Scale (DDS). Subjects were allowed to
continue taking their current routine of pain medications, which
included opioids, non-narcotic analgesics, antidepressants, and
anticonvulsants. Previous experience with marijuana was not required
for participation in the study, but 27 of 28 subjects (96%) reported
previous experience with marijuana. However, of these 27 experienced
subjects, 63% (n = 18) reported no marijuana use within the past year.
The study procedures compared the effects of the target dose of
marijuana and placebo during two treatment periods lasting 5 days, with
2 weeks washout periods. The marijuana strengths available were 1%, 2%,
4%, 6%, or 8% THC concentration by weight. Subjects smoked marijuana or
placebo cigarettes four times per day, approximately 90-120 minutes
apart, using a standardized cued smoking procedure: (1) 5 second smoke
inhalation, (2) 10 second hold of smoke in lungs, (3) 40 second exhale
and normal breathing between puffs. The investigators did not provide a
description of the number of puffs taken at any smoking session. All
subjects practiced the smoking procedures using placebo marijuana prior
to test sessions.
On the first day of each test period, dose titration occurred
throughout the four smoking sessions scheduled for that day, with a
starting strength of 4% THC concentration. Subjects were allowed to
titrate to a personalized ``target dose'', which was defined as the
dose that provided the best pain relief without intolerable adverse
effects. This dose titration was accomplished by allowing subjects to
either increase the dose incrementally (to 6% or 8% THC) to improve
analgesia, or to decrease the dose incrementally (to 1% or 2% THC) if
AEs were intolerable. For the next 4 days of each test period, the
subjects smoked their target dose during each of the four daily smoking
sessions. To maintain the blind, placebo marijuana was represented as
containing 1%-8% THC, even though it did not contain any cannabinoids.
The primary outcome measure was the change in pain magnitude on the
DDS at the end of each test period compared to baseline, with a
clinically significant level of analgesia considered to be a reduction
in pain of at least 30%. Additional measures included the POMS, the
Sickness Impact Profile (SIP), the Brief Symptom Inventory (BSI) and
the UKU Side Effect Rating Scale and a subjective highness/sedation
VAS.
During the marijuana treatment week, 19 subjects titrated to the
2%-4% THC dose while the 6%-8% dose was
[[Page 53797]]
preferred by 8 subjects and 1 subject chose the 1% dose. In contrast,
during the placebo treatment week, all 28 subjects titrated to the
highest possible dose of ``8% THC'' that contained no actual
cannabinoids, suggesting that placebo treatment provided little
analgesic relief.
The degree of pain reduction was significantly greater after
administration of marijuana compared to placebo (median change of 3.3
points on DDS, p = 0.016). The median change from baseline in VAS pain
scores was -17 for marijuana treatment compared to -4 for placebo
treatment (p < 0.001). A larger proportion of subjects who were treated
with marijuana (0.46) reported a >30% reduction in pain, compared to
placebo (0.18). Additionally, the authors report improvements in total
mood disturbance, physical disability, and quality of life as measured
on POMS, SIP, and BSI scales after both placebo and marijuana treatment
(data not provided in paper).
In terms of safety, there were no alterations in HIV disease
parameters in response to marijuana or placebo. The authors report that
marijuana led to a greater degree of UKU responses as well as AEs such
as difficulty in concentration, fatigue, sleepiness or sedation,
increased duration of sleep, reduced salivation and thirst compared to
placebo (data not provided in paper). Two subjects withdrew from the
study because of marijuana-related AEs: one subject developed an
intractable smoking-related cough during marijuana administration and
the sole marijuana-na[iuml]ve subject in the study experienced an
incident of acute cannabis-induced psychosis.\33\
---------------------------------------------------------------------------
\33\ At the time of the study, the following criteria from the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR,
2000) were used to diagnose substance-induced psychotic disorders:
Prominent hallucinations or delusions; Hallucinations and/or
delusions that develop during, or within one month of, intoxication
or withdrawal; The disturbance is not better accounted for by a
psychotic disorder that is not substance induced. The disturbance
does not occur exclusively during the course of a delirium.
---------------------------------------------------------------------------
The authors conclude that smoked marijuana effectively reduced
chronic neuropathic pain from HIV-associated sensory neuropathy. The
limitations of this study include: a lack of information about the
number of puffs during each inhalation of smoke; a lack of information
about the specific timing of the subjective assessments and collection
of AEs relative to initiation of the smoking sessions; and the
inclusion of only one marijuana-na[iuml]ve subject. These limitations
make it difficult to conclude that the actual AEs experienced during
the study in response to marijuana are tolerable. It is especially
concerning that the only marijuana-na[iuml]ve subject left the study
because of serious psychiatric responses to marijuana exposure at
analgesic doses. However, the study produced positive results
suggesting that marijuana should be studied further as an adjunct
treatment for uncontrolled HIV-associated sensory neuropathy.
3.1.2 Central and Peripheral Neuropathic Pain
Three studies examined the effect of marijuana on chronic
neuropathic pain.
Wilsey et al. (2008) examined chronic neuropathic pain from
multiple causes in the study entitled, ``A Randomized, Placebo-
Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic
Pain''. The subjects were 32 patients with a variety of neuropathic
pain conditions, including 22 with complex regional pain syndrome, 6
with spinal cord injury, 4 with multiple sclerosis, 3 with diabetic
neuropathy, 2 with ilioinguinal neuralgia, and 1 with lumbosacral
plexopathy. All subjects reported a pain intensity of at least 30 on a
0-100 VAS and were allowed to continue taking their regular medications
during the study period, which included opioids, antidepressants,
anticonvulsants, and NSAIDs. All subjects were required to have
experience with marijuana but could not use any cannabinoids for 30
days before study sessions.
The study consisted of three test sessions with an interval of 3-21
days between sessions. Treatment conditions were high-strength
marijuana (7% delta-9-THC), low-strength marijuana (3.5% delta-9-THC),
and placebo cigarettes, administered through a standardized cued-puff
procedure: (1) ``light the cigarette'' (30 seconds), (2) ``get ready''
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold smoke in lungs''
(10 seconds), (5) ``exhale,'' and (6) wait before repeating the puff
cycle (40 seconds). Participants took 2 puffs after baseline
measurements, 3 puffs an hour later, and 4 puffs an hour after that,
for a cumulative dose of 9 puffs per test session.
Hourly assessment periods were scheduled before and after each set
of puffs and for 2 additional hours during the recovery period. Plasma
cannabinoids were measured at baseline, 5 minutes after the first puff
and again at 3 hours after the last puff cycle.
The primary outcome measure was spontaneous pain relief, as
measured by a 0-100 point VAS for current pain. Pain unpleasantness was
measured on a 0-100 point VAS, and degree of pain relief was measured
on a 7-point Patient Global Impression of Change (PGIC) scale.
Secondary measures included the Neuropathic Pain Scale (NPS), a 0-100
point VAS for allodynia, and changes in thermal pain threshold.
Subjective measures were also evaluated with unipolar 0-100 point VAS
for any drug effect, good drug effect, bad drug effect, high, drunk,
impaired, stoned, like the drug effect, sedated, confused, nauseated,
desire more of the drug, anxious, down, hungry, and bipolar 0-100 point
VAS for sad/happy, anxious/relaxed, jittery/calm, bad/good, paranoid/
self-assured, fearful/unafraid. Neurocognitive assessments measured
attention and concentration, learning and memory, and fine motor speed.
Marijuana produced a reduction in pain compared to placebo, as
measured by the pain VAS, the PGIC and on pain descriptors in the NPS,
including sharp (P < .001), burning (P < .001), aching (P < .001),
sensitive (P = .03), superficial (P < .01) and deep pain (P < .001).
Notably, there were no additional benefits from the 7% THC strength of
marijuana compared to the 3.5% THC strength, seemingly because of
cumulative drug effects over time. There were no changes in allodynia
or thermal pain responsivity following administration of either dose of
marijuana.
Marijuana at both strengths produced increases on measures of any
drug effect, good drug effect, high, stoned, impairment, sedation,
confusion, and hunger. The 7% THC marijuana increased anxiety scores
and bad drug effect (later in session) compared to placebo. Neither
strength of marijuana affected the measures of mood. On neurocognitive
measures, both the 3.5% THC and 7% THC marijuana produced impairment in
learning and memory, while only the 7% THC marijuana impaired attention
and psychomotor speed, compared to placebo. There were no adverse
cardiovascular side effects and no subjects dropped out because of an
adverse event related to marijuana.
The authors conclude that marijuana may be effective at
ameliorating neuropathic pain at doses that induce mild cognitive
effects, but that smoking is not an optimum route of administration.
The limitations of this study include: Inclusion of subjects with many
forms of neuropathic pain and maintenance of subjects on other
analgesic medication while being tested with marijuana. These
limitations make it difficult to conclude that marijuana has analgesic
properties on its own and that the actual AEs experienced during the
study in response to marijuana are tolerable. The authors compared pain
score results by the type of pain
[[Page 53798]]
condition, with no significant differences found; however, the sample
size of this study was small thus a type II error may have been
present. Thus, it is difficult to determine if any particular subset of
neuropathic pain conditions would benefit specifically from marijuana
administration. However, the study produced positive results suggesting
that marijuana should be studied further as an adjunct treatment for
uncontrolled neuropathic pain.
The second study, conducted by Ware et al. (2010) in Canada is
entitled, ``Smoked cannabis for chronic neuropathic pain: a randomized
controlled trial''. The subjects were 21 adult patients with
neuropathic pain caused by trauma or surgery compounded with allodynia
or hyperalgesia, and a pain intensity score greater than 4 on a 10
point VAS. All subjects maintained their current analgesic medication
and they were allowed to use acetaminophen for breakthrough pain.
Eighteen subjects had previous experience with marijuana but none of
them had used marijuana within a year before the study.
The study design used a four-period crossover design, testing
marijuana (2.5%, 6.0% and 9.4% THC) and placebo marijuana. The 2.5% and
6.0% doses of marijuana were included to increase successful blinding.
Each period was 14 days in duration, beginning with 5 days on the study
drug followed by a 9-day washout period. Doses were delivered as 25 mg
of marijuana that was smoked in a single inhalation using a titanium
pipe. The first dose of each period was self-administered using a
standardized puff procedure: (1) Inhale for 5 seconds, (2) hold the
smoke in their lungs for 10 seconds, and (3) exhale. Subsequent doses
were self-administered in the same manner for a total of three times
daily at home on an outpatient basis for the first five days of each
period.
The primary measure was an 11-point pain intensity scale, averaged
over the 5 day treatment period, which was administered once daily for
present, worst, least and average pain intensity during the previous 24
hours. Secondary measures included an acute pain 0-100 point VAS, pain
quality assessed with the McGill Pain Questionnaire, sleep assessed
with the Leeds Sleep Evaluation Questionnaire, mood assessed with the
POMS, quality of life assessed using the EQ-5D health outcome
instrument. Subjective measures included 0-100 point VAS scales for
high, relaxed, stressed and happy.
Over the first three hours after smoking marijuana, ratings of
pain, high, relaxation, stress, happiness and heart rate were recorded.
During the five days of each study period, participants were contacted
daily to administer questionnaires on pain intensity, sleep, medication
and AEs. Subjects returned on the fifth day to complete questionnaires
on pain quality, mood, quality of life and assessments of potency. At
the end of the study, participants completed final adverse event
reports and potency assessments.
The average daily pain intensity was significantly lower on 9.4%
THC marijuana (5.4) than on placebo marijuana (6.1) (p = 0.023). The
9.4% THC strength also produced more drowsiness, better sleep, with
less anxiety and depression, compared to placebo (all p < 0.05).
However, there were no significant differences on POMS scores or on VAS
scores for high, happy, relaxed or stressed between THC doses.
The most frequent drug-related adverse events reported in the group
receiving 9.4% THC marijuana were headache, dry eyes, burning
sensation, dizziness, numbness and cough. Reports of high and euphoria
occurred on only three occasions, once in each dose of THC. There were
no significant changes in vital signs, heart-rate variability, or renal
function. One subject withdrew from the study due to increased pain
during administration of 6% THC marijuana.
The authors conclude that smoked marijuana reduces neuropathic
pain, improves mood and aids in sleep, but that smoking marijuana is
not a preferable route of administration. The limitations of this study
include: The lack of information on timing of assessments during the
outpatient portion of the study and maintenance of subjects on other
analgesic medication while being tested with marijuana. These
limitations make it difficult to conclude that marijuana has analgesic
properties on its own and that the actual AEs experienced during the
study in response to marijuana are tolerable. However, the study
produced positive results suggesting that marijuana should be studied
further as an adjunct treatment for uncontrolled neuropathic pain.
Wilsey et al. (2013) conducted the most recent study entitled,
``Low-Dose Vaporized Cannabis Significantly Improves Neuropathic
Pain''. This study is the only one in this review that utilized
vaporization as a method of marijuana administration. The subjects were
36 patients with a neuropathic pain disorder (CRPS, thalamic pain,
spinal cord injury, peripheral neuropathy, radiculopathy, or nerve
injury) who were maintained on their current medications (opioids,
anticonvulsants, antidepressants, and NSAIDs). Although subjects were
required to have a history of marijuana use, they refrained from use of
cannabinoids for 30 days before study sessions.
Subjects participated in three sessions in which they received
1.29% or 3.53% THC marijuana or placebo marijuana. The marijuana was
vaporized using the Volcano vaporizer and a standardized cued-puff
procedure: (1) ``hold the vaporizer bag with one hand and put the
vaporizer mouthpiece in their mouth'' (30 seconds), (2) ``get ready''
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold vapor in lungs''
(10 seconds), (5) ``exhale and wait'' before repeating puff cycle (40
seconds). Subjects inhaled 4 puffs at 60 minutes. At 180 minutes, the
vaporizer was refilled with marijuana vapor and subjects were allowed
to inhale 4 to 8 puffs using the cued procedure. Thus, cumulative
dosing allowed for a range of 8 to12 puffs in total for each session,
depending on the subjects desired response and tolerance. The washout
time between each session ranged from 3-14 days.
The primary outcome variable was spontaneous pain relief, as
assessed using a 0-100 point VAS for current pain. Secondary measures
included the Patient Global Impression of Change (PGIC), the
Neuropathic Pain Scale (NPS), a 0-100 point VAS for allodynia. Acute
pain threshold was measured with a thermal pain model. Subjective
measures included 0-100 point unipolar VAS for any drug effect, good
drug effect, bad drug effect, high, drunk, impaired, stoned, drug
liking, sedated, confused, nauseated, desire more drug, anxious, down
and hungry. Bipolar 0-100 point VAS included sad/happy, anxious/
relaxed, jittery/calm, bad/good, paranoid/self-assured, and fearful/
unafraid.
Neurocognitive assessments assessed attention and concentration,
learning and memory, and fine motor speed.
A 30% reduction in pain was achieved in 61% of subjects who
received the 3.53% THC marijuana, in 57% of subjects who received the
1.29% THC marijuana and in 26% of subjects who received the placebo
marijuana (p = 0.002 for placebo vs. 3.53% THC, p = 0.007 for placebo
vs 1.29% THC; p > 0.05 1.29% THC vs. 3.53% THC). Both strengths of
marijuana significantly decreased pain intensity, unpleasantness,
sharpness, and deepness on the NPS, as well as pain ratings on the
PGIC, compared to placebo. These effects on pain were maximal with
cumulative dosing over
[[Page 53799]]
the course of the study session, with maximal effects at 180 minutes.
There were no effects of marijuana compared to placebo on measures of
allodynia or thermal pain. Subjects correctly identified the study
treatment 63% of the time for placebo, 61% of the time for 1.29% THC,
and 89% of the time for 3.53% THC.
On subjective measures, marijuana produced dose-dependent increases
compared to placebo on ratings for: any drug effect, good drug effect,
drug liking, high, stoned, sedated, confused, and hungry. Both
strengths of marijuana produced similar increases in drunk or impaired
compared to placebo. In contrast, desire for drug was rated as higher
for the 1.29% THC marijuana compared to the 3.53% THC marijuana. There
were no changes compared to placebo for bad effect, nauseous, anxiety,
feeling down or any of the bipolar mood assessments. There was dose-
dependent impairment on learning and memory from marijuana compared to
placebo, but similar effects between the two strengths of marijuana on
attention.
The authors conclude that vaporization of relatively low doses of
marijuana can produce improvements in analgesia in neuropathic pain
patients, especially when patients are allowed to titrate their
exposure. However, this individualization of doses may account for the
general lack of difference between the two strengths of marijuana. No
data were presented regarding the total amount of THC consumed by each
subject, so it is difficult to determine a proper dose-response
evaluation. Additional limitations of this study are the inclusion of
subjects with many forms of neuropathic pain and maintenance of
subjects on other analgesic medication while being tested with
marijuana. These limitations make it difficult to conclude that
marijuana has analgesic properties on its own. It is also difficult to
determine if any particular subset of neuropathic pain conditions would
benefit specifically from marijuana administration. However, the study
produced positive results suggesting that marijuana should be studied
further as an adjunct treatment for uncontrolled neuropathic pain.
3.2 Appetite Stimulation in HIV
Two randomized, double-blind, placebo-controlled Phase 2 studies
examined the effects of smoked marijuana on appetite in HIV-positive
subjects (Haney et al., 2005; Haney et al., 2007). Table 2 of the
Appendix summarizes both studies.
The first study, conducted by Haney et al. (2005) is entitled,
``Dronabinol and marijuana in HIV+ marijuana smokers: Acute effects on
caloric intake and mood''. The subjects were 30 HIV-positive patients
who were maintained on two antiretroviral medications and either had
clinically significant decreases in lean muscle mass \34\ (low-BIA
group, n = 15) or normal lean muscle mass (normal-BIA group, n = 15).
All subjects had a history of smoking marijuana at least twice weekly
for 4 weeks prior to entry into the study. On average, individuals had
smoked 3 marijuana cigarettes per day, 5-6 times per week for 10-12
years.
---------------------------------------------------------------------------
\34\ Lean muscle mass was assessed using bioelectrical impedance
analysis (BIA). The low-BIA group was classified with having <90%
BIA, and the normal-BIA group was classified with having >90% BIA.
---------------------------------------------------------------------------
Subjects participated in 8 sessions that tested the acute effects
of 0, 10, 20, and 30 mg dronabinol oral capsules and marijuana
cigarettes with 0%, 1.8%, 2.8%, and 3.9% THC concentration by weight,
using a double-dummy design (with only one active drug per session).
The doses of dronabinol are higher than those doses typically
prescribed for appetite stimulation in order to help preserve the
blinding. There was a one-day washout period between test sessions.
Marijuana was administered using a standardized cued procedure: (1)
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3)
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a
40-second interval between each puff.
Caloric intake was used as a surrogate measure for weight gain.
Subjects received a box containing a variety of food and beverage items
and were told to record consumption of these items following that day's
administration of the test drug. Subjective measures included 0-100
point VAS for feel drug effect, good effect, bad effect, take drug
again, drug liking, hungry, full, nauseated, thirsty, desire to eat.
Neurocognitive measures and vital signs were monitored.
The low BIA group consumed significantly more calories in the 1.8%
and 3.9% THC marijuana conditions (p<0.01) and the 10, 20, and 30 mg
dronabinol conditions (p<0.01) compared with the placebo condition. In
contrast, in the normal BIA group, neither marijuana nor dronabinol
significantly affected caloric intake. This lack of effect may be
accountable, however, by the fact that this group consumed
approximately 200 calories more than the low BIA group under baseline
conditions.
Ratings of high and good drug effect were increased by all drug
treatments in both the low-BIA and normal-BIA groups, except in
response to the 10 mg dose of dronabinol. The 3.9% THC marijuana
increased ratings of good drug effect, drug liking and desire to smoke
again compared with placebo. Ratings of sedation were increased in both
groups by 10 and 30 mg dronabinol, and in the normal BIA group by the
2.8% THC marijuana. Ratings of stimulation were increased in the normal
BIA group by 2.8% and 3.9% THC marijuana and by 20 mg dronabinol.
Increases in ratings of forgetfulness, withdrawn, dreaming, clumsy,
heavy limbs, heart pounding, jittery, and decreases in ratings of
energetic, social, and talkative were reported in the normal BIA group
with 30 mg dronabinol. There were no significant changes in vital signs
or performance on neurocognitive measures in response to marijuana.
Notably, the time course of subjective effects peaked quickly and
declined thereafter for smoked marijuana, while oral dronabinol
responses took longer to peak and persisted longer. Additionally,
marijuana but not dronabinol produced dry mouth and thirst.
In general, AEs reported in this study were low in both drug
conditions for both subject groups. In the low BIA group, nausea was
reported by one subject in both the 10 and 20 mg dronabinol conditions,
while an uncomfortable level of intoxication was produced by the 30 mg
dose in two subjects. There were no AEs reported in this group
following marijuana at any dose. In the normal BIA group, the 30 mg
dose of dronabinol produced an uncomfortable level of intoxication in
three subjects and headache in one subject, while the 3.9% marijuana
produced diarrhea in one subject.
The authors conclude that smoked marijuana can acutely increase
caloric intake in low BIA subjects without significant cognitive
impairment. However, it is possible that the low degree of cognitive
impairment reported in this study may reflect the development of
tolerance to cannabinoids in this patient population, since all
individuals had current histories of chronic marijuana use. Additional
limitations in this study include not utilizing actual weight gain as a
primary measure. However, the study produced positive results
suggesting that marijuana should be studied further as a treatment for
appetite stimulation in HIV patients.
[[Page 53800]]
A second study conducted by Haney et al. (2007) is entitled,
``Dronabinol and marijuana in HIV-positive marijuana smokers: Caloric
intake, mood, and sleep''. The design of this study was nearly
identical to the one conducted by this laboratory in 2005 (see above),
but there was no stratification of subjects by BIA. The subjects were
10 HIV-positive patients who were maintained on two antiretroviral
medications and had a history of smoking marijuana at least twice
weekly for 4 weeks prior to entry into the study. On average,
individuals had smoked 3 marijuana cigarettes per day, 5 times per week
for 19 years.
Subjects participated in 8 sessions that tested the acute effects
of 0, 5 and 10 mg dronabinol oral capsules and marijuana cigarettes
with 0, 2.0% and 3.9% THC concentration by weight, using a double-dummy
design (with 4 sessions involving only one active drug and 4
interspersed placebo sessions). Both drug and placebo sessions lasted
for 4 days each, with active drug administration occurring 4 times per
day (every 4 hours). Testing occurred in two 16-day inpatient stays. In
the intervening outpatient period, subjects were allowed to smoke
marijuana prior to re-entry to the study unit for the second inpatient
stay.
Marijuana was administered using a standardized cued procedure: (1)
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3)
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a
40-second interval between each puff.
Caloric intake was used as a surrogate measure for weight gain, but
subjects were also weighed throughout the study (a measure which was
not collected in the 2005 study by this group). Subjects received a box
containing a variety of food and beverage items and were told to record
consumption of these items following that day's administration of the
test drug. Subjective measures included 0-100 point VAS for drug
effect, good effect, bad effect, take drug again, drug liking, hungry,
full, nauseated, thirsty, desire to eat. Neurocognitive measures and
vital signs were monitored. Sleep was assessed using both the Nightcap
sleep monitoring system and selected VAS measures related to sleep.
Both 5 and 10 mg dronabinol (p < 0.008) and 2.0% and 3.9% THC
marijuana (p < 0.01) dose-dependently increased caloric intake compared
with placebo. This increase was generally accomplished through
increases in incidents of eating, rather than an increase in the
calories consumed in each incident. Subjects also gained similar
amounts of weight after the highest dose of each cannabinoid treatment:
1.2 kg (2.6 lbs) after 4 days of 10 mg dronabinol, and 1.1 kg (2.4 lbs)
after 4 days of 3.9% THC marijuana. The 3.9% THC marijuana dose also
increased the desire to eat and ratings of hunger.
Ratings of good drug effect, high, drug liking, and desire to smoke
again were significantly increased by 10 mg dronabinol and 2.0% and
3.9% THC marijuana doses compared to placebo. Both marijuana doses
increased ratings of stimulated, friendly, and self-confident. The 10
mg dose of dronabinol increased ratings of concentration impairment,
and the 2.0% THC marijuana dose increased ratings of anxious. Dry mouth
was induced by 10 mg dronabinol (10 mg) and 2.0% THC marijuana. There
were no changes in neurocognitive performance or objective sleep
measures from administration of either cannabinoid. However, 3.9% THC
marijuana increased subjective ratings of sleep.
The authors conclude that both dronabinol and smoked marijuana
increase caloric intake and produce weight gain in HIV-positive
patients. However, it is possible that the low degree of cognitive
impairment reported in this study may reflect the development of
tolerance to cannabinoids in this subject population, since all
individuals had current histories of chronic marijuana use. This study
produced positive results suggesting that marijuana should be studied
further as a treatment for appetite stimulation in HIV patients.
3.3 Spasticity in Multiple Sclerosis
Only one randomized, double-blind, placebo-controlled Phase 2 study
examined the effects of smoked marijuana on spasticity in MS.
This study was conducted by Corey-Bloom et al. (2012) and is
entitled, ``Smoked cannabis for spasticity in multiple sclerosis: a
randomized, placebo-controlled trial''. The subjects were 30 patients
with MS-associated spasticity and had moderate increase in tone (score
>= 3 points on the modified Ashworth scale). Participants were allowed
to continue other MS medications, with the exception of
benzodiazepines. Eighty percent of subjects had a history of marijuana
use and 33% had used marijuana within the previous year.
Subjects participated in two 3-day test sessions, with an 11 day
washout period. During each test session they smoked a 4.0% THC
marijuana cigarette once per day or a placebo cigarette once per day.
Smoking occurred through a standardized cued-puff procedure: (1)
Inhalation for 5 seconds, (2) breath-hold and exhalation for 10
seconds, (3) pause between puffs for 45 seconds. Subjects completed an
average of four puffs per cigarette.
The primary outcome measure was change in spasticity on the
modified Ashworth scale. Additionally, subjects were assessed using a
VAS for pain, a timed walk, and cognitive tests (Paced Auditory Serial
Addition Test) and AEs.
Treatment with 4.0% THC marijuana reduced subject scores on the
modified Ashworth scale by an average of 2.74 points more than placebo
(p <0.0001) and reduced VAS pain scores compared to placebo (p =
0.008). Scores on the cognitive measure decreased by 8.7 points more
than placebo (p = 0.003). However, marijuana did not affect scores for
the timed walk compared to placebo. Marijuana increased rating of
feeling high compared to placebo.
7 subjects did not complete the study due to adverse events (two
subjects felt uncomfortably ``high'', two had dizziness and one had
fatigue). Of those 7 subjects who withdrew, 5 had little or no previous
experience with marijuana. When the data were re-analyzed to include
these drop-out subjects, with the presumption they did not have a
positive response to treatment, the effect of marijuana was still
significant on spasticity.
The authors conclude that smoked marijuana had usefulness in
reducing pain and spasticity associated with MS. It is concerning that
marijuana-na[iuml]ve subjects dropped out of the study because they
were unable to tolerate the psychiatric AEs induced by marijuana. The
authors suggest that future studies should examine whether different
doses can result in similar beneficial effects with less cognitive
impact. However, the current study produced positive results suggesting
that marijuana should be studied further as an adjunct treatment for
spasticity in MS patients.
3.4 Asthma
Tashkin et al. (1974) examined bronchodilation in 10 subjects with
bronchial asthma in the study entitled, ``Acute Effects of Smoked
Marijuana and Oral [Delta]\9\-Tetrahydrocannabinol on Specific Airway
Conductance in Asthmatic Subjects''. The study was a double-blind,
placebo-controlled, crossover design. All subjects were clinically
stable at the time of the study; four subjects were symptom free, and
six subjects had chronic symptoms of mild to moderate severity.
Subjects were tested with 0.25ml of isoproterenol HCl prior to the
study to ensure they responded to bronchodilator
[[Page 53801]]
medications. Subjects were not allowed to take bronchodilator
medication within 8 hours prior to the study. Previous experience with
marijuana was not required for participation in the study, but 7 of the
10 subjects reported previous use of marijuana at a rate of less than 1
marijuana cigarette per month. No subjects reported marijuana use
within 7 days of the study.
The study consisted of four test sessions with an interval of at
least 48 hours between sessions. On two test sessions subjects smoked 7
mg/kg of body weight of either marijuana, with 2% THC concentration by
weight, or placebo marijuana. During the other two test sessions,
subjects ingested capsules with either 15 mg of synthetic THC or
placebo. Marijuana was administered using a uniform smoking technique:
subjects inhaled deeply for 2-4 seconds, held smoke in lungs for 15
seconds, and resumed normal breathing for approximately 5 seconds. The
author did not provide a description of the number of puffs taken at
any smoking session. The authors state that the smoking procedure was
repeated until the cigarette was consumed, which took approximately 10
minutes.
The outcome measure used was specific airway conductance (SGaw), as
calculated using measurements of thoracic gas volume (TGV) and airway
resistance (Raw) using a variable-pressure body plethysmograph.
Additionally, an assessment of degree of intoxication was administered
only to those subjects reporting previous marijuana use. This
assessment consisted of subjects rating ``how `high' they felt'' on a
scale of 0-7, 7 representing ``the `highest' they had ever felt after
smoking marijuana''.
Marijuana produced a significant increase of 33-48% in average SGaw
compared to both baseline and placebo (P < 0.05). This significant
increase in SGaw lasted for at least 2 hours after administration. The
average TGV significantly decreased by 4-13% compared to baseline and
placebo (P < 0.05). The author stated that all subjects reported
feelings of intoxication after marijuana administration.
The authors conclude that marijuana produced bronchodilation in
clinically stable asthmatic subjects with minimal to moderate
bronchospasms. Study limitations include: inclusion of subjects with
varying severity of asthmatic symptoms, use of SGaw to measure lung
responses to marijuana administration, and administration of smoke to
asthmatic subjects. Smoke delivers a number of harmful substances and
is not an optimal delivery symptom, especially for asthmatic patients.
FEV1 via spirometry is the gold standard to assess changes in lung
function, pre and post asthma treatment, by pharmacotherapy. SGaw has
been shown to be a valid tool in bronchoconstriction lung assessment;
however, since the FEV1 method was not utilized, it is unclear whether
these results would correlate if the FEV1 method had been employed.
3.5 Glaucoma
Two randomized, double-blind, placebo-controlled Phase 2 clinical
studies examined smoked marijuana in glaucoma (Crawford and Merritt,
1979; Merritt et al., 1980). In both studies, intraocular pressure
(IOP) was significantly reduced 30 minutes after smoking marijuana.
Maximal effects occurred 60-90 minutes after smoking, with IOP
returning to baseline within 3-4 hours. These two studies were included
in the 1999 IOM report on the medical uses of marijuana. Because our
independent analysis of these studies concurred with the conclusions
from the 1999 IOM report, these studies will not be discussed in
further detail in this review. No recent studies have been conducted
examining the effect of inhaled marijuana on IOP in glaucoma patients.
This lack of recent studies may be attributed to the conclusions made
in the 1999 IOM report that while cannabinoids can reduce intraocular
pressure (IOP), the therapeutic effects require high doses that produce
short-lasting responses, with a high degree of AEs. This high degree of
AEs means that the potential harmful effects of chronic marijuana
smoking may outweigh its modest benefits in the treatment of glaucoma.
3.6 Conclusions
Of the eleven randomized, double-blind, placebo-controlled Phase 2
clinical studies that met the criteria for review (see Sections 2.2 and
2.3), ten studies administered marijuana through smoking, while one
study utilized marijuana vaporization. In these eleven studies, there
were five different therapeutic indications: five examined chronic
neuropathic pain, two examined appetite stimulation in HIV patients,
two examined glaucoma, one examined spasticity in MS, and one examined
asthma.
There are limited conclusions that can be drawn from the data in
these published studies evaluating marijuana for the treatment of
different therapeutic indications. The analysis relied on published
studies, thus information available about protocols, procedures, and
results were limited to documents published and widely available in the
public domain. The published studies on medical marijuana are
effectively proof-of-concept studies. Proof-of-concept studies provide
preliminary evidence on a proposed hypothesis regarding a drug's
effect. For drugs under development, the effect often relates to a
short-term clinical outcome being investigated. Proof-of-concept
studies serve as the link between preclinical studies and dose ranging
clinical studies. Therefore, proof-of-concept studies are not
sufficient to demonstrate efficacy of a drug because they provide only
preliminary information about the effects of a drug. Although these
studies do not provide evidence that marijuana is effective in treating
a specific, recognized disorder, these studies do support future larger
well-controlled studies to assess the safety and efficacy of marijuana
for a specific medical indication. Overall, the conclusions below are
preliminary, based on very limited evidence.
3.6.1 Conclusions for Chronic Neuropathic Pain
In subjects with chronic neuropathic pain who are refractory to
other pain treatments, five proof-of-concept studies produced positive
results regarding the use of smoked marijuana for analgesia. However,
the subjects in these studies continued to use their current analgesic
drug regime, and thus no conclusions can be made regarding the
potential efficacy of marijuana for neuropathic pain in patients not
taking other analgesic drugs. Subjects also had numerous forms of
neuropathic pain, making it difficult to identify whether a specific
set of symptoms might be more responsive to the effects of marijuana.
It is especially concerning that some marijuana-na[iuml]ve subjects had
intolerable psychiatric responses to marijuana exposure at analgesic
doses.
3.6.2 Conclusions for Appetite Stimulation in HIV
In subjects who were HIV-positive, two proof-of-concept studies
produced positive results with the use of both dronabinol and smoked
marijuana to increase caloric intake and produce weight gain in HIV-
positive patients. However, the amount of THC in the marijuana tested
in these studies is four times greater than the dose of dronabinol
typically tested for appetite stimulation (10 mg vs. 2.5 mg; Haney et
al., 2005). Thus, it is possible that the low degree of AEs reported in
this study may reflect the development of tolerance to cannabinoids in
this patient population, since all individuals had current histories of
chronic marijuana use. Thus, individuals with little prior
[[Page 53802]]
exposure to marijuana may not respond similarly and may not be able to
tolerate sufficient marijuana to produce appetite stimulation.
3.6.3 Conclusions for Spasticity in MS
In subjects with MS, a proof of concept study produced positive
results using smoked marijuana as a treatment for pain and symptoms
associated with treatment-resistant spasticity. The subjects in this
study continued to take their current medication regiment, and thus no
conclusions can be made regarding the potential efficacy of marijuana
when taken on its own. It is also concerning that marijuana-na[iuml]ve
subjects dropped out of the study because they were unable to tolerate
the psychiatric AEs induced by marijuana. The authors suggest that
future studies should examine whether different doses can result in
similar beneficial effects with less cognitive impact.
3.6.4 Conclusions for Asthma
In subjects with clinically stable asthma, a proof of concept study
produced positive results of smoked marijuana producing
bronchodilation. However, in this study marijuana was administered at
rest and not while experiencing bronchospasms. Additionally, the
administration of marijuana through smoking introduces harmful and
irritating substances to the subject, which is undesirable especially
in asthmatic patients. Thus the results suggest marijuana may have
bronchodilator effects, but it may also have undesirable adverse
effects in subjects with asthma.
3.6.5 Conclusions for Glaucoma
As noted in Sections 3.5, the two studies that evaluated smoked
marijuana for glaucoma were conducted decades ago, and they have been
thoroughly evaluated in the 1999 IOM report. The 1999 IOM report
concludes that while the studies with marijuana showed positive results
for reduction in IOP, the effect is short-lasting, requires a high
dose, and is associated with many AEs. Thus, the potential harmful
effects may outweigh any modest benefit of marijuana for this
condition. We agree with the conclusions drawn in the 1999 IOM report.
3.7 Design Challenges for Future Studies
The positive results reported by the studies discussed in this
review support the conduct of more rigorous studies in the future. This
section discusses methodological challenges that have occurred in
clinical studies with smoked marijuana. These design issues should be
addressed when larger-scale clinical studies are conducted to ensure
that valid scientific data are generated in studies evaluating
marijuana's safety and efficacy for a particular therapeutic use.
3.7.1 Sample Size
The ability for results from a clinical study to be generalized to
a broader population is reliant on having a sufficiently large study
sample size. However, as noted above, all of the 11 studies reviewed in
this document were early Phase 2 proof of concept studies for efficacy
and safety. Thus, the sample sizes used in these studies were
inherently small, ranging from 10 subjects per treatment group (Tashkin
et al., 1974; Haney et al., 2007) to 25 subjects per treatment group
(Abrams et al., 2007). These sample sizes are statistically inadequate
to support a showing of safety or efficacy. FDA's recommendations about
sample sizes for clinical trials can be found in the Guidance for
Industry: E9 Statistical Principles for Clinical Trials (1998).\35\ For
example, ``the number of subjects in a clinical trial should always be
large enough to provide a reliable answer to the questions addressed.
This number is usually determined by the primary objective of the
trial. The method by which the sample size is calculated should be
given in the protocol, together with the estimates of any quantities
used in the calculations (such as variances, mean values, response
rates, event rates, difference to be detected).'' (pg. 21). Other
clinical FDA Guidance for Industry \36\ may also contain
recommendations regarding the appropriate number of subjects that
should be investigated for a specific medical indication.
---------------------------------------------------------------------------
\35\ The Guidance for Industry: E9 Statistical Principles for
Clinical Trials can be found at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073137.pdf.
\36\ Other Guidances for Industry can be found at: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm.
---------------------------------------------------------------------------
3.7.2 Marijuana Dose Standardization
Dose standardization is critical for any clinical study in order to
ensure that each subject receives a consistent exposure to the test
drug. The Guidance for Industry: Botanical Drug Products (2004) \37\
provides specific information on the development of botanical drug
products. Specifically, this guidance includes information about the
need for well-characterized and consistent chemistry for the botanical
plant product and for consistent and reliable dosing. Specifically for
marijuana studies, dose standardization is important because if
marijuana leads to plasma levels of cannabinoids that are significantly
different between subjects, this variation may lead to differences in
therapeutic responsivity or in the prevalence of psychiatric AEs.
---------------------------------------------------------------------------
\37\ The Guidance for Industry: Botanical Drug Products can be
found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf.
---------------------------------------------------------------------------
In most marijuana studies discussed in this review, investigators
use a standardized cued smoking procedure. In this procedure, a subject
is instructed to inhale marijuana smoke for 5 seconds, hold the smoke
in the lungs for 10 seconds, exhale and breathe normally for 40
seconds. This process is repeated to obtain the desired dose of the
drug. However, this procedure may not lead to equivalent exposure to
marijuana and its constituent cannabinoids, based on several factors:
Intentional or unintentional differences in the depth of
inhalation may change the amount of smoke in the subject's lungs.
Smoking results in loss from side stream smoke, such that
the entire dose is not delivered to the subject.
There may be differences in THC concentration along the
length of a marijuana cigarette. According to Tashkin et al. (1991),
the area of the cigarette closest to the mouth tends to accumulate a
higher concentration of THC, but this section of the cigarette is not
smoked during a study.
For example, Wilsey et al. (2008) used this standardized smoking
procedure. The reported mean (range) of marijuana cigarettes consumed
was 550 mg (200-830mg) for the low strength marijuana (3.5% THC) and
490 mg (270-870mg) for the high strength marijuana (7% THC). This wide
range of amounts of marijuana cigarette smoked by the individual
subjects, even with standardized smoking procedure and controlled
number of puffs, supports the issues with delivering consistent doses
with smoke marijuana.
In other marijuana studies that do not use a cued smoking
procedure, subjects are simply told to smoke the marijuana cigarette
over a specific amount of time (usually 10 minutes) without further
instruction (Crawford and Merritt, 1979; Merritt et al., 1980; Ellis et
al., 2009). The use of a nonstandardized procedure may lead to non-
equivalent exposures to marijuana and its constituent cannabinoids
between subjects because of additional factors that are not listed
above, such as:
Differences in absorption and drug response if subjects
(especially
[[Page 53803]]
marijuana-na[iuml]ve ones) are not instructed to hold marijuana smoke
in their lungs for a certain period of time.
Prolonged periods between puffs may increase loss to side
stream smoke.
Subjects may attempt to smoke the marijuana cigarette in
the way they would smoke a tobacco cigarette, which relies primarily on
short, shallow puffs.
In both standardized and non-standardized smoking procedures,
subjects may seek to control the dose of THC through self-titration
(Crawford and Merritt, 1979; Merritt et al., 1980; Tashkin et al.,
1974; Abrams et al., 2007; Ellis et al., 2009). Self-titration involves
an individual moderating the amount of marijuana smoke inhaled over
time in order to obtain a preferred level of psychoactive or clinical
response. The ability of an individual to self-titrate by smoking is
one reason given by advocates of ``medical marijuana'' in support of
smoking of marijuana rather than through its ingestion via edibles.
However, for research purposes, self-titration interferes with the
ability to maintain consistent dosing levels between subjects, and
thus, valid comparisons between study groups.
All of these factors can make the exact dose of cannabinoids
received by a subject in a marijuana study difficult to determine with
accuracy. Testing whether plasma levels of THC or other cannabinoids
are similar between subjects following the smoking procedure would
establish whether the procedure is producing appropriate results.
Additionally, studies could be conducted to determine if vaporization
can be used to deliver consistent doses of cannabinoids from marijuana
plant material. Specifically, vaporization devices that involve the
collection of vapors in an enclosed bag or chamber may help with
delivery of consistent doses of marijuana. Thus, more information could
be collected on whether vaporization is comparable to or different than
smoking in terms of producing similar plasma levels of THC in subjects
using identical marijuana plant material.
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use
The studies that were reviewed administered the drug for short
durations lasting no longer than 5 days (Abrams et al., 2007; Ellis et
al., 2009; Ware et al., 2010). Thus all studies examined the short-term
effect of marijuana administration for therapeutic purposes. However,
many of the medical conditions that have been studied are persistent or
expected to last the rest of a patient's life. Therefore, data on
chronic exposure to smoked marijuana in clinical studies is needed. In
this way, more information will be available regarding whether
tolerance, physical dependence, or specific adverse events develop over
the course of time with continuing use of therapeutic marijuana.
3.7.4 Smoking as a Route of Administration
As has been pointed out by the IOM and other groups, smoking is not
an optimum route of administration for marijuana-derived therapeutic
drug products, primarily because introducing the smoke from a burnt
botanical substance into the lungs of individuals with a disease state
is not recommended when their bodies may be physically compromised. The
1999 IOM report on medicinal uses of marijuana noted that alternative
delivery methods offering the same ability of dose titration as smoking
marijuana will be beneficial and may limit some of the possible long-
term health consequences of smoking marijuana. The primary alternative
to smoked marijuana is vaporization, which can reduce exposure to
combusted plant material containing cannabinoids. The only study to use
vaporization as the delivery method was Wilsey et al. (2013). The
results from Wilsey et al. (2013) showed a similar effect of decreased
pain as seen in the other studies using smoking as the delivery method
(Ware et al., 2010; Wilsey et al., 2008). This similar effect of
decrease pain supports vaporization as a possibly viable route to
administer marijuana in research, while potentially limiting the risks
associated with smoking.
3.7.5 Difficulty in Blinding of Drug Conditions
An adequate and well-controlled clinical study involves double-
blinding, where both the subjects and the investigators are unable to
tell the difference between the test treatments (typically consisting
of at least a test drug and placebo) when they are administered. All of
the studies reviewed in this document administered study treatments
under double-blind conditions and thus were considered to have an
appropriate study design.
However, even under the most rigorous experimental conditions,
blinding can be difficult in studies with smoked marijuana because the
rapid onset of psychoactive effects readily distinguishes active from
placebo marijuana. The presence of psychoactive effects also occurs
with other drugs. However, most other drugs have a similar psychoactive
effect with substances with similar mechanisms of actions. These
substances can be used as positive controls to help maintain blinding
to the active drug being tested. Marijuana on the other hand, has a
unique set of psychoactive effects which makes the use of appropriate
positive controls difficult (Barrett et al., 1995). However, two
studies did use Dronabinol as a positive control drug to help maintain
blinding (Haney et al., 2005; Haney et al., 2007).
When blinding is done using only placebo marijuana, the ability to
distinguish active from placebo marijuana may lead to expectation bias
and an alteration in perceived responsivity to the therapeutic outcome
measures. With marijuana-experienced subjects, for example, there may
be an early recognition of the more subtle cannabinoid effects that can
serve as a harbinger of stronger effects, which is less likely to occur
with marijuana-na[iuml]ve subjects. To reduce this possibility,
investigators have tested doses of marijuana other than the one they
were interested in experimentally to maintain the blind (Ware et al.,
2010).
Blinding can also be compromised by differences in the appearance
of marijuana plant material based on THC concentration. Marijuana with
higher concentrations of THC tends to be heavier and seemingly darker,
with more ``tar-like'' substance. Subjects who have experience with
marijuana have reported being able to identify marijuana from placebo
cigarettes by sight alone when the plant material in a cigarette was
visible (Tashkin et al., 1974; Ware et al., 2010). Thus, to maintain a
double-blind design, many studies obscure the appearance of plant
material by closing both ends of the marijuana cigarette and placing it
in in an opaque plastic tube.
While none of these methods to secure blinding may be completely
effective, it is important to reduce bias as much as possible to
produce consistent results between subjects under the same experimental
conditions.
3.7.6 Prior Marijuana Experience
Marijuana use histories in test subjects may influence outcomes,
related to both therapeutic responsivity and psychiatric AEs.
Marijuana-na[iuml]ve subjects may also experience a marijuana drug
product as so aversive that they would not want to use the drug
product. Thus, subjects' prior experience with marijuana may affect the
conduct and results of studies.
Most of the studies reviewed in this document required that
subjects have a history of marijuana use (see tables in Appendix that
describe specific
[[Page 53804]]
requirements for each study). However, in studies published in the
scientific literature, the full inclusion criteria with regard to
specific amount of experience with marijuana may not be provided. For
those studies that do provide inclusion criteria, acceptable experience
with marijuana can range from once in a lifetime to use multiple times
a day.
The varying histories of use might affect everything from scores on
adverse event measures, safety measures, or efficacy measures.
Additionally, varying amounts of experience can impact cognitive effect
measures assessed during acute administration studies. For instance,
Schreiner and Dunn (2012) contend cognitive deficits in heavy marijuana
users continue for approximately 28 days after cessation of smoking.
Studies requiring less than a month of abstinence prior to the study
may still see residual effects of heavy use at baseline and after
placebo marijuana administration, thus showing no significant effects
on cognitive measures. However, these same measurements in occasional
or na[iuml]ve marijuana users may demonstrate a significant effect
after acute marijuana administration. Therefore, the amount of
experience and the duration of abstinence of marijuana use are
important to keep in mind when analyzing results for cognitive and
other adverse event measures. Lastly, a study population with previous
experience with marijuana may underreport the incidence and severity of
adverse events. Because most studies used subjects with prior marijuana
experience, we are limited in our ability to generalize the results,
especially for safety measures, to marijuana na[iuml]ve populations.
Five of 11 studies reviewed in this document included both
marijuana-na[iuml]ve and marijuana-experienced subjects (Corey-Bloom et
al., 2012; Ellis et al., 2009; Ware et al., 2010; Merritt et al., 1980;
Tashkin et al., 1974). Since the number of marijuana-na[iuml]ve
subjects in these studies was low, it was not possible to conduct a
separate analysis compared to experienced users. However,
systematically evaluating the effect of marijuana experience on study
outcomes is important, since many patients who might use a marijuana
product for a therapeutic use will be marijuana-na[iuml]ve.
Research shows that marijuana-experienced subjects have a higher
ability to tolerate stronger doses of oral dronabinol than marijuana-
na[iuml]ve subjects (Haney et al., 2005). Possibly, this increased
tolerance is also the case when subjects smoke or vaporize marijuana.
Thus, studies could be conducted that investigate the role of marijuana
experience in determining tolerability of and responses to a variety of
THC concentrations in marijuana.
3.7.7 Inclusion and Exclusion Criteria
For safety reasons, all clinical studies have inclusion and
exclusion criteria that restrict the participation of individuals with
certain medical conditions. For studies that test marijuana, these
criteria may be based on risks associated with exposure to smoked
material and the effects of THC. Thus, most studies investigating
marijuana require that subjects qualify for the study based on
restrictive symptom criteria such that individuals do not have other
symptoms that may be known to interact poorly with cannabinoids.
Similarly, clinical studies with marijuana typically exclude
individuals with cardiac or pulmonary problems, as well as psychiatric
disorders. These exclusion criteria are based on the well-known effects
of marijuana smoke to produce increases in heart rate and blood
pressure, lung irritation, and the exacerbation of psychiatric
disturbances in vulnerable individuals. Although these criteria are
medically reasonable for research protocols, it is likely that future
marijuana products will be used in patients who have cardiac, pulmonary
or psychiatric conditions. Thus, individuals with these conditions
should be evaluated, whenever possible.
Additionally, all studies reviewed in this document allowed the
subjects to continue taking their current regimen of medications. Thus
all results evaluated marijuana as an adjunct treatment for each
therapeutic indication.
3.7.8 Number of Female Subjects
A common problem in clinical research is the limited number of
females who participate in the studies. This problem is present in the
11 studies reviewed in this document, in which one study did not
include any female subjects (Ellis et al., 2009), and three studies had
a low percentage of female subjects (Abrams et al., 2007; Haney et al.,
2005; Haney et al., 2007). However, each of these four studies
investigated an HIV-positive patient population, where there may have
been a larger male population pool from which to recruit compared to
females.
Since there is some evidence that the density of CB1 receptors in
the brain may vary between males and females (Crane et al., 2012),
there may be differing therapeutic or subjective responsivity to
marijuana. Studies using a study population that is equal parts male
and female may show whether and how the effects of marijuana differ
between male and female subjects.
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Washington, DC: National Academy Press.
Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT,
Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF,
Mulligan K, Bacchetti P, McCune JM, and Schambelan M. 2003. Short-
term effects of cannabinoids in patients with HIV-1 infection: a
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Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME,
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associated sensory neuropathy: A randomized placebo-controlled
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Appendino G, Chianese G, Taglialatela-Scafati O. 2011. Cannabinoids:
occurrence and medicinal chemistry. Curr Med Chem. 18(7):1085-99.
Barrett RL, Wiley JL, Balster RL, and Martin BR. 1995.
Pharmacological specificity of [Delta]\9\-tetrahydrocannabinol
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Chait LD, and Pierri J. 1989. Some physical characteristics of NIDA
marijuana cigarettes. Addictive Behaviors 14 (1): 61-67.
Chang AE, Shiling DJ, Stillman RC, Godlberg NH, Seipp CA, Barofsky
I, Simon RM, and Rosenberg SA. 1979. Delta-9-tetrahydrocannabinol as
an antiemetic in cancer patients receiving high-dose methotrexate.
Annals of Internal Medicine 91: 819-824.
Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H,
and Gouaux B. 2012. Smoked cannabis for spasticity in multiple
sclerosis: a randomized, placebo-controlled trial. Canadian Medical
Association Journal 184 (10): 1143-1150.
Crane NA, Schuster RM, Fusar-Poli P, and Gonzalez R. 2012. Effects
of Cannabis on Neurocognitive Functioning: Recent Advances,
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Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol
on arterial and intraocular hypertension. International Journal of
Clinical Pharmacology and biopharmacy 17 (5): 191-196.
Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux
B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for
neuropathic pain in HIV: A randomized, crossover clinical trial.
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Flom MC, Adams AJ, and Jones RT. 1975. Marijuana smoking and reduced
pressure in human eyes: drug action or epiphenomenon? Investigative
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Foltin RW, Brady JV, and Fischamn MW. 1986. Behavioral analysis of
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Foltin RW, Fischman MW, and Byrne MF. 1988. Effects of smoked
marijuana on food intake and body weight of humans living in a
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Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, and
Domino EF. 1994. Short-term effects of smoking marijuana on balance
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Greenwald MK and Stitzer ML. 2000. Antinociceptive, subjective, and
behavioral effects of smoked marijuana in humans. Drug and Alcohol
Dependence 59: 261-275.
Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and
Foltin RW. 2007. Dronabinol and marijuana in HIV-positive marijuana
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Deficiency Syndromes (1999) 45 (5): 545-554.
Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and
marijuana in HIV(+) marijuana smokers: acute effects on caloric
intake and mood. Psychopharmacology 181 (1): 170-178.
Hill SY, Schwin R, Goodwin DW, and Powell BJ. 1974. Marihuana and
pain. Journal of Pharmacology and Experimental Therapeutics 188(2):
415-418.
Jampel H. 2010. American glaucoma society position statement:
marijuana and the treatment of glaucoma. Journal of Glaucoma 19 (2):
75-76.
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS.
1980. Effect of marihuana on intraocular and blood pressure in
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Milstein SL, MacCannell KL, Karr GW, and Clark S. 1974. Marijuana
produced changes in cutaneous sensitivity and affect: users and non-
users. Pharmacology Biochemistry and Behavior 2:367-374.
Milstein SL, MacCannell K, Karr G, and Clark S. 1975. Marijuana-
produced changes in pain tolerance: Experiences and non-experienced
subjects. Int. Pharmacopsychiat 10: 177-182.
Naftali T, Schleider LB, Dotan I, Lansky EP, Benjaminov FS, and
Konikoff FM. 2013. Cannabis induces a clinical response in patients
with Crohn's disease: A prospective placebo-controlled study.
Clinical Gastroenterology and Hepatology 11: 1276-1280.
Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, and
Kirlin KA. 2002. Chronic Cannabis Use in the Compassionate
Investigational New Drug Program: An Examination of Benefits and
Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis
Therapeutics 2 (1): 3-57.
Soderpalm AHV, Schuster A, and de Wit H. 2001. Antiemetic efficacy
of smoked marijuana subjective and behavioral effects on nausea
induced by syrup of ipecac. Pharmacology Biochemistry and Behavior
69: 343-350.
Tashkin DP, Gliederer F, Rose J, Chang P, Hui KK, Yu JL, and Wu TC.
1991. Tar, CO and delta 9THC delivery from the 1st and 2nd halves of
a marijuana cigarette. Pharmacology Biochemistry and Behavior 40
(3): 657-661.
Tashkin DP, Shapiro BJ, Lee YE, Harper CE. 1975. Effects of smoked
marijuana in experimentally induced asthma. American Review of
Respiratory Disease 112: 377-386.
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D,
Bentley H, Gouaux B, and Abramson I. 2007. Dose-dependent effects of
smoked cannabis on capsaicin-induced pain and hyperalgesia in
healthy volunteers. Anesthesiology 107 (5): 785-796.
Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A,
Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic
neuropathic pain: a randomized controlled trial. Canadian Medical
Association Journal 182 (14): E694-E701.
Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B,
and Fishman S. 2008. A randomized, placebo-controlled, crossover
trial of cannabis cigarettes in neuropathic pain. J. Pain 9 (6):
506-521.
Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H.
2013. Low-dose vaporized cannabis significantly improves neuropathic
pain. J. Pain 14(2):136-48.
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U.S. Department of Justice--Drug Enforcement Administration
Schedule of Controlled Substances: Maintaining Marijuana in Schedule I
of the Controlled Substances Act
Background, Data, and Analysis: Eight Factors Determinative of Control
and Findings Pursuant to 21 U.S.C. 812(b)
Prepared by: Office of Diversion Control, Drug and Chemical Evaluation
Section, Washington, DC 20537
July 2016
Background
On December 17, 2009, Bryan Krumm, CNP, submitted a petition to the
Drug Enforcement Administration (DEA) to initiate proceedings for a
repeal of the rules or regulations that place marijuana \38\ in
schedule I of the Controlled Substances Act (CSA). The petition
requests that marijuana be rescheduled in any schedule other than
schedule I of the CSA. The petitioner claims that:
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\38\ The Controlled Substances Act (CSA) defines marijuana as
the following: ``All parts of the plant Cannabis sativa L., whether
growing or not; the seeds thereof; the resin extracted from any part
of such plant; and every compound, manufacture, salt, derivative,
mixture, or preparation of such plant, its seeds or resin. Such term
does not include the mature stalks of such plant, fiber produced
from such stalks, oil or cake made from the seeds of such plant, any
other compound, manufacture, salt, derivative, mixture, or
preparation of such mature stalks (except the resin extracted there
from), fiber, oil, or cake, or the sterilized seed of such plant
which is incapable of germination. 21 U.S.C. 802(16). Note that
``marihuana'' is the spelling originally used in the CSA. This
document uses the spelling that is more common in current usage,
``marijuana.''
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1. Marijuana has accepted medical use in the United States;
2. Studies have shown that smoked marijuana has proven safety and
efficacy;
3. Marijuana is safe for use under medical supervision; and
4. Marijuana does not have the abuse potential for placement in
schedule I
The DEA accepted this petition for filing on April 3, 2010.
The Attorney General may by rule transfer a drug or other substance
between schedules of the CSA if she finds that such drug or other
substance has a potential for abuse, and makes the findings prescribed
by 21 U.S.C. 812(b) for the schedule in which such drug is to be
placed. 21 U.S.C. 811(a)(1). The Attorney General has delegated this
responsibility to the Acting Administrator of the DEA. 28 CFR 0.100(b).
In accordance with 21 U.S.C. 811(b), after gathering the necessary
data, the DEA submitted the petition and necessary data to the
Department of Health and Human Services (HHS) on May 6, 2011, and
requested that HHS provide a scientific and medical evaluation and
scheduling recommendation for marijuana. In documents dated June 3 and
June 25, 2015, the acting Assistant Secretary for Health of the HHS
\39\ recommended to the DEA that marijuana continue to be controlled in
Schedule I of the CSA, and provided to the DEA its scientific and
medical evaluation titled ``Basis for the Recommendation for
Maintaining Marijuana in Schedule I of the Controlled Substances Act.''
The HHS's recommendations are binding on the DEA as to scientific and
medical matters. 21 U.S.C. 811(b).
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\39\ As set forth in a memorandum of understanding entered into
by the HHS, the Food and Drug Administration (FDA), and the National
Institute on Drug Abuse (NIDA), the FDA acts as the lead agency
within the HHS in carrying out the Secretary's scheduling
responsibilities under the CSA, with the concurrence of the NIDA. 50
FR 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the
Assistant Secretary for Health of the HHS the authority to make
domestic drug scheduling recommendations.
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Before initiating proceedings to reschedule a substance, the CSA
requires the Acting Administrator to determine whether the HHS
scheduling recommendation, scientific and medical evaluation, and ``all
other relevant data'' constitute substantial evidence that the drug
should be rescheduled as proposed. 21 U.S.C. 811(b). The Acting
Administrator must determine whether there is substantial evidence to
conclude that the drug meets the criteria for placement in another
schedule based on the criteria set forth in 21 U.S.C. 812(b). The CSA
requires that both the DEA and the HHS consider the eight factors
specified by Congress in 21 U.S.C. 811(c). This document lays out those
considerations and is organized according to the eight factors. As DEA
sets forth in detail below, the evidence shows:
1. Actual or relative potential for abuse. Marijuana has a high
potential for abuse. Preclinical and clinical data show that it has
reinforcing effects characteristic of drugs of abuse. National
databases on actual abuse show marijuana is the most widely abused
drug, including significant numbers of substance abuse treatment
admissions. Data on marijuana seizures show widespread availability and
trafficking.
2. Scientific evidence of its pharmacological effect. The
scientific understanding of marijuana, cannabinoid receptors, and the
endocannabinoid system continues to be studied and elucidated.
Marijuana produces various pharmacological effects, including
subjective (e.g., euphoria, dizziness, disinhibition), cardiovascular,
acute and chronic respiratory, immune system, and prenatal exposure
effects, as well as behavioral and cognitive impairment.
3. Current scientific knowledge. There is no currently accepted
medical use for marijuana in the United States. Marijuana sources are
derived from numerous cultivated strains and may have different levels
of [Delta]\9\-THC and other cannabinoids. Under the five-element test
for currently accepted medical use discussed in more detail below and
upheld by the Court of Appeals for the District of Columbia in Alliance
for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)
(hereinafter ``ACT''), there is no complete scientific analysis of
marijuana's chemical components; there are not adequate safety studies;
there are not adequate and well-controlled efficacy studies; there is
not a consensus of medical opinion concerning medical applications of
marijuana; and the scientific evidence regarding marijuana's safety and
efficacy is not widely available. To date, scientific and medical
research has not progressed to the point that marijuana has a currently
accepted medical use, even under conditions where its use is severely
restricted.
4. History and current pattern of abuse. Marijuana continues to be
the most widely used illicit drug. In 2014, there were 22.2 million
current users. There were also 2.6 million new users, most of whom were
less than 18 years of age. During the same period, marijuana was the
most frequently identified drug exhibit in federal, state, and local
forensic laboratories.
5. Scope, duration, and significance of abuse. Abuse of marijuana
is widespread and significant. In 2014, for example, an estimated 6.5
million people aged 12 or older used marijuana on a daily or almost
daily basis over a 12-month period. In addition, a significant
proportion of all admissions for substance abuse treatment are for
marijuana/hashish as their primary drug of abuse. In 2013, 16.8% of all
such admissions--281,991 over the course of the year--were for primary
marijuana/hashish abuse.
6. Risk, if any, to public health. Together with the health risks
outlined in terms of pharmacological effects above, public health risks
from acute use of marijuana include impaired psychomotor performance,
impaired driving, and impaired performance on tests of learning and
associative processes. Chronic use of marijuana
[[Page 53821]]
poses a number of other risks to the public health including physical
as well as psychological dependence.
7. Psychic or physiological dependence liability. Long-term, heavy
use of marijuana can lead to physical dependence and withdrawal
following discontinuation, as well as psychic or psychological
dependence. In addition, a significant proportion of all admissions for
treatment for substance abuse are for primary marijuana abuse; in 2013,
16.8% of all admissions were for primary marijuana/hashish abuse,
representing 281,991 individuals.
8. Immediate precursor. Marijuana is not an immediate precursor of
any controlled substance.
As specified in 21 U.S.C. 812(b)(1), in order for a substance to be
placed in schedule I, the Acting Administrator must find that:
A. The drug or other substance has a high potential for abuse.
B. The drug or other substance has no currently accepted medical
use in treatment in the United States.
C. There is a lack of accepted safety for use of the drug or other
substance under medical supervision.
To be classified in another schedule under the CSA (e.g., II, III,
IV, or V), a substance must have a ``currently accepted medical use in
treatment in the United States.'' 21 U.S.C. 812(b)(2)-(5). A substance
also may be placed in schedule II if it is found to have ``a currently
accepted medical use with severe restrictions.'' 21 U.S.C. 812(b)(2).
If a controlled substance has no such currently accepted medical use,
it must be placed in schedule I. See Notice of Denial of Petition, 66
FR 20038 (Apr. 18, 2001) (``Congress established only one schedule--
schedule I--for drugs of abuse with `no currently accepted medical use
in treatment in the United States' and `lack of accepted safety for use
. . . under medical supervision.' '').
A drug that is the subject of an approved new drug application
(NDA) or abbreviated new drug application (ANDA) under Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355), is considered to have a
currently accepted medical use in treatment in the United States for
purposes of the CSA. The HHS stated in its review, however, that FDA
has not approved any NDA for marijuana for any indication.
In the absence of NDA or ANDA approval, DEA has established a five-
element test for determining whether the drug has a currently accepted
medical use in treatment in the United States. Under this test, a drug
will be considered to have a currently accepted medical use only if the
following five elements are satisfied:
1. The drug's chemistry is known and reproducible;
2. There are adequate safety studies;
3. There are adequate and well-controlled studies proving efficacy;
4. The drug is accepted by qualified experts; and
5. The scientific evidence is widely available.
57 FR 10499, 10506 (March 26, 1992). See also ACT, 15 F.3d at 1135.
As discussed in Factor 3, below, HHS concluded, and DEA agrees,
that the scientific evidence is insufficient to demonstrate that
marijuana has a currently accepted medical use under the five-element
test. The evidence was insufficient in this regard also when the DEA
considered petitions to reschedule marijuana in 1992 (57 FR 10499),\40\
in 2001 (66 FR 20038), and in 2011 (76 FR 40552).\41\ Little has
changed since 2011 with respect to the lack of clinical evidence
necessary to establish that marijuana has a currently accepted medical
use. No studies have scientifically assessed the efficacy and full
safety profile of marijuana for any specific medical condition.
---------------------------------------------------------------------------
\40\ See Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131
(D.C. Cir. 1994).
\41\ See Americans for Safe Access v. DEA, 706 F.3d 438 (D.C.
Cir. 2013)(rhg den. 2013).
---------------------------------------------------------------------------
The limited existing clinical evidence is not adequate to warrant
rescheduling of marijuana under the CSA. To the contrary, the data in
this scheduling review document show that marijuana continues to meet
the criteria for schedule I control under the CSA for the following
reasons:
1. Marijuana has a high potential for abuse.
2. Marijuana has no currently accepted medical use in treatment in
the United States.
3. Marijuana lacks accepted safety for use under medical
supervision.
Factor 1: The Drug's Actual or Relative Potential for Abuse
Marijuana is the most commonly abused illegal drug in the United
States. It is also the most commonly used illicit drug by high school
students in the United States. Further, marijuana is the most
frequently identified drug by state, local and federal forensic
laboratories. Marijuana's main psychoactive ingredient, [Delta]\9\-
tetrahydrocannabinol ([Delta]\9\-THC),\42\ is an effective reinforcer
in laboratory animals, including primates and rodents. These animal
studies both predict and support the observations that marijuana
produces reinforcing effects in humans. Such reinforcing effects can
account for the repeated abuse of marijuana.
---------------------------------------------------------------------------
\42\ The terms [Delta]\9\-THC and THC are used interchangeably
thoughout this document.
---------------------------------------------------------------------------
A. Indicators of Abuse Potential
The HHS has concluded in its document, ``Basis for the
Recommendation for Maintaining Marijuana in Schedule I of the
Controlled Substances Act,'' that marijuana has a high potential for
abuse. The finding of ``abuse potential'' is critical for control under
the Controlled Substances Act (CSA). Although the term is not defined
in the CSA, guidance in determining abuse potential is provided in the
legislative history of the Act (Comprehensive Drug Abuse Prevention and
Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 2 (1970),
reprinted in 1970 U.S.C.C.A.N. 4566, 4603). Accordingly, the following
items are indicators that a drug or other substance has potential for
abuse:
There is evidence that individuals are taking the drug or
drugs containing such a substance in amounts sufficient to create a
hazard to their health or to the safety of other individuals or of the
community; or
There is significant diversion of the drug or drugs
containing such a substance from legitimate drug channels; or
Individuals are taking the drug or drugs containing such a
substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice; or
The drug or drugs containing such a substance are new
drugs so related in their action to a drug or drugs already listed as
having a potential for abuse to make it likely that the drug will have
the same potentiality for abuse as such drugs, thus making it
reasonable to assume that there may be significant diversions from
legitimate channels, significant use contrary to or without medical
advice, or that it has a substantial capability of creating hazards to
the health of the user or to the safety of the community.
Of course, evidence of actual abuse of a substance is indicative
that a drug has a potential for abuse.
In its recommendation, the HHS analyzed and evaluated data on
marijuana as applied to each of the above four criteria. The analysis
presented in the recommendation (HHS, 2015) is discussed below:
1. There is evidence that individuals are taking the drug or drugs
containing such a substance in amounts sufficient to create a hazard to
their health or to the safety of other individuals or of the community.
[[Page 53822]]
The HHS stated that some individuals are taking marijuana in
amounts sufficient to create a hazard to their health and to the safety
of other individuals and the community. Data from national databases on
actual abuse of marijuana support the idea that a large number of
individuals use marijuana. In its recommendation (HHS, 2015), the HHS
presented data from the National Survey on Drug and Health (NSDUH) of
the Substance Abuse and Mental Health Services Administration (SAMHSA)
and the Monitoring the Future (MTF) survey of the National Institute on
Drug Abuse (NIDA), and the DEA has since updated this information. The
most recent data from SAMHSA's NSDUH in 2014 reported that marijuana
was the most used illicit drug. Among Americans aged 12 years and
older, an estimated 22.2 million Americans used marijuana within the
past month according to the 2014 NSDUH. In 2004, an estimated 14.6
million individuals reported using marijuana within the month prior to
the study. The estimated rates in 2014 thus reflect an increase of
approximately 7.6 million individuals over a 10-year period. According
to the 2013 NSDUH report, an estimated 19.8 million individuals
reported using marijuana. Thus, over a period of one year (2013 NSDUH-
2014 NSDUH), there was an estimated increase of 2.4 million individuals
in the United States using marijuana.
The results from the 2015 Monitoring the Future survey of 8th,
10th, and 12th grade students indicate that marijuana was the most
widely used illicit drug in these age groups. Current monthly use was
6.5% of 8th graders, 14.8% of 10th graders, and 21.3% of 12th graders.
The Treatment Episode Data Set (TEDS) in 2013 reported that marijuana
abuse was the primary factor in 16.8 percent of non-private substance-
abuse treatment facility admissions. In 2011, SAMHSA's Drug Abuse
Warning Network (DAWN) reported that marijuana was mentioned in 36.4%
(455,668 out of approximately 1.25 million) of illicit drug-related
Emergency Department (ED) visits.
Data on the extent and scope of marijuana abuse are presented under
Factors 4 and 5 of this analysis. Discussion of the health effects of
marijuana is presented under Factor 2, and the assessment of risk to
the public health posed by acute and chronic marijuana abuse is
presented under Factor 6 of this analysis.
2. There is significant diversion of the drug or drugs containing
such a substance from legitimate drug channels.
In accordance with the CSA, the only lawful source of marijuana in
the United States is that produced and distributed for research
purposes under the oversight of NIDA and in conformity with United
States obligations under the Single Convention on Narcotic Drugs.\43\
The HHS stated that there is a lack of significant diversion from
legitimate drug sources, but that this is likely due to high
availability of marijuana from illicit sources. Marijuana is not an
FDA-approved drug product. Neither a New Drug Application (NDA) nor a
Biologics License Application (BLA) has been approved for marketing in
the United States. However, the marijuana used for nonclinical and
clinical research represents a very small amount of the total amount of
marijuana available in the United States and therefore information
about marijuana diversion from legitimate sources is limited or not
available.
---------------------------------------------------------------------------
\43\ See 76 FR 51403, 51409-51410 (2011) (discussing cannabis
controls required under the Single Convention).
---------------------------------------------------------------------------
The DEA notes that the magnitude of the demand for illicit
marijuana is evidenced by information from a number of databases
presented under Factor 4. Briefly, marijuana is the most commonly used
illegal drug in the United States. It is also the most commonly used
illicit drug by American high schoolers. Marijuana is the most
frequently identified drug in state, local, and federal forensic
laboratories, with increasing amounts of both domestically grown and of
illicitly smuggled marijuana.
Given that marijuana has long been the most widely trafficked and
abused controlled substance in the United States, and that all aspects
of such illicit activity are entirely outside of the closed system of
distribution mandated by the CSA, it may well be the case that there is
little thought given to diverting marijuana from the small supplies
produced for legitimate research purposes. Thus, the lack of data
indicating diversion of marijuana from legitimate channels to the
illicit market is not indicative of a lack of potential for abuse of
the drug.
3. Individuals are taking the drug or drugs containing such a
substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice.
The HHS stated that the FDA has not evaluated or approved an NDA or
BLA for marijuana for any therapeutic indication. Consistent with
federal law, therefore, an individual legitimately can take marijuana
based on medical advice from a practitioner only by participating in
research that is being conducted under an Investigational New Drug
(IND) application. The HHS noted that there are several states as well
as the District of Columbia which have passed laws allowing for
individuals to use marijuana for purported ``medical'' use under
certain circumstances, but data are not available yet to determine the
number of individuals using marijuana under these state laws.
Nonetheless, according to 2014 NSDUH data, 22.2 million American adults
currently use marijuana (SAMHSA, 2015a). Based on the large number of
individuals who use marijuana and the lack of an FDA-approved drug
product, the HHS concluded that the majority of individuals using
marijuana do so on their own initiative rather than by following
medical advice from a licensed practitioner.
4. The drug or drugs containing such a substance are new drugs so
related in their action to a drug or drugs already listed as having a
potential for abuse to make it likely that the drug will have the same
potentiality for abuse as such drugs, thus making it reasonable to
assume that there may be significant diversions from legitimate
channels, significant use contrary to or without medical advice, or
that it has a substantial capability of creating hazards to the health
of the user or to the safety of the community.
Marijuana and its primary psychoactive ingredient, [Delta]\9\-THC,
are controlled substances in schedule I under the CSA.
The HHS stated that one approved, marketed drug product contains
synthetic [Delta]\9\-THC, also known as dronabinol, and another
approved, marketed drug product contains a cannabinoid-like synthetic
compound that is structurally related to [Delta]\9\-THC, the main
active component in marijuana. Both products are controlled under the
CSA.
Marinol is a schedule III drug product containing synthetic
[Delta]\9\-THC (dronabinol) formulated in sesame oil in soft gelatin
capsules. Marinol was approved by the FDA in 1985 for the treatment of
nausea and vomiting associated with cancer chemotherapy in patients who
did not respond to conventional anti-emetic treatments. In 1992, FDA
approved Marinol for the treatment of anorexia associated with weight
loss in patients with acquired immunodeficiency syndrome (AIDS).
Marinol was originally placed into schedule II and later rescheduled to
schedule III under the CSA due to the low reports of abuse relative to
marijuana.
[[Page 53823]]
Cesamet is a drug product containing the schedule II substance
nabilone, a synthetic substance structurally related to [Delta]\9\-THC.
Cesamet was approved for marketing by the FDA in 1985 for the treatment
of nausea and vomiting associated with cancer chemotherapy. All other
naturally occurring cannabinoids in marijuana and their synthetic
equivalents with similar chemical structure and pharmacological
activity are already included as schedule I drugs under the CSA.
B. Abuse Liability Studies
In addition to the indicators suggested by the CSA's legislative
history, data as to preclinical and clinical abuse liability studies,
as well as actual abuse, including clandestine manufacture,
trafficking, and diversion from legitimate sources, are considered in
this factor.
Abuse liability evaluations are obtained from studies in the
scientific and medical literature. There are many preclinical measures
of a drug's effects that when taken together provide an accurate
prediction of the human abuse liability. Clinical studies of the
subjective and reinforcing effects in humans and epidemiological
studies provide quantitative data on abuse liability in humans and some
indication of actual abuse trends. Both preclinical and clinical
studies have clearly demonstrated that marijuana and [Delta]\9\-THC
possess the attributes associated with drugs of abuse: They function as
a positive reinforcer to maintain drug-seeking behavior, they function
as a discriminative stimulus, and they have dependence potential.
Preclinical and most clinical abuse liability studies have been
conducted with the psychoactive constituents of marijuana, primarily
[Delta]\9\-THC and its metabolite, 11-hydroxy-[Delta]\9\-THC.
[Delta]\9\-THC's subjective effects are considered to be the basis for
marijuana's abuse liability. The following studies provide a summary of
that data.
1. Preclinical Studies
[Delta]\9\-THC, the primary psychoactive component in marijuana, is
an effective reinforcer in laboratory animals, including primates and
rodents, as these animals will self-administer [Delta]\9\-THC. These
animal studies both predict and support the observations that
[Delta]\9\-THC, whether smoked as marijuana or administered by other
routes, produces reinforcing effects in humans. Such reinforcing
effects can account for the repeated abuse of marijuana.
a. Drug Discrimination Studies
The drug discrimination paradigm is used as an animal model of
human subjective effects (Solinas et al., 2006) and is a method where
animals are able to indicate whether a test drug is able to produce
physical or psychological changes similar to a known drug of abuse.
Animals are trained to press one bar (in an operant chamber) when they
receive a known drug of abuse and another bar when they receive a
placebo. When a trained animal receives a test drug, if the drug is
similar to the known drug of abuse, it will press the bar associated
with the drug.
Discriminative stimulus effects of [Delta]\9\-THC have specificity
for the pharmacological effects of cannabinoids found in marijuana
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al.,
1993; Wiley et al., 1995). As mentioned by the HHS, the discriminative
stimulus effects of cannabinoids appear to be unique because abused
drugs of other classes including stimulants, hallucinogens, opioids,
benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do
not fully substitute for [Delta]\9\-THC.
Laboratory animals including monkeys (McMahon et al., 2009), mice
(McMahon et al., 2008), and rats (Gold et al., 1992) are able to
discriminate cannabinoids from other drugs and placebo. The major
active metabolite of [Delta]\9\-THC, 11-hydroxy-[Delta]\9\-THC,
generalizes to [Delta]\9\-THC (Browne and Weissman, 1981). In addition,
according to the HHS, twenty-two other cannabinoids found in marijuana
also substitute for [Delta]\9\-THC. At least one cannabinoid, CBD, does
not substitute for [Delta]\9\-THC in rats (Vann et al., 2008).
b. Self-Administration Studies
Animal self-administration behavior associated with a drug is a
commonly used method for evaluating if the drug produces rewarding
effects and for predicting abuse potential (Balster, 1991; Balster and
Bigelow, 2003). Drugs that are self-administered by animals are likely
to produce rewarding effects in humans. As mentioned in the HHS review
document, earlier attempts to demonstrate self-administration of
[Delta]\9\-THC were unsuccessful and confounded by diet restrictions,
animal restraint, and known analgesic activity of [Delta]\9\-THC at
testing doses (Tanda and Goldberg, 2003; Justinova et al., 2003). Self-
administration of [Delta]\9\-THC was first demonstrated by Tanda et al.
(2000). Tanda et al. (2000) showed that squirrel monkeys that were
initially trained to self-administer cocaine (30 [micro]g/kg, i.v.)
self-administered 2 [micro]g/kg [Delta]\9\-THC (i.v.) and at a rate of
30 injections per one hour session. Tanda et al. (2000) used a lower
dose of [Delta]\9\-THC that was rapidly delivered (0.2 ml injection
over 200 ms) than in previous self-administration studies such that
analgesic activity of [Delta]\9\-THC was not a confounding factor. The
authors also stated that the doses were comparable to those doses used
by humans who smoke marijuana. A CB1 receptor antagonist (SR141716)
blocked this rewarding effect of THC.
Justinova et al. (2003) were able to demonstrate self-
administration of [Delta]\9\-THC in drug-na[iuml]ve squirrel monkeys
(no previous exposure to other drugs). The authors tested the monkeys
with several doses of [Delta]\9\-THC (1, 2, 4, 8, and 16 [micro]g/kg,
i.v.) and found that the maximal rates of self-administration were
observed with the 4 [micro]g/kg/infusion. Subsequently, Braida et al.
(2004) reported that rats will self-administer [Delta]\9\-THC when
delivered intracerebroventricularly (i.c.v.), but only at the lowest
doses tested (0.01-0.02 [micro]g/infusion, i.c.v.).
Self-administration behavior with [Delta]\9\-THC was found to be
antagonized in rats and squirrel monkeys by rimonabant (SR141716A, CB1
antagonist) and the opioid antagonists (naloxone and naltrexone) (Tanda
et al., 2000; Braida et al., 2004; Justinova et al., 2004).
c. Conditioned Place Preference Studies
Conditioned place preference (CPP) is a behavioral assay where
animals are given the opportunity to spend time in two distinct
environments: one where they previously received a drug and one where
they received a placebo. If the drug is reinforcing, animals in a drug-
free state will choose to spend more time in the environment paired
with the drug when both environments are presented simultaneously.
CPP has been demonstrated with [Delta]\9\-THC in rats but only at
low doses (0.075-1.0 mg/kg, i.p.; Braida et al., 2004). Rimonabant
(0.25-1.0 mg/kg, i.p.) and naloxone (0.5-2.0 mg/kg, i.p.) antagonized
[Delta]\9\-THC-mediated CPP (Braida et al., 2004). However, in another
study with rats, rimonabant was demonstrated to induce CPP at doses
ranging from 0.25-3.0 mg/kg (Cheer et al., 2000). Mice without [micro]-
opioid receptors did not exhibit CPP to [Delta]\9\-THC (paired with 1
mg/kg [Delta]\9\-THC, i.p.) (Ghozland et al., 2002).
2. Clinical Studies
In its scientific review (HHS, 2015), the HHS provided a list of
common subjective psychoactive responses to cannabinoids based on
information from several references (Adams and Martin, 1996; Gonzalez,
2007; Hollister, 1986;
[[Page 53824]]
Hollister, 1988; Institute of Medicine, 1982). Furthermore, Maldonado
(2002) characterized these subjective responses as pleasurable to most
humans and are generally associated with drug-seeking and/or drug-
taking. Later studies (Scherrer et al., 2009; Zeiger et al., 2010)
reported that high levels of positive psychoactive effects correlate
with increased marijuana use, abuse, and dependence. The list of the
common subjective psychoactive effects provided by the HHS (HHS, 2015)
is presented below:
(1) Disinhibition, relaxation, increased sociability, and
talkativeness.
(2) Increased merriment and appetite, and even exhilaration at high
doses.
(3) Enhanced sensory perception, which can generate an increased
appreciation of music, art, and touch.
(4) Heightened imagination, which can lead to a subjective sense of
increased creativity.
(5) Initial dizziness, nausea, tachycardia, facial flushing, dry
mouth, and tremor.
(6) Disorganized thinking, inability to converse logically, time
distortions, and short-term memory impairment.
(7) Ataxia and impaired judgment, which can impede driving ability
or lead to an increase in risk-taking behavior.
(8) Illusions, delusions, and hallucinations that intensify with
higher doses.
(9) Emotional lability, incongruity of affect, dysphoria,
agitation, paranoia, confusion, drowsiness, and panic attacks, which
are more common in inexperienced or high-dosed users.
The HHS mentioned that marijuana users prefer higher concentrations
of the principal psychoactive component ([Delta]\9\-THC) over lower
concentrations. In a clinical study with marijuana users (n = 12, usage
ranged from once a month to 4 times a week), subjects were given a
choice of 1.95% [Delta]\9\-THC marijuana or 0.63% [Delta]\9\-THC
marijuana after sampling both marijuana cigarettes in two choice
sessions. The marijuana cigarette with high THC was chosen in 21 out of
24 choice sessions or 87.5% of the time (Chait and Burke, 1994).
Furthermore, in a double-blind study, frequent marijuana users (n = 11,
usage at least 2 times per month with at least 100 occasions) when
given a low-dose of oral [Delta]\9\-THC (7.5 mg) were able to
distinguish the psychoactive effects better than occasional users (n =
10, no use within the past 4 years with 10 or fewer lifetime uses) and
also experienced fewer sedative effects (Kirk and de Wit, 1999).
Marijuana has also been recognized by scientific experts to have
withdrawal symptoms (negative reinforcement) following moderate and
heavy use. As discussed further in Factor 7, the DEA notes that the
American Psychiatric Association's (APA) Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5) included a list of
withdrawal symptoms following marijuana [cannabis] use (DSM-5, 2013).
C. Actual Abuse of Marijuana--National Databases Related to Marijuana
Abuse and Trafficking
Marijuana continues to be the most widely used illicit drug.
Evidence of actual abuse can be defined by episodes/mentions in
databases indicative of abuse/dependence. The HHS provided in its
recommendation (HHS, 2015) information relevant to actual abuse of
marijuana including data results from the National Survey on Drug Use
and Health (NSDUH), a Monitoring the Future (MTF) survey, the Drug
Abuse Warning Network (DAWN), and the Treatment Episode Data Set
(TEDS). These data sources provide quantitative information on many
factors related to abuse of a particular substance, including incidence
and patterns of use, and profile of the abuser of specific substances.
The DEA is providing updated information from these databases in this
discussion. The DEA also includes data on trafficking and illicit
availability of marijuana from DEA databases including the National
Forensic Laboratory Information System (NFLIS) and the National Seizure
System (NSS), formerly the Federal-wide Drug Seizure System (FDSS), as
well as other sources of data specific to marijuana, including the
Potency Monitoring Project and the Domestic Cannabis Eradication and
Suppression Program (DCE/SP).
1. National Survey on Drug Use and Health (NSDUH)
The National Survey on Drug Use and Health (NSDUH) is conducted
annually by the Department of Health and Human Service's Substance
Abuse and Mental Health Services Administration (SAMHSA). SAMHSA is the
primary source of estimates of the prevalence and incidence of
pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the
United States. The survey is based on a nationally representative
sample of the civilian, non-institutionalized population 12 years of
age and older. The survey excludes homeless people who do not use
shelters, active military personnel, and residents of institutional
group quarters such as jails and hospitals.
According to the 2014 NSDUH report, marijuana was the most commonly
used and abused illicit drug. That data showed that there were 22.2
million people who were past month users (8.4%) among those aged 12 and
older in the United States. (Note: NSDUH figures on marijuana use
include hashish use; the relative proportion of hashish use to
marijuana use is very low). Marijuana had the highest rate of past-year
dependence or abuse in 2014. The NSDUH report estimates that 3.0
million people aged 12 or older used an illicit drug for the first time
in 2014; a majority (70.3%) of these past year initiates reported that
their first drug used was marijuana. Among those who began using
illicit drugs in the past year, 65.6%, 70.3%, and 67.6% reported
marijuana as the first illicit drug initiated in 2012, 2013, and 2014
respectively. In 2014, the average age of marijuana initiates among 12-
to 49-year-olds was 18.5 years. These usage rates and demographics are
relevant in light of the risks presented.
Marijuana had the highest rate of past year dependence or abuse of
any illicit drug in 2014. The 2014 NSDUH report stated that 4.2 million
persons were classified with substance dependence or abuse of marijuana
in the past year (representing 1.6% of the total population aged 12 or
older, and 59.0% of those classified with illicit drug dependence or
abuse) based on criteria specified in the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition (DSM-IV).
Among past year marijuana users age 12 or older, 18.5% used
marijuana on 300 or more days within the previous 12 months in 2014.
This translates into 6.5 million people using marijuana on a daily or
almost daily basis over a 12-month period, significantly more than the
estimated 5.7 million daily or almost daily users in just the year
before. Among past month marijuana users, 41.6% (9.2 million) used the
drug on 20 or more days in the past month, a significant increase from
the 8.1 million who used marijuana 20 days or more in 2013.
2. Monitoring the Future (MTF)
Monitoring the Future (MTF) is an ongoing study which is funded
under a series of investigator-initiated competing research grants from
the National Institute on Drug Abuse (NIDA). MTF tracks drug use trends
among American adolescents in the 8th, 10th, and 12th grades. According
to its 2015 survey results, marijuana was the most commonly used
illicit drug, as was the case in previous years. Approximately 6.5% of
8th graders,
[[Page 53825]]
14.8% of 10th graders, and 21.3% of 12th graders surveyed in 2015
reported marijuana use during the past month prior to the survey. A
number of high school students in 2015 also reported daily use in the
past month, including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th
graders, respectively.
3. Drug Abuse Warning Network (DAWN), Emergency Department (ED) Visits
The Drug Abuse Warning Network (DAWN) is a public health
surveillance system that monitors drug-related hospital emergency
department (ED) visits to track the impact of drug use, misuse, and
abuse in the United States. For the purposes of DAWN, the term ``drug
abuse'' applies if the following conditions are met: (1) The case
involved at least one of the following: use of an illegal drug, use of
a legal drug contrary to directions, or inhalation of a non-
pharmaceutical substance; and (2) the substance was used for one of the
following reasons: because of drug dependence, to commit suicide (or
attempt to commit suicide), for recreational purposes, or to achieve
other psychic effects. Importantly, many factors can influence the
estimates of ED visits, including trends in overall use of a substance
as well as trends in the reasons for ED usage. For instance, some drug
users may visit EDs for life-threatening issues while others may visit
to seek care for detoxification because they needed certification
before entering treatment. Additionally, DAWN data do not distinguish
the drug responsible for the ED visit from other drugs that may have
been used concomitantly. As stated in a DAWN report, ``Since marijuana/
hashish is frequently present in combination with other drugs, the
reason for the ED visit may be more relevant to the other drug(s)
involved in the episode.''
In 2011, marijuana was involved in 455,668 ED visits out of
2,462,948 total ED visits involving all abuse or misuse in the United
States and out of 1.25 million visits involving abuse or misuse of
illicit drugs (excluding alcohol-related visits), as estimated by DAWN.
This is lower than the number of ED visits involving cocaine (505,224)
and higher than the number of ED visits involving heroin (258,482) and
stimulants (e.g., amphetamine, methamphetamine) (159,840). Visits
involving the other major illicit drugs, such as MDMA, GHB, LSD and
other hallucinogens, PCP, and inhalants, were much less frequent,
comparatively.
In young patients, marijuana is the illicit drug most frequently
involved in ED visits, according to DAWN estimates, with 240.2
marijuana-related ED visits per 100,000 population ages 12 to 17, 443.8
per 100,000 population ages 18 to 20, and 446.9 per 100,000 population
ages 21 to 24.
4. Treatment Episode Data Set (TEDS) System
The Treatment Episode Data Set (TEDS) system is part of the SAMHSA
Drug and Alcohol Services Information System and is a national census
of annual admissions to state licensed or certified, or
administratively tracked, substance abuse treatment facilities. The
TEDS system contains information on patient demographics and substance
abuse problems of admissions to treatment for abuse of alcohol and/or
drugs in facilities that report to state administrative data systems.
For this database, the primary substance of abuse is defined as the
main substance of abuse reported at the time of admission. TEDS also
allows for the recording of two other substances of abuse (secondary
and tertiary).
In 2011, the TEDS system included 1,928,792 admissions to substance
abuse treatment; in 2012 there were 1,801,385 admissions; and in 2013
there were 1,683,451 admissions. Marijuana/hashish was the primary
substance of abuse for 18.3% (352,397) of admissions in 2011; 17.5%
(315,200) in 2012; and 16.8% (281,991) in 2013. Of the 281,991
admissions for marijuana/hashish treatment in 2013, 24.3% used
marijuana/hashish daily. Among those treated for marijuana/hashish as
the primary substance in 2013, 27.4% were ages 12 to 17 years and 29.7%
were ages 18 to 24 years. Those admitted for marijuana/hashish were
mostly male (72.6%) and non-Hispanic (82.2%). Non-hispanic whites
(43.2%) represented the largest ethnic group of marijuana admissions.
5. Forensic Laboratory Data
Data on marijuana seizures from federal, state, and local forensic
laboratories have indicated that there is significant trafficking of
marijuana. The National Forensic Laboratory System (NFLIS) is a program
sponsored by the Drug Enforcement Administration's Office of Diversion
Control. NFLIS systematically collects drug identification results and
associated information from drug exhibits encountered by law
enforcement and analyzed in federal, state, and local forensic
laboratories. NFLIS is a comprehensive information system that includes
data from 278 individual forensic laboratories that report more than
91% of the drug caseload in the U.S. NFLIS captures data for all drugs
and chemicals identified and reported by forensic laboratories. More
than 1,700 unique substances are represented in the NFLIS database.
Data from NFLIS showed that marijuana was the most frequently
identified drug in federal, state, and local laboratories from January
2004 through December 2014. Marijuana accounted for between 29.47% and
34.84% of all drug exhibits analyzed annually during that time frame
(Table 1).
[[Page 53826]]
[GRAPHIC] [TIFF OMITTED] TP12AU16.040
Since 2004, the total number of reports of marijuana and the amount
of marijuana encountered federally has remained high (see data from
Federal-wide Drug Seizure System and Domestic Cannabis Eradication and
Suppression Program below).
6. Federal-Wide Drug Seizure System
The Federal-wide Drug Seizure System (FDSS) contains information
about drug seizures made within the jurisdiction of the United States
by the Drug Enforcement Administration, the Federal Bureau of
Investigation, United States Customs and Border Protection, and United
States Immigration and Customs Enforcement. It also records maritime
seizures made by the United States Coast Guard. Drug seizures made by
other Federal agencies are included in the FDSS database when drug
evidence custody is transferred to one of the agencies identified
above. FDSS is now incorporated into the National Seizure System (NSS),
which is a repository for information on clandestine laboratory and
contraband (chemicals and precursors, currency, drugs, equipment and
weapons). FDSS reports total federal drug seizures [in kilograms (kg)]
of substances such as cocaine, heroin, MDMA, methamphetamine, and
cannabis (marijuana and hashish). The yearly volume of cannabis seized
(Table 2), consistently exceeding a thousand metric tons per year,
shows that cannabis is very widely trafficked in the United States.
[GRAPHIC] [TIFF OMITTED] TP12AU16.041
7. Potency Monitoring Project
The University of Mississippi's Potency Monitoring Project (PMP),
through a contract with the National Institute on Drug Abuse (NIDA),
analyzes and compiles data on the [Delta]\9\-THC concentrations of
marijuana, hashish and hash oil samples provided by DEA regional
laboratories and by state and local police agencies. After 2010, PMP
has analyzed only marijuana samples provided by DEA regional
laboratories. As indicated in Figure 1, the percentage of [Delta]\9\-
THC increased from 1995 to 2010 with an average THC content of 3.75% in
1995 and 9.53% in 2010. In examining marijuana samples only provided by
DEA laboratories, the average [Delta]\9\-THC content was 3.96% in 1995
in comparison to 11.16% in 2015.
[[Page 53827]]
[GRAPHIC] [TIFF OMITTED] TP12AU16.042
8. The Domestic Cannabis Eradication and Suppression Program
The Domestic Cannabis Eradication and Suppression Program (DCE/SP)
was established in 1979 to reduce the supply of domestically cultivated
marijuana in the United States. The program was designed to serve as a
partnership between federal, state, and local agencies. Only California
and Hawaii were active participants in the program at its inception.
However, by 1982 the program had expanded to 25 states and by 1985 all
50 states were participants. Cannabis is cultivated in remote locations
and frequently on public lands and illicitly grown in all states. Data
provided by the DCE/SP (Table 3) show that in the United States in
2014, there were 3,904,213 plants eradicated in outdoor cannabis
cultivation areas compared to 2,597,798 plants in 2000. Significant
quantities of marijuana were also eradicated from indoor cultivation
operations. There were 396,620 indoor plants eradicated in 2014
compared to 217,105 eradicated in 2000.
[[Page 53828]]
[GRAPHIC] [TIFF OMITTED] TP12AU16.043
The recent statistics from these various surveys and databases show
that marijuana continues to be the most commonly used illicit drug,
with considerable rates of heavy abuse and dependence. They also show
that marijuana is the most readily available illicit drug in the United
States.
Petitioners' Major Comment in Relation to Factor 1 and the Government's
Responses
(1) The petitioner states on pages 1-2 of the petition that
``[p]ure THC (Marinol), the primary psychoactive ingredient in
marijuana has been placed in Schedule III. However, unlike Marinol,
marijuana has other cannabinoids that help to mitigate the psychoactive
effects of THC and reduce the potential for abuse. Therefore, the THC
in marijuana can not have the high potential for abuse required for
placement in Schedule I.''
First, the petitioners failed to review the indicators of abuse
potential, as discussed in the legislative history of the CSA. The
petitioners did not use data on marijuana usage, diversion,
psychoactive properties, and dependence in their evaluation of
marijuana abuse potential. The HHS and the DEA discuss those indicators
above in this factor. HHS's evaluation of the full range of data led
HHS and DEA to conclude that marijuana has a high potential for abuse.
Second, the HHS indicated that modulating effects of the other
cannabinoids in marijuana on [Delta]\9\-THC have not been demonstrated
in controlled studies. Specifically, HHS concluded in its 8-factor
analysis that ``any possible mitigation of delta-9-THC's psychoactive
effects by CBD will not occur for most marijuana users.''
Marinol was rescheduled from schedule II to schedule III on July 2,
1999 (64 FR 35928, DEA 1999). In assessing Marinol, HHS compared
Marinol to marijuana on several aspects of abuse potential and found
that major differences between the two, such as formulation,
availability, and usage, contribute to differences in abuse potential.
The psychoactive effects from smoking are generally more rapid and
intense that those that occur through oral administration (HHS, 2015;
Wesson and Washburn, 1990; Hollister and Gillespie, 1973). Therefore,
as concluded by both the HHS and the DEA, the delayed onset of action
and longer duration of action from an oral dose of Marinol may
contribute in limiting the abuse potential of Marinol relative to
marijuana, which is most often smoked. The HHS also stated that the
extraction and purification of dronabinol from the encapsulated sesame
oil mixture of Marinol is highly complex and difficult and that the
presence of sesame oil mixture may preclude the smoking of Marinol-
laced cigarettes.
Additionally, the FDA approved a New Drug Application (NDA) for
Marinol, indicating a legitimate medical use for Marinol in the United
States and allowing for Marinol to be rescheduled into schedule II and
subsequently into schedule III of the CSA. The HHS mentioned that
marijuana and Marinol differ on a wide variety of factors and these
differences are major reasons for differential scheduling of marijuana
and Marinol. Marijuana, as discussed more fully in Factors 3 and 6,
does not have a currently accepted medical use in the United States, is
highly abused, and has a lack of accepted safety.
Finally, the DEA notes that under the CSA, for a substance to be
placed in schedule II, III, IV, or V, it must have a currently accepted
medical use in treatment in the United States.\44\ As DEA has
previously stated, Congress established only one schedule, schedule I,
for drugs of abuse with ``no currently accepted medical use in
treatment in the United States.'' 76 FR 40552 (2011). Thus, any attempt
to compare the relative abuse potential of schedule I substance to that
of a substance in another schedule is inconsequential since a schedule
I substance must remain in schedule I until it has been found to have a
currently accepted medical use in treatment in the United States.
---------------------------------------------------------------------------
\44\ See Americans for Safe Access, 706 F.3d at 440.
---------------------------------------------------------------------------
Factor 2: Scientific Evidence of the Drug's Pharmacological Effects, if
Known
The HHS stated that there are large amounts of scientific data on
the neurochemistry, mechanistic effects, toxicology, and pharmacology
of marijuana. A scientific evaluation, as conducted by the HHS and the
DEA, of marijuana's neurochemistry, human and animal behavioral
pharmacology, central nervous system effects, and other pharmacological
effects (e.g. cardiovascular, immunological effects) is presented
below.
[[Page 53829]]
Neurochemistry
Marijuana contains numerous constituents such as cannabinoids that
have a variety of pharmacological actions. The HHS stated that
different marijuana samples derived from various cultivated strains may
differ in their chemical constituents including [Delta]\9\-THC and
other cannabinoids. Therefore marijuana products from different strains
will have different biological and pharmacological effects. The
chemical constituents of marijuana are discussed further in Factor 3.
The primary site of action for cannabinoids such as [Delta]\9\-THC
is at the cannabinoid receptor. Two cannabinoid receptors, CB1 and CB2,
have been identified and characterized (Battista et al., 2012;
Piomelli, 2005) and are G-protein-coupled receptors. Activation of
these inhibitory G-protein-coupled receptors inhibits adenylate cyclase
activity, which prevents conversion of ATP to cyclic AMP. Cannabinoid
receptor activation also results in inhibition of N- and P/Q-type
calcium channels and activates inwardly rectifying potassium channels
(Mackie et al., 1995; Twitchell et al., 1997). The HHS mentioned that
inhibition of N-type calcium channels decreases neurotransmitter
release and this may be the underlying mechanism in the ability of
cannabinoids to inhibit acetylcholine, norepinephrine and glutamate
from specific areas of the brain. These cellular actions may underlie
the antinociceptive and psychoactive effects of cannabinoids.
[Delta]\9\-THC acts as an agonist at cannabinoid receptors.
CB1 receptors are primarily found in the central nervous system and
are located mainly in the basal ganglia, hippocampus and cerebellum of
the brain (Howlett et al., 2004). CB1 receptors are also located in
peripheral tissues such as the immune system (De Petrocellis and Di
Marzo, 2009), but the concentration of CB1 receptors there is
considerably lower than in the central nervous system (Herkenham et
al., 1990; 1992). CB2 receptors are found primarily in the immune
system and predominantly in B lymphocytes and natural killer cells
(Bouaboula et al., 1993). CB2 receptors are also found in the central
nervous system, primarily in the cerebellum and hippocampus (Gong et
al., 2006).
Two endogenous ligands to the cannabinoid receptors, anandamide and
arachidonyl glycerol (2-AG), were identified in 1992 (Devane et al.,
1992) and 1995 (Mechoulam et al., 1995), respectively. Anandamide is a
low-efficacy agonist (Brievogel and Childers, 2000) and 2-AG is a high
efficacy agonist (Gonsiorek et al., 2000) to the cannabinoid receptors.
These endogenous ligands are present in both the central nervous system
and in the periphery (HHS, 2015).
[Delta]\9\-THC and cannabidiol (CBD) are two of the major
cannabinoids in marijuana. [Delta]\9\-THC is the major psychoactive
cannabinoid (Wachtel et al., 2002). [Delta]\9\-THC has similar affinity
for CB1 and CB2 receptors and acts as a weak agonist at CB2 receptors.
The HHS indicated that activation of CB1 receptors mediates
psychotropic effects of cannabinoids. CBD has low affinity for both CB1
and CB2 receptors. CBD has antagonistic effects at CB1 receptors, and
some inverse agonistic properties at CB2 receptors.
Animal Behavioral Effects
Animal abuse potential studies (drug discrimination, self-
administration, conditioned place preference) are discussed more fully
in Factor 1. Briefly, it was consistently demonstrated that [Delta]\9\-
THC, the primary psychoactive component in marijuana, and other
cannabinoids in marijuana have a distinct drug discriminative profile.
In addition, animals self-administer [Delta]\9\-THC, and [Delta]\9\-THC
in low doses produces conditioned place preference.
Central Nervous System Effects
Psychoactive Effects
The clinical psychoactive effects of marijuana are discussed more
fully in Factor 1. Briefly, the psychoactive effects from marijuana use
are considered pleasurable and associated with drug-seeking or drug-
taking (HHS, 2015; Maldonado, 2002). Further, it was noted by HHS that
marijuana users prefer higher concentrations of the principal
psychoactive component ([Delta]\9\-THC) over lower concentrations (HHS,
2015).
Studies have evaluated psychoactive effects of THC in the presence
of high CBD, CBC, or CBN ratios. Even though some studies suggest that
CBD may decrease some of [Delta]\9\-THC's psychoactive effects, the HHS
found that the ratios of CBD to [Delta]\9\-THC administered in the
studies were not comparable to the amounts found in marijuana used by
most people (Dalton et al., 1976; Karniol et al., 1974; Zwardi et al.,
1982). In fact, the CBD ratios in these studies are significantly
higher than the CBD found in most marijuana currently found on the
streets (Mehmedic et al., 2010). HHS indicated that most of the
marijuana available on the street has a high THC and low CBD content
and therefore any lessening of THC's psychoactive effects by CBD will
not occur for most marijuana users (HHS, 2015). Dalton et al. (1976)
reported that when volunteers smoked cigarettes with a ratio of 7 CBD
to 1 [Delta]\9\-THC (0.15 mg/kg CBD and 0.025 mg/kg [Delta]\9\-THC),
there was a significant decrease in ratings of acute subjective effects
and achieving a ``high'' in comparison to smoking [Delta]\9\-THC alone.
In oral administration studies, the subjective effects and anxiety
produced by combination of CBD and THC in a ratio of at least 1:2 CBD
to [Delta]\9\-THC (15, 30, 60 mg CBD to 30 mg [Delta]\9\-THC; Karniol
et al., 1974) or a ratio of 2:1 CBD to [Delta]\9\-THC (1 mg/kg CBD to
0.5 mg/kg [Delta]\9\-THC; Zuardi et al., 1982) are less than those
produced by [Delta]\9\-THC administered alone.
In one study (Ilan et al., 2005), the authors calculated the
naturally occurring concentrations of CBC and CBD in marijuana
cigarettes with either 1.8 or 3.6% [Delta]\9\-THC by weight. The
authors varied the concentrations of CBC and CBD for each concentration
of [Delta]\9\-THC in the marijuana cigarettes. Administrations in
healthy marijuana users (n=23) consisted of either: (1) Low CBC (0.1%
by weight) and low CBD (0.2% by weight); (2) high CBC (0.5% by weight)
and low CBD; (3) low CBC and high CBD (1.0% by weight); or 4) high CBC
and high CBD and the users were divided into low [Delta]\9\-THC (1.8%
by weight) and high [Delta]\9\-THC (3.6% by weight) groups. Subjective
psychoactive effects were significantly greater for all groups in
comparison to placebo and there were no significant differences in
effects among the treatments (Ilan et al., 2005).
The HHS also referred to a study with [Delta]\9\-THC and cannabinol
(CBN) (Karniol et al., 1975). In this study, oral administration of
either 12.5, 25, or 50 mg CBN combined with 25 mg [Delta]\9\-THC (ratio
of at least 1:2 CBN to [Delta]\9\-THC) significantly increased
subjective psychoactive ratings of [Delta]\9\-THC compared to
[Delta]\9\-THC alone (Karniol et al., 1975).
Behavioral Impairment
Several factors may influence marijuana's behavioral effects
including the duration (chronic or short term), frequency (daily,
weekly, or occasionally), and amount of use (heavy or moderate).
Researchers have examined how long behavioral impairments persist
following chronic marijuana use. These studies used self-reported
histories of exposure duration, frequency, and amount of marijuana use,
and administered several performance and cognitive tests at different
time points following
[[Page 53830]]
marijuana abstinence. According to HHS, behavioral impairments may
persist for up to 28 days of abstinence in chronic marijuana users.
Psychoactive effects of marijuana can lead to behavioral impairment
including cognitive decrements and decreased ability to operate motor
vehicles (HHS, 2015). Block et al. (1992) evaluated cognitive measures
in 48 healthy male subjects following smoking a marijuana cigarette
that contained 2.57% or 19 mg [Delta]\9\-THC by weight or placebo. Each
subject participated in eight sessions (four sessions with marijuana;
four sessions with placebo) and several cognitive and psychomotor tests
were administered (e.g. verbal recall, facial recognition, text
learning, reaction time). Marijuana significantly impaired performances
in most of these cognitive and psychomotor tests (Block et al., 1992).
Ramaekers et al. (2006) reported that in 20 recreational users of
marijuana, acute administration of 250 [micro]g/kg and 500 [micro]g/kg
[Delta]\9\-THC in smoked marijuana resulted in dose-dependent
impairments in cognition, motor impulsivity, motor control (tracking
impairments), and risk taking. In another study (Kurzthaler et al.,
1999), when 290 [micro]g/kg [Delta]\9\-THC was administered via a
smoked marijuana cigarette in 30 healthy volunteers with no history of
substance abuse there were significant impairments of motor speed and
accuracy. Furthermore, administration of 3.95% [Delta]\9\-THC in a
smoked marijuana cigarette increased the latency in a task of simulated
braking in a vehicle (Liguori et al., 1998). The HHS noted that the
motor impairments reported in these studies (Kurzthaler et al., 1999;
Liguori et al., 1998) are critical skills needed for operating a
vehicle.
As mentioned in the HHS document, some studies examined the
persistence of the behavioral impairments immediately after marijuana
administration. Some of marijuana's acute effects may still be present
for at least 24 hours after the acute psychoactive effects have
subsided. In a brief communication, Heishmann et al. (1990) reported
that there were cognitive impairments (digit recall and arithmetic
tasks) in two out of three experienced marijuana smokers for 24 hours
after smoking marijuana cigarettes containing 2.57% [Delta]\9\-THC.
However, Fant et al. (1998) evaluated subjective effects and
performance measures for up to 25 hours in 10 healthy males after
exposure to either 1.8% or 3.6% [Delta]\9\-THC in marijuana cigarettes.
Peak decrements in subjective and performance measures were noted
within 2 hours of marijuana exposure but there were minimal residual
alterations in subjective or performance measures at 23-25 hours after
exposure.
Persistence of behavioral impairments following repeated and
chronic use of marijuana has also been investigated and was reviewed in
the HHS document (HHS, 2015). In particular, researchers examined how
long behavioral impairments last following chronic marijuana use. In
studies examining persistence of effects in chronic and heavy marijuana
users, there were significant decrements in cognitive and motor
function tasks in all studies of up to 27 days, and in most studies at
28 days (Solowij et al., 2002; Messinis et al., 2006; Lisdahl and
Price, 2012; Pope et al., 2002; Bolla et al., 2002; Bolla et al.,
2005). In studies that followed heavy marijuana users for longer than
28 days and up to 20 years of marijuana abstinence, cognitive and
psychomotor impairments were no longer detected (Fried et al., 2005;
Lyons et al., 2004; Tait et al., 2011). For example, Fried et al.
(2005) reported that after 3 months of abstinence from marijuana, any
deficits in intelligence (IQ), memory, and processing speeds following
heavy marijuana use were no longer observed (Fried et al., 2005). In a
meta-analysis that examined non-acute and long-lasting effects of
marijuana, any deficits in neurocognitive performance that were
observed within the first month were no longer apparent after
approximately one month of abstinence (Schreiner and Dunn, 2012). HHS
further notes that in moderate marijuana users deficits in decision-
making skills were not observed after 25 days of abstinence and
additionally IQ, immediate memory and delayed memory skills were not
significantly impacted as observed with heavy and chronic marijuana
users (Fried et al., 2005; HHS, 2015)
As mentioned in the HHS document (HHS, 2015), the intensity and
persistence of neurological impairment from chronic marijuana use also
may be dependent on the age of first use. In two separate smaller scale
studies (less than 100 participants per exposure group), Fontes et al.
(2011) and Gruber et al. (2012) compared neurological function in early
onset (chronic marijuana use prior to age 15 or 16) and late onset
(chronic marijuana use after age 15 or 16) heavy marijuana users and
found that there were significant deficits in executive neurological
function in early onset users which were not observed or were less
apparent in late onset users. In a prospective longitudinal birth
cohort study following 1,037 individuals (Meier et al., 2012), a
significant decrease in IQ and neuropsychological performance was
observed in adolescent-onset users and persisted even after abstinence
from marijuana for at least one year. However, Meier et al (2012)
reported in there was no significant change in IQ in adult-onset users.
The HHS noted that there is some evidence that the severity of the
persistent neurological impairments may also be due in part to the
amount of marijuana usage. In the study mentioned above, Gruber et al.
(2012) found that the early onset users consumed three times as much
marijuana per week and used it twice as often as late onset users.
Meier et al. (2012) reported in their study, mentioned above, that
there was a correlation between IQ deficits in adolescent onset users
and the increased amount of marijuana used.
Behavioral Effects of Prenatal Exposure
In studies that examined effects of prenatal marijuana exposure,
many of the pregnant women also used alcohol and tobacco in addition to
marijuana. Even though other drugs were used in conjunction with
marijuana, there is evidence of an association between heavy prenatal
marijuana exposure and deficits in some cognitive function. There have
been two prospective longitudinal birth cohort studies following
individuals prenatally exposed to marijuana from birth until adulthood:
The Ottawa Prenatal Prospective Study (OPPS; Fried et al., 1980), and
the Maternal Health Practices and Child Development Project (MHPCD; Day
et al., 1985). Both longitudinal studies report that heavy prenatal
marijuana use is associated with decreased performance on tasks
assessing memory, verbal and quantitative reasoning in 4-year-olds
(Fried and Watkinson, 1990) and in 6 year olds (Goldschmidt et al.,
2008). In subsequent studies with the OPPS cohort, deficits in
sustained attention were reported in children ages 6 and 13-16 years
(Fried et al., 1992; Fried, 2002) and deficits in executive
neurological function were observed in 9- and 12-year-old children
(Fried et al., 1998). DEA further notes that with the MHPCD cohort,
follow-up studies reported an increased rate of delinquent behavior
(Day et al., 2011) and decreased achievement test scores (Goldschmidt
et al., 2012) at age 14. When the MHPCD cohort was followed to age 22,
there was a marginal (p = 0.06) increase in psychosis with prenatal
marijuana exposure and early onset of marijuana use (Day et al., 2015).
[[Page 53831]]
Association of Marijuana Use With Psychosis
There has been extensive research to determine whether marijuana
usage is associated with development of schizophrenia or other
psychoses, and the HHS indicated that the available data do not suggest
a causative link between marijuana and the development of psychosis
(HHS, 2015; Minozzi et al., 2010). As mentioned in the HHS review (HHS,
2015), numerous large scale longitudinal studies demonstrated that
subjects who used marijuana do not have a greater incidence of
psychotic diagnoses compared to non-marijuana users (van Os et al.,
2002; Fergusson et al., 2005; Kuepper et al., 2011). Further, the HHS
commented that when analyzing the available data examining the
association between marijuana and psychosis, it is critical to
differentiate whether the patients in a study are already diagnosed
with psychosis or if the individuals have a limited number of symptoms
associated with psychosis without qualifying for a diagnosis of the
disorder.
As mentioned by the HHS, some of the studies examining the
association between marijuana and psychosis utilized non-standard
methods to categorize psychosis and these methods did not conform to
the criteria in the Diagnostic and Statistical Manual (DSM-5) or the
International Classification of Diseases (ICD-10) and would not be
appropriate for use in evaluating the association between marijuana use
and psychosis. For example, researchers characterized psychosis as
``schizophrenic cluster'' (Maremmani et al., 2004), ``subclinical
psychotic symptoms'' (van Gastel et al., 2012), ``pre-psychotic
clinical high risk'' (van der Meer et al., 2012), and symptoms related
to ``psychosis vulnerability'' (Griffith-Lendering et al., 2012).
The HHS discussed an early epidemiological study conducted by
Andreasson et al. (1987), which examined the link between psychosis and
marijuana use. In this study, about 45,000 18- and 19-year-old male
Swedish subjects provided detailed information on their drug-taking
history and 274 of these subjects were diagnosed with schizophrenia
over a 14-year period (1969-1983). Out of the 274 subjects diagnosed
with psychosis, 21 individuals (7.7%) had used marijuana more than 50
times, while 197 individuals (72%) never used marijuana. As presented
by the authors (Andreasson et al., 1987), individuals who claimed to
take marijuana on more than 50 occasions were 6 times more likely to be
diagnosed with schizophrenia than those who had never consumed the
drug. The authors concluded that marijuana users who are vulnerable to
developing psychoses are at the greatest risk for schizophrenia. In a
35 year follow up to the subjects evaluated in Andreasson et al.
(1987), Manrique-Garcia et al. (2012) reported similar findings. In the
follow up study, 354 individuals developed schizophrenia. Of those, 32
individuals (9%) had used marijuana more than 50 times and were 6.3
times more likely to develop schizophrenia. 255 of the 354 individuals
(72%) never used marijuana.
The HHS also noted that many studies support the assertion that
psychosis from marijuana usage may manifest only in individuals already
predisposed to development of psychotic disorders. Marijuana use may
precede diagnosis of psychosis (Schimmelmann et al., 2011), but most
reports indicate that prodromal symptoms of schizophrenia are observed
prior to marijuana use (Schiffman et al., 2005). In a review examining
gene-environmental interaction between marijuana exposure and the
development of psychosis, it was concluded that there is some evidence
to support that marijuana use may influence the development of
psychosis but only for susceptible individuals (Pelayo-Teran et al.,
2012).
Degenhardt et al. (2003) modeled the prevalence of schizophrenia
against marijuana use across eight birth cohorts in individuals born
during 1940 to 1979 in Australia. Even though there was an increase in
marijuana use in the adult subjects over this time period, there was
not an increase in diagnoses of psychosis for these same subjects. The
authors concluded that use of marijuana may increase schizophrenia only
in persons vulnerable to developing psychosis.
Cardiovascular and Autonomic Effects
The HHS stated that acute use of marijuana causes an increase in
heart rate (tachycardia) and may increase blood pressure (Capriotti et
al., 1988; Benowitz and Jones, 1975). There is some evidence that
associates the increased heart rate from [Delta]\9\-THC exposure with
excitation of the sympathetic and depression of the parasympathetic
nervous systems (Malinowska et al., 2012). Tolerance to tachycardia
develops with chronic exposure to marijuana (Jones, 2002; Sidney,
2002).
Prolonged exposure to [Delta]\9\-THC results in a decrease in heart
rate (bradycardia) and hypotension (Benowitz and Jones, 1975). These
effects are thought to be mediated through peripherally located,
presynaptic CB1 receptor inhibition of norepinephrine release with
possible direct activation of vascular cannabinoid receptors (Wagner et
al., 1998; Pacher et al., 2006).
As stated in the HHS recommendation (HHS, 2015), marijuana exposure
causes orthostatic hypotension (fainting-like feeling; sudden drop in
blood pressure upon standing up) and tolerance can develop to this
effect upon repeated, chronic exposure (Jones, 2002). Tolerance to
orthostatic hypotension is potentially related to plasma volume
expansion, but tolerance does not develop to supine hypotensive effects
(Benowitz and Jones, 1975).
Marijuana smoking, particularly by those with some degree of
coronary artery or cerebrovascular disease, poses risks such as
increased cardiac work, increased catecholamines and carboxyhemoglobin,
myocardial infarction and postural hypotension (Benowitz and Jones,
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al.,
2012). However, electrocardiographic changes were minimal after
administration of large cumulative doses of [Delta]\9\-THC (Benowitz
and Jones, 1975)
The DEA notes two recent reports that reviewed several case studies
on marijuana and cardiovascular complications (Panayiotides, 2015;
Hackam, 2015). Panayiotides (2015) reported that approximately 25.6% of
the cardiovascular cases from marijuana use resulted in death from data
provided by the French Addictovigilance Network during the period of
2006-2010. Several case studies on marijuana usage and cardiovascular
events were discussed and it was concluded that although a causal link
cannot be established due to not knowing exact amounts of marijuana
used in the cases and confounding variables, the available evidence
supports a link between marijuana and cardiotoxicity. Hackham (2015)
reviewed 34 case reports or case series reports of marijuana and
stroke/ischemia in 64 stroke patients and reported that in 81% of the
cases there was a temporal relationship between marijuana usage and
stroke or ischemic event. The author concluded that collective analysis
of the case reports supports a causal link between marijuana use and
stroke.
Respiratory Effects
The HHS stated that transient bronchodilation is the most typical
respiratory effect of acute exposure to marijuana (Gong et al., 1984).
In a recent
[[Page 53832]]
longitudinal study, information on marijuana use and pulmonary data
function were collected from 5,115 individuals over 20 years from 4
communities in the United States (Oakland, CA; Chicago, IL;
Minneapolis, MN; Birmingham, AL) (Pletcher et al., 2012). Of the 5,115
individuals, 795 individuals reported use of only marijuana (without
tobacco). The authors reported that occasional use of marijuana (7
joint-years for lifetime or 1 joint/day for 7 years or 1 joint/week for
49 years) does not adversely affect pulmonary function. Pletcher et al.
(2012) further concluded that there is some preliminary evidence
suggesting that heavy marijuana use may have a detrimental effect on
pulmonary function, but the sample size of heavy marijuana users in the
study was too small. Further, as mentioned in the HHS recommendation
document (HHS, 2015), long-term use of marijuana may lead to chronic
cough, increased sputum, as well as increased frequency of chronic
bronchitis and pharyngitis (Adams and Martin, 1996; Hollister, 1986).
The HHS stated that the evidence that marijuana may lead to cancer
of the respiratory system is inconsistent, with some studies suggesting
a positive correlation while others do not (Lee and Hancox, 2011;
Tashkin, 2005). The HHS noted a case series that reported lung cancer
occurrences in three marijuana smokers (age range 31-37 years) with no
history of tobacco smoking (Fung et al., 1999). Furthermore, in a case-
control study (n = 173 individuals with squamous cell carcinoma of the
head and neck; n = 176 controls; Zhang et al., 1999), prevalence of
marijuana use was 9.7% in controls and 13.9% in cases and the authors
reported that marijuana use may dose-dependently interact with
mutagenic sensitivity, cigarette smoking, and alcohol use to increase
risk associated with head and neck cancers (Zhang et al., 1999).
However, in a large clinical study with 1,650 subjects, no positive
correlation was found between marijuana use and lung cancer (Tashkin et
al., 2006). This finding held true regardless of the extent of
marijuana use when both tobacco use and other potential confounding
factors were controlled. The HHS concluded that new evidence suggests
that the effects of smoking marijuana on respiratory function and
cancer are different from the effects of smoking tobacco (Lee and
Hancox, 2011).
The DEA further notes the publication of recent review articles
critically evaluating the association between marijuana and lung
cancer. Most of the reviews agree that the association is weak or
inconsistent (Huang et al., 2015; Zhang et al., 2015; Gates et al.,
2014; Hall and Degenhardt, 2014). Huang et al. (2015) identified and
reviewed six studies evaluating the association between marijuana use
and lung cancer and the authors concluded that an association is not
supported most likely due to the small amounts of marijuana smoked in
comparison to tobacco. Zhang et al. (2015) examined six case control
studies from the US, UK, New Zealand, and Canada within the
International Lung Cancer Consortium and found that there was a weak
association between smoking marijuana and lung cancer in individuals
who never smoked tobacco, but precision of the association was low at
high marijuana exposure levels. Hall and Degenhardt (2014) noted that
even though marijuana smoke contains several of the same carcinogens
and co-carcinogens as tobacco smoke (Roth et al., 1998) and has been
found to be mutagenic and carcinogenic in the mouse skin test,
epidemiological studies have been inconsistent, but more consistent
positive associations have been reported in case control studies.
Finally Gates et al. (2014), reviewed the studies evaluating marijuana
use and lung cancer and concluded that there is evidence that marijuana
produces changes in the respiratory system (precursors to cancer) that
could lead to lung cancer, but overall association is weak between
marijuana use and lung cancer especially when controlling for tobacco
use.
Endocrine System
Reproductive Hormones
The HHS stated that administration of marijuana to humans does not
consistently alter the endocrine system. In a controlled human exposure
study (n = 4 males), subjects were acutely administered smoked
marijuana containing 2.8% [Delta]\9\-THC or placebo and an immediate
significant decrease in luteinizing hormone and an increase in cortisol
was reported in the subjects that smoked marijuana (Cone et al., 1986).
Furthermore, as cited by the HHS, two later studies (Dax et al., 1989;
Block et al., 1991) reported no changes in hormone levels. Dax et al.
(1989) recruited male volunteers (n = 17) that were occasional or heavy
users of marijuana. Following exposure to smoked [Delta]\9\-THC (18 mg/
cigarette) or oral [Delta]\9\-THC (10 mg three times per day for three
days and on the morning of the fourth day), the subjects in that study
showed no changes in plasma adrenocorticotropic hormone (ACTH),
cortisol, prolactin, luteinizing hormone, or testosterone levels.
Additionally, Block et al. (1991) compared plasma hormone levels
amongst non-users as well as infrequent, moderate, and frequent users
of marijuana (n = 93 men and 56 women) and found that chronic use of
marijuana (infrequent, moderate, and frequent users) did not
significantly alter concentrations of testosterone, luteinizing
hormone, follicle stimulating hormone, prolactin, or cortisol.
The HHS noted that there is a discrepancy in the effect of
marijuana on female reproductive system functionality between animals
and humans (HHS, 2015). Female rhesus monkeys that were administered
2.5 mg/kg [Delta]\9\-THC, i.m., during days 1-18 of the menstrual cycle
had reduced progesterone levels and ovulation was suppressed (Asch et
al., 1981). However, women who smoked marijuana (1 gram marijuana
cigarette with 1.8% [Delta]\9\-THC) during the periovulatory period
(24-36 hours prior to ovulation) did not exhibit changes in
reproductive hormone levels or their menstrual cycles (Mendelson and
Mello, 1984). In a review article by Brown and Dobs (2002), the authors
state that endocrine changes observed with marijuana are no longer
observed with chronic administration and this may be due to drug
tolerance.
Reproductive Cancers
The HHS stated that recent studies support a possible association
between frequent, long-term marijuana use and increased risk of
testicular germ cell tumors. In a hospital-based case-control study,
the frequency of marijuana use was compared between testicular germ
cell tumor (TGCT) patients (n = 187) and controls (n = 148) (Trabert et
al., 2011). TGCT patients were more likely to be frequent marijuana
users than controls with an odds ratio (OR) of 2.2 (95% confidence
limits of 1.0-5.1) and were less likely to be infrequent or short-term
users with odds ratios of 0.5 and 0.6, respectively in comparison to
controls (Trabert et al., 2011). The DEA further notes that in two
population-based case-control studies (Daling et al., 2009; Lacson et
al., 2012), marijuana use was compared between patients diagnosed with
TGCT and matched controls in Washington State or Los Angeles County. In
both studies, it was reported that TCGT patients were twice as likely
as controls to use marijuana. Authors of both studies concluded that
marijuana use is associated with an elevated risk of TGCT (Daling et
al., 2009; Lacson et al., 2012).
The HHS cited a study (Sarfaraz et al., 2005) demonstrating that
WIN 55,212-2 (a mixed CB1/CB2 agonist) induces apoptosis (one form of
cell death) in
[[Page 53833]]
prostate cancer cells and decreases expression of androgen receptors
and prostate specific antigens, suggesting a potential therapeutic
value for cannabinoid agonists in the treatment of prostate cancer, an
androgen-stimulated type of carcinoma.
Other hormones (e.g. Thyroid, Appetite)
In more recent studies, as cited by the HHS, chronic marijuana use
by subjects (n = 39) characterized as dependent on marijuana according
to the ICD-10 criteria did not affect serum levels of thyroid hormones:
TSH (thyrotropin), T4 (thyroxine), and T3 (triiodothyronine) (Bonnet,
2013). With respect to appetite hormones, in a pilot study with HIV-
positive males, smoking marijuana dose-dependently increased plasma
levels of ghrelin and leptin and decreased plasma levels of peptide YY
(Riggs et al., 2012).
The HHS stated that [Delta]\9\-THC reduces binding of the
corticosteroid dexamethasone in hippocampal tissue from
adrenalectomized rats and acute [Delta]\9\-THC releases corticosterone,
with tolerance developing to this effect with chronic administration
(Eldridge >et al., 1991). These data suggest that [Delta]\9\-THC may
interact with the glucocorticoid receptor system.
Immune System
The HHS stated that cannabinoids alter immune function but that
there can be differences between the effects of synthetic, natural, and
endogenous cannabinoids (Croxford and Yamamura, 2005; Tanasescu and
Constantinescu, 2010).
The HHS noted that there are conflicting results in animal and
human studies with respect to cannabinoid effects on immune functioning
in subjects with compromised immune systems. Abrams et al. (2003)
examined the effects of marijuana and [Delta]\9\-THC in 62 HIV-1-
infected patients. Subjects received one of three treatments, three
times a day: smoked marijuana cigarette containing 3.95% [Delta]\9\-
THC, oral tablet containing [Delta]\9\-THC (2.5 mg oral dronabinol), or
oral placebo. There were no changes in CD4+ and CD8+ cell counts, HIV
RNA levels, or protease inhibitor levels in any of the treatment groups
(Abrams et al., 2003). Therefore, use of cannabinoids showed no short-
term adverse virologic effects in individuals with compromised immune
systems. Conversely, Roth et al. (2005) reported that in
immunodeficient mice implanted with human blood cells infected with
HIV, exposure to [Delta]\9\-THC in vivo suppresses immune function,
increases HIV co-receptor expression, and acts as a cofactor to enhance
HIV replication.
The DEA notes two recent clinical studies reporting a decrease in
cytokine and interleukin levels following marijuana use. Keen et al.
(2014) compared the differences in the levels of IL-6 (interleukin-6),
a proinflammatory cytokine, amongst non-drug users (n = 78), marijuana
only users (n = 46) and marijuana plus other drug users (n = 45) in a
community-based sample of middle-aged African Americans (Keen et al.,
2014). After adjusting for confounders, analyses revealed that lifetime
marijuana only users had significantly lower IL-6 levels than the
nonuser group. Further, Sexton et al. (2014) compared several immune
parameters in healthy individuals and subjects with multiple sclerosis
(MS) and found that the chronic use of marijuana resulted in reduced
monocyte migration, and decreased levels of CCL2 and IL-17 in both
healthy and MS groups.
The DEA also notes a review suggesting that [Delta]\9\-THC
suppresses the immune responses in experimental animal models and in
vitro and that these changes may be primarily mediated through the CB2
cannabinoid receptor (Eisenstein and Meissler, 2015).
Factor 3: The State of the Current Scientific Knowledge Regarding the
Drug or Substance
Chemistry
The HHS stated that marijuana, also known as Cannabis sativa L., is
part of the Cannabaceae plant family and is one of the oldest
cultivated crops. The term ``marijuana'' is generally used to refer to
a mixture of the dried flowering tops and leaves from Cannabis.
Marijuana users primarily smoke the marijuana leaves, but individuals
also ingest marijuana through food infused with marijuana and its
extracts. Cannabis sativa is the primary species of Cannabis that is
illegally marketed in the United States. Marijuana is one of three
major derivatives sold as separate illicit products, the other two
being hashish and hash oil. Hashish is composed of the dried and
compressed cannabinoid-rich resinous material of Cannabis and is found
as balls and cakes as well as other forms. Individuals may break off
pieces and place them into a pipe to smoke. Hash oil, a viscous brown
or amber colored liquid, is produced by solvent extraction of
cannabinoids from Cannabis and contains approximately 50% cannabinoids.
One to two drops of hash oil on a cigarette has been reported to
produce the equivalent of a single marijuana cigarette (DEA, 2015).
Different marijuana samples are derived from numerous cultivated
strains and may have different chemical compositions including levels
of [Delta]\9\-THC and other cannabinoids (Appendino et al., 2011). A
consequence of having different chemical compositions in the various
marijuana samples is that there will be significant differences in
safety, biological, pharmacological, and toxicological profiles and
therefore, according to the HHS, all Cannabis strains cannot be
considered collectively because of the variations in chemical
composition. Furthermore, the concentration of [Delta]\9\-THC and other
cannabinoids present in marijuana may vary due to growing conditions
and processing of the plant after harvesting. For example, the plant
parts collected such as flowers, leaves and stems can influence
marijuana's potency, quality, and purity (Adams and Martin, 1996;
Agurell et al., 1984; Mechoulam, 1973). Variations in marijuana
harvesting have resulted in potencies ranging from a low of 1 to 2% up
to a high of 17% as indicated by cannabinoid content. The concentration
of [Delta]\9\-THC averages approximately 12% by weight in a typical
marijuana mixture of leaves and stems. However, some specifically grown
and selected marijuana samples can contain 15% or greater [Delta]\9\-
THC (Appendino et al., 2011). As a result, the [Delta]\9\-THC content
in a 1 gram marijuana cigarette can range from as little as 3
milligrams to 150 milligrams or more. In a systematic review conducted
by Cascini et al. (2012), it was reported that marijuana's [Delta]\9\-
THC content has increased significantly from 1979-2009.
Since there is considerable variability in the cannabinoid
concentrations and chemical constituency among marijuana samples, the
interpretation of clinical data with marijuana is complicated. A
primary issue is the lack of consistent concentrations of [Delta]\9\-
THC and other substances in marijuana which complicates the
interpretation of the effects of different marijuana constituents. An
added issue is that the non-cannabinoid components in marijuana may
potentially modify the overall pharmacological and toxicological
properties of various marijuana strains and products.
Various Cannabis strains contain more than 525 identified natural
constituents including cannabinoids, 21 (or 22) carbon terpenoids found
in the plant, as well as their carboxylic acids, analogues, and
transformation products (Agurell et al., 1984; 1986; Mechoulam, 1973;
Appendino et al., 2011). To date,
[[Page 53834]]
more than 100 cannabinoids have been characterized (ElSohly and Slade,
2005; Radwan et al., 2009; Appendino et al., 2011), and most major
cannabinoid compounds occurring naturally have been identified. There
are still new and comparably more minor cannabinoids being
characterized (Pollastro et al., 2011). The majority of the
cannabinoids are found in Cannabis. One study reported accumulation of
two cannabinoids, cannabigerol and its corresponding acid, in
Helichrysum (H. umbraculigerum) which is a non-Cannabis source
(Appendino et al., 2011).
Of the cannabinoids found in marijuana, [Delta]\9\-THC (previously
known as [Delta]\1\-THC) and delta-8-tetrahydrocannabinol ([Delta]\8\-
THC, [Delta]\6\-THC) have been demonstrated to produce marijuana's
psychoactive effects. Psychoactive effects from marijuana usage have
been mainly attributed to [Delta]\9\-THC because [Delta]\9\-THC is
present in significantly more quantities than [Delta]\8\-THC in most
marijuana varieties. There are only a few marijuana strains that
contain [Delta]\8\-THC in significant amounts (Hively et al., 1966).
[Delta]\9\-THC is an optically active resinous substance that is
extremely lipophilic. The chemical name for [Delta]\9\-THC is (6aR-
trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-
[b,d]pyran-1-ol, or (-)-delta9-(trans)-tetrahydrocannabinol. The (-)-
trans [Delta]\9\-THC isomer is pharmacologically 6 to 100 times more
potent than the (+)-trans isomer (Dewey et al., 1984).
Other relatively well-characterized cannabinoids present in
marijuana include cannabidiol (CBD), cannabichromene (CBC), and
cannabinol (CBN). CBD and CBC are major cannabinoids in marijuana and
are both lipophilic. The chemical name for CBD is 2-[(1R,6R)-3-methyl-
6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and the
chemical name for CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-pentyl-5-
chromenol. CBN is a minor naturally-occurring cannabinoid with weak
psychoactivity and is also a major metabolite of [Delta]\9\-THC. The
chemical name for CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
In summary, marijuana has several strains with high variability in
the concentrations of [Delta]\9\-THC, the main psychoactive component,
as well as other cannabinoids and compounds. Marijuana is not a single
chemical and does not have a consistent and reproducible chemical
profile with predictable or consistent clinical effects. In the HHS
recommendation for marijuana scheduling (HHS, 2015), it was recommended
that investigators consult a guidance for industry entitled, Botanical
Drug Products,\45\ which provides information on the approval of
botanical drug products. Specifically, in order to investigate
marijuana in support of a New Drug Application (NDA), clinical studies
under an Investigational New Drug (IND) application should include
``consistent batches of a particular marijuana product for [a]
particular disease.'' (HHS, 2015). Furthermore, the HHS noted that
investigators must provide data meeting the requirements for new drug
approval as stipulated in 21 CFR 314.50 (HHS, 2015).
---------------------------------------------------------------------------
\45\ Available at http://www.fda.gov/Drugs/default.htm under
Guidance (Drugs).
---------------------------------------------------------------------------
Human Pharmacokinetics
Pharmacokinetics of marijuana in humans is dependent on the route
of administration and formulation (Adams and Martin, 1996; Agurell et
al., 1984; Agurell et al., 1986). Individuals primarily smoke marijuana
as a cigarette (weighing between 0.5 and 1 gram) or in a pipe. More
recently, vaporizers have been used as another means for individuals to
inhale marijuana. Marijuana may also be ingested orally in foods or as
an extract in ethanol or other solvents. Pharmacokinetic studies with
marijuana focused on evaluating the absorption, metabolism, and
elimination profile of [Delta]\9\-THC and other cannabinoids (Adams and
Martin, 1996; Agurell et al., 1984; Agurell et al., 1986).
Absorption and Distribution of Inhaled Marijuana Smoke
There is high variability in the pharmacokinetics of [Delta]\9\-THC
and other cannabinoids from smoked marijuana due to differences in
individual smoking behavior even under controlled experimental
conditions (Agurell et al., 1986; Herning et al., 1986; Huestis et al.,
1992a). Experienced marijuana users can titrate and regulate the dose
by holding marijuana smoke in their lungs for an extended period of
time resulting in increased psychoactive effects by prolonging
absorption of the smoke. This property may also help explain why there
is a poor correlation between venous levels of [Delta]\9\-THC and the
intensity of effects and intoxication (Agurell et al., 1986; Barnett et
al., 1985; Huestis et al., 1992a). The HHS recommended that puff and
inhalation volumes should be tracked in experimental studies because
the concentration of cannabinoids can vary at different stages of
smoking.
[Delta]\9\-THC from smoked marijuana is rapidly absorbed within
seconds. Psychoactive effects are observed immediately following
absorption with measurable neurological and behavioral changes for up
to 6 hours (Grotenhermen, 2003; Hollister, 1986; Hollister, 1988).
[Delta]\9\-THC is distributed to the brain in a rapid and efficient
manner. Bioavailability of [Delta]\9\-THC from marijuana (from a
cigarette or pipe) ranges from 1 to 24% with the fraction absorbed
rarely exceeding 10 to 20% (Agurell et al., 1986; Hollister, 1988). The
low and variable bioavailability of [Delta]\9\-THC is due to loss in
side-stream smoke, variation in individual smoking behaviors and
experience, incomplete absorption of inhaled smoke, and metabolism in
lungs (Herning et al., 1986; Johansson et al., 1989). After cessation
of smoking, [Delta]\9\-THC venous levels decline within minutes and
continue to decline to about 5% to 10% of the peak level within an hour
(Agurell et al., 1986; Huestis et al., 1992a; Huestis et al., 1992b).
Absorption and Distribution of Orally Administered Marijuana
Following oral administration of [Delta]\9\-THC or marijuana, onset
of effects start within 30 to 90 minutes, peak after 2 to 3 hours and
effects remain for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin,
1996; Agurell et al., 1984; Agurell et al., 1986). Dose titration of
[Delta]\9\-THC from orally ingested marijuana is difficult for users in
comparison to smoked or inhaled marijuana due to the delay in the onset
of effects. Oral bioavailability of [Delta]\9\-THC, either in its pure
form or in marijuana, is low and variable with a range from 5% to 20%
(Agurell et al., 1984; Agurell et al., 1986). There is also inter- and
intra-subject variability of orally administered [Delta]\9\-THC under
experimental conditions and even under repeated dosing experiments
(HHS, 2015). The HHS noted that in bioavailability studies using
radiolabeled [Delta]\9\-THC, [Delta]\9\-THC plasma levels following
oral administration of [Delta]\9\-THC were low relative to plasma
levels after inhaled or intravenously administered [Delta]\9\-THC. The
low and variable bioavailability of orally administered [Delta]\9\-THC
is due to first pass hepatic elimination from blood and erratic
absorption from stomach and bowel (HHS, 2015).
Metabolism and Excretion of Cannabinoids From Marijuana
Studies evaluating cannabinoid metabolism and excretion focused on
[Delta]\9\-THC because it is the primary psychoactive component in
marijuana.
[Delta]\9\-THC is metabolized via microsomal hydroxylation and
oxidation to both active and inactive
[[Page 53835]]
metabolites (Lemberger et al., 1970; Lemberger et al., 1972a; Lemberger
et al., 1972b; Agurell et al., 1986; Hollister, 1988). Metabolism of
[Delta]\9\-THC is consistent among frequent and infrequent marijuana
users (Agurell et al., 1986). The primary active metabolite of
[Delta]\9\-THC following oral ingestion is 11-hydroxy-[Delta]\9\-THC
which is equipotent to [Delta]\9\-THC in producing marijuana-like
subjective effects (Agurell et al., 1986; Lemberger and Rubin, 1975).
Metabolite levels following oral administration may be greater than
that of [Delta]\9\-THC and may contribute greatly to the
pharmacological effects of oral [Delta]\9\-THC or marijuana.
Plasma clearance of [Delta]\9\-THC approximates hepatic blood flow
at a rate of approximately 950 ml/min or greater. Rapid clearance of
[Delta]\9\-THC from blood is primarily due to redistribution to other
tissues in the body rather than to metabolism (Agurell et al., 1984;
Agurell et al., 1986). Outside of the liver, metabolism in most tissues
is considerably slow or does not occur. The elimination half-life of
[Delta]\9\-THC ranges from 20 hours to between 10 and 13 days (Hunt and
Jones, 1980). Lemberger et al. (1970) reported that the half-life of
[Delta]\9\-THC ranged from 23-28 hours in heavy marijuana users and up
to 60 to 70 hours in na[iuml]ve users. The long elimination half-life
of [Delta]\9\-THC is due to slow release of [Delta]\9\-THC and other
cannabinoids from tissues and subsequent metabolism. Inactive carboxy
metabolites of [Delta]\9\-THC have terminal half-lives of 50 hours to 6
days or more and serve as long-term markers in urine tests for
marijuana use.
Most of the absorbed [Delta]\9\-THC dose is eliminated in the feces
and about 33% in urine. The glucuronide metabolite of [Delta]\9\-THC is
excreted as the major urine metabolite along with 18 non-conjugated
metabolites (Agurell et al., 1986).
Research Status and Test of Currently Accepted Medical Use for
Marijuana
According to the HHS, there are numerous human clinical studies
with marijuana in the United States under FDA-regulated IND
applications. Results of small clinical exploratory studies have been
published in the medical literature. Approval of a human drug for
marketing, however, is contingent upon FDA approval of a New Drug
Application (NDA) or a Biologics License Application (BLA). According
to the HHS, the FDA has not approved any drug product containing
marijuana for marketing.
The HHS noted that a drug may be found to have a medical use in
treatment in the United States for purposes of the CSA if the drug
meets the five elements described by the DEA in 1992. Those five
elements ``are both necessary and sufficient to establish a prima facie
case of currently accepted medical use'' in treatment in the United
States.'' (57 FR 10499, 10504 (March 26, 1992)). This five-element
test, which the HHS and DEA have utilized in all such analyses for more
than two decades, has been upheld by the Court of Appeals. ACT, 15 F.3d
at 1135. The five elements that characterize ``currently accepted
medical use'' for a drug are summarized here and expanded upon in the
discussion below:
1. The drug's chemistry must be known and reproducible;
2. There must be adequate safety studies;
3. There must be adequate and well-controlled studies proving
efficacy;
4. The drug must be accepted by qualified experts; and
5. Scientific evidence must be widely available.
In its review (HHS, 2015), the HHS evaluated the five elements with
respect to the currently available research for marijuana. The HHS
concluded that marijuana does not meet any of the five elements--all of
which must be demonstrated to find that a drug has a ``currently
accepted medical use.'' A brief summary of the HHS's evaluation is
provided below.
Element #1: The drug's chemistry must be known and reproducible.
``The substance's chemistry must be scientifically established to
permit it to be reproduced into dosages which can be standardized. The
listing of the substance in a current edition of one of the official
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic
Act, 21 U.S.C. 321(j), is sufficient generally to meet this
requirement.'' 57 FR 10499, 10506 (March 26, 1992).
As defined by the CSA, marijuana includes all species of the genus
Cannabis, including all strains therein.\46\ Chemical constituents
including [Delta]\9\-THC and other cannabinoids vary significantly in
marijuana samples derived from different strains (Appendino et al.,
2011). As a result, there will be significant differences in safety,
biological, pharmacological, and toxicological parameters amongst the
various marijuana samples. Due to the variation of the chemical
composition in marijuana samples, it is not possible to reproduce a
standardized dose when considering all strains together. The HHS does
advise that if a specific Cannabis strain is cultivated and processed
under controlled conditions, the plant chemistry may be consistent
enough to derive reproducible and standardized doses.
---------------------------------------------------------------------------
\46\ Although the CSA definition of marijuana refers only to the
species ``Cannabis sativa L.,'' federal courts have consistently
ruled that all species of the genus cannabis are included in this
definition. See United States v. Kelly, 527 F.2d 961, 963-964 (9th
Cir. 1976) (collecting and examining cases). The Single Convention
(article 1, par. 1(c)) likewise defines the ``cannabis plant'' to
mean ``any plant of the genus Cannabis.'' As explained above in the
attachment titled ``Preliminary Note Regarding Treaty
Considerations,'' 21 U.S.C. 811(d)(1) provides that, where a drug is
subject to control under the Single Convention, the DEA
Administrator must control the drug under the schedule he deems most
appropriate to carry out such treaty obligations, without regard to
the findings required by 21 U.S.C. 811(a) or 812(b) and without
regard to the procedures prescribed by 21 U.S.C. 811(a) and (b).
---------------------------------------------------------------------------
Element #2: There must be adequate safety studies.
``There must be adequate pharmacological and toxicological studies,
done by all methods reasonably applicable, on the basis of which it
could fairly and responsibly be concluded, by experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, that the substance is safe for treating a
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
The HHS stated that there are no adequate safety studies on
marijuana. As indicated in their evaluation of Element #1, the
considerable variation in the chemistry of marijuana complicates the
safety evaluation. The HHS concluded that marijuana does not satisfy
Element #2 for having adequate safety studies such that medical and
scientific experts may conclude that it is safe for treating a specific
ailment.
Element #3: There must be adequate and well-controlled studies of
efficacy.
``There must be adequate, well-controlled, well-designed, well-
conducted and well-documented studies, including clinical
investigations, by experts qualified by scientific training and
experience to evaluate the safety and effectiveness of drugs, on the
basis of which it could be fairly and responsibly concluded by such
exports that the substance will have the intended effect in treating a
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
As indicated in the HHS's review of marijuana (HHS, 2015), there
are no adequate or well-controlled studies that prove marijuana's
efficacy. The FDA independently reviewed (FDA, 2015) publicly available
clinical studies on marijuana published prior to February 2013 to
determine if there were appropriate studies to determine marijuana's
efficacy (please refer to FDA, 2015 and HHS, 2015 for more
[[Page 53836]]
details). After review, the FDA determined that out of the identified
articles, including those identified through a search of bibliographic
references and 566 abstracts located on PubMed, 11 studies met the a
priori selection criteria, including placebo control and double-
blinding. FDA and HHS critically reviewed each of the 11 studies to
determine if the studies met accepted scientific standards. FDA and HHS
concluded that these studies do not ``currently prove efficacy of
marijuana'' for any therapeutic indication due to limitations in the
study designs. The HHS indicated that these studies could be used as
proof of concept studies, providing preliminary evidence on a proposed
hypothesis involving a drug's effect.
Element #4: The drug must be accepted by qualified experts.
``[A] consensus of the national community of experts, qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, accepts the safety and effectiveness of the
substance for use in treating a specific, recognized disorder. A
material conflict of opinion among experts precludes a finding of
consensus.'' 57 FR 10499, 10506 (March 26, 1992).
The HHS concluded that there is currently no evidence of a
consensus among qualified experts that marijuana is safe and effective
in treating a specific and recognized disorder. The HHS indicated that
medical practitioners who are not experts in evaluating drugs cannot be
considered qualified experts (HHS, 2015; 57 FR 10499, 10505). Further,
the HHS noted that the 2009 American Medical Association (AMA) report
entitled, ``Use of Cannabis for Medicinal Purposes'' does not conclude
that there is a currently accepted medical use for marijuana. HHS also
pointed out that state-level ``medical marijuana'' laws do not provide
evidence of such a consensus among qualified experts.
Element #5: The scientific evidence must be widely available.
``In the absence of NDA approval, information concerning the
chemistry, pharmacology, toxicology, and effectiveness of the substance
must be reported, published, or otherwise widely available, in
sufficient detail to permit experts, qualified by scientific training
and experience to evaluate the safety and effectiveness of drugs, to
fairly and responsibly conclude the substance is safe and effective for
use in treating a specific, recognized disorder.'' 57 FR 10499, 10506
(March 26, 1992).
The HHS concluded that the currently available data and information
on marijuana is not sufficient to allow scientific scrutiny of the
chemistry, pharmacology, toxicology, and effectiveness. In particular,
scientific evidence demonstrating the chemistry of a specific Cannabis
strain that could provide standardized and reproducible doses is not
available.
Petitioners' Major Comments in Relation to Factor 3 and the
Government's Responses
(1) The petitioner states on page 2 of the petition, ``Marijuana
has accepted medical use in the United States. Thirteen states accept
the safety of marijuana for medical use . . . . Marijuana has been
accepted as having medical use by dozens of professional medical and
nursing organizations throughout the U.S. . . . Even the American
Medical Association has now accepted the safety and efficacy of
cannabinoid medicines and supports removal of marijuana from schedule I
of the CSA in order to support further research.''
As noted above, the HHS concluded that there is currently no
evidence of a consensus among qualified experts that marijuana is safe
and effective in treating a specific and recognized disorder, as
required by the established standards. HHS pointed out that state-level
``medical marijuana'' laws do not provide evidence of such a consensus
among qualified experts. HHS also indicated that medical practitioners
who are not experts in evaluating drugs cannot be considered qualified
experts (HHS, 2015; 57 FR 10499, 10505).
Further, the HHS pointed out that the 2009 AMA report entitled,
``Use of Cannabis for Medicinal Purposes'' does not conclude that there
is a currently accepted medical use for marijuana. Instead, the AMA,
like several other professional and medical associations, recommended
further testing with marijuana to determine its medicinal value. The
AMA official policy on medicinal use of marijuana is as follows: ``Our
AMA urges that marijuana's status as a federal Schedule I controlled
substance be reviewed with the goal of facilitating the conduct of
clinical research and development of cannabinoid-based medicines, and
alternative delivery methods. This should not be viewed as an
endorsement of state-based medical cannabis programs, the legalization
of marijuana, or that scientific evidence on the therapeutic use of
cannabis meets the current standards for a prescription drug product.''
(AMA, 2009). The DEA further notes that the 2013 AMA House of Delegates
report states that, ``cannabis is a dangerous drug and as such is a
public health concern.'' (AMA, 2013).
(2) The petitioner asserts on page 3 of the petition that,
``Several recent studies of smoked marijuana have confirmed the safety
and efficacy of smoked marijuana for medical use.''
The HHS, in its scientific and medical evaluation, reviewed
marijuana clinical studies evaluating therapeutic properties and
concluded that there is not enough data to confirm the safety and
efficacy of smoked marijuana for use in treating a specific and
recognized disorder. Relevant to efficacy, for instance, the HHS
concluded, for instance, that ``smoking marijuana currently has not
been shown to allow delivery of consistent and reproducible doses,''
and that the bioavailability of the delta-9 -THC from marijuana in a
cigarette or pipe can range from 1 percent to 24 percent with the
fraction absorbed rarely exceeding 10 to 20%. Issues relating to the
safety of smoked marijuana were discussed above in Factor 2.
(3) On page 3, the petitioner states that ``marijuana has been
determined to be safe for use under medical supervision by the DEA's
own administrative law judge.''
As described above, in the absence of NDA or ANDA approval, DEA has
established a five-element test for determining whether the drug has a
currently accepted medical use in treatment in the United States. 57 FR
10499, 10506 (March 26, 1992)). See also ACT, 15 F.3d at 1135. In
response to this petition, HHS concluded, and DEA agrees, that the
scientific evidence is insufficient to demonstrate that marijuana has a
currently accepted medical use under the five-element test. The
evidence was insufficient in this regard also when the DEA considered
petitions to reschedule marijuana in 1992 (57 FR 10499), in 2001 (66 FR
20038), and in 2011 (76 FR 40552). Little has changed since 2011 with
respect to the lack of clinical evidence necessary to establish that
marijuana has a currently accepted medical use. No studies have
scientifically assessed the efficacy and full safety profile of
marijuana for any specific medical condition.
Factor 4: Its History and Current Pattern of Abuse
Marijuana continues to be the most widely used illicit drug. In
2013, an estimated 24.6 million Americans age 12 or older were current
(past month) illicit drug users. Of those, 19.8 million were current
(past month) marijuana users. As of 2013, an estimated 114.7 million
Americans age 12 and older had
[[Page 53837]]
used marijuana or hashish in their lifetime and 33.0 million had used
it in the past year.
According to the NSDUH estimates, 3.0 million people age 12 or
older used an illicit drug for the first time in 2014. Marijuana
initiates totaled 2.6 million in 2014. Nearly half (46.8%) of the 2.6
million new users were less than 18 years of age. In 2014, marijuana
was used by 82.2% of current (past month) illicit drug users. In 2014,
among past year marijuana users age 12 or older, 18.5% used marijuana
on 300 or more days within the previous 12 months. This translates into
6.5 million people using marijuana on a daily or almost daily basis
over a 12-month period, a significant increase from the 3.1 million
daily or almost daily users in 2006 and from the 5.7 million in just
the previous year. In 2014, among past month marijuana users, 41.6%
(9.2 million people) used the drug on 20 or more days in the past
month, a significant increase from the 8.1 million in 2013.
Marijuana is also the illicit drug with the highest numbers of past
year dependence or abuse in the U.S. population. According to the 2014
NSDUH report, of the 7.1 million persons aged 12 or older who were
classified with illicit drug dependence or abuse, 4.2 million of them
abused or were dependent on marijuana (representing 59.0% of all those
classified with illicit drug dependence or abuse and 1.6% of the total
U.S. non-institutionalized population aged 12 or older).
According to the 2015 Monitoring the Future (MTF) survey, marijuana
is used by a large percentage of American youths, and is the most
commonly used illicit drug among American youth. Among students
surveyed in 2015, 15.5% of 8th graders, 31.1% of 10th graders, and
44.7% of 12th graders reported that they had used marijuana in their
lifetime. In addition, 11.8%, 25.4%, and 34.9% of 8th, 10th, and 12th
graders, respectively, reported using marijuana in the past year. A
number of high school students reported daily use in the past month,
including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th graders,
respectively.
The prevalence of marijuana use and abuse is also indicated by
criminal investigations for which drug evidence was analyzed in
federal, state, and local forensic laboratories, as discussed above in
Factor 1. The National Forensic Laboratory System (NFLIS), a DEA
program, systematically collects drug identification results and
associated information from drug cases submitted to and analyzed by
federal, state, and local forensic laboratories. NFLIS data shows that
marijuana was the most frequently identified drug from January 2001
through December 2014. In 2014, marijuana accounted for 29.3% (432,989)
of all drug exhibits in NFLIS.
The high consumption of marijuana is being fueled by increasing
amounts of domestically grown marijuana as well as increased amounts of
foreign source marijuana being illicitly smuggled into the United
States. In 2014, the Domestic Cannabis Eradication and Suppression
Program (DCE/SP) reported that 3,904,213 plants were eradicated in
outdoor cannabis cultivation areas compared to 2,597,798 in 2000, as
shown above in Table 3. Significant quantities of marijuana were also
eradicated from indoor cultivation operations. There were 396,620
indoor plants eradicated in 2014 compared to 217,105 eradicated in
2000. As shown in Table 2 above, in 2014, the National Seizure System
(NSS) reported seizures of 1,767,741 kg of marijuana.
Factor 5: The Scope, Duration, and Significance of Abuse
Abuse of marijuana is widespread and significant. As previously
noted, according to the NSDUH, in 2014, an estimated 117.2 million
Americans (44.2%) age 12 or older had used marijuana or hashish in
their lifetime, 35.1 million (13.2%) had used it in the past year, and
22.2 million (8.4%) had used it in the past month. Past year and past
month marijuana use has increased significantly since 2013. Past month
marijuana use is highest among 18-21 year olds and it declines among
those 22 years of age and older. In 2014, an estimated 18.5% of past
year marijuana users age 12 or older used marijuana on 300 or more days
within the past 12 months. This translates into 6.5 million persons
using marijuana on a daily or almost daily basis over a 12-month
period. In 2014, an estimated 41.6% (9.2 million) of past month
marijuana users age 12 or older used the drug on 20 or more days in the
past month (SAMHSA, NSDUH). Chronic use of marijuana is associated with
a number of health risks (see Factors 2 and 6).
Furthermore, the average percentage of [Delta]\9\-THC in seized
marijuana has increased over the past two decades (The University of
Mississippi Potency Monitoring Project). Additional studies are needed
to clarify the impact of greater potency, but one study shows that
higher levels of [Delta]\9\-THC in the body are associated with greater
psychoactive effects (Harder and Rietbrock, 1997), which can be
correlated with higher abuse potential (Chait and Burke, 1994).
TEDS data show that in 2013, marijuana/hashish was the primary
substance of abuse in 16.8% of all admissions to substance abuse
treatment among patients age 12 and older. TEDS data also show that
marijuana/hashish was the primary substance of abuse for 77.0% of all
12- to 14-year-olds admitted for drug treatment and 75.5% of all 15- to
17-year-olds admitted for drug treatment in 2013. Among the 281,991
admissions to drug treatment in 2013 in which marijuana/hashish was the
primary drug, the average age at admission was 25 years and the peak
age cohort was 15 to 17 years (22.5%). Thirty-nine percent of the
281,991 primary marijuana/hashish admissions (35.9%) were under the age
of 20.
In summary, the recent statistics from these various surveys and
databases (see Factor 1 for more details) demonstrate that marijuana
continues to be the most commonly used illicit drug, with large
incidences of heavy use and dependence in teenagers and young adults.
Factor 6: What, if Any, Risk There Is to the Public Health
In its recommendation, the HHS discussed public health risks
associated with acute and chronic marijuana use in Factor 6. Public
health risks as measured by emergency department visits and drug
treatment admissions are discussed by HHS and DEA in Factors 1, 4, and
5. Similarly, Factor 2 discusses marijuana's pharmacology and presents
some of the adverse health effects associated with use. Marijuana use
may affect the physical and/or psychological functioning of an
individual user, but may also have broader public impacts including
driving impairments and fatalities from car accidents.
Risks From Acute Use of Marijuana
As discussed in the HHS review document (HHS, 2015), acute usage of
marijuana impairs psychomotor performance including motor control and
impulsivity, risk taking and executive function (Ramaekers et al.,
2004; Ramaekers et al., 2006). In a minority of individuals using
marijuana, dysphoria, prolonged anxiety, and psychological distress may
be observed (Haney et al., 1999). The DEA further notes a recent review
of acute marijuana effects (Wilkinson et al., 2014) that reported
impaired neurological function including altered perception, paranoia,
delayed response time, and memory deficits.
In its recommendation, HHS references a meta-analysis conducted by
Li et al. (2012) where the authors concluded that psychomotor
impairments associated with acute marijuana usage have also been
[[Page 53838]]
associated with increased risk of car accidents with individuals
experiencing acute marijuana intoxication (Li et al., 2012; HHS, 2015).
The DEA further notes more recent studies examining the risk associated
with marijuana use and driving. Younger drivers (under 21) have been
characterized as the highest risk group associated with marijuana use
and driving (Whitehill et al., 2014). Furthermore, in 2013, marijuana
was found in 13% of the drivers involved in automobile-related fatal
accidents (McCartt, 2015). The potential risk of automobile accidents
associated with marijuana use appears to be increasing since there has
been a steady increase in individuals intoxicated with marijuana over
the past 20 years (Wilson et al., 2014). However, a recent study
commissioned by the National Highway Traffic Safety Administration
(NHTSA) reported that when adjusted for confounders (e.g., alcohol use,
age, gender, ethnicity), there was not a significant increase in crash
risk (fatal and nonfatal, n = 2,682) associated with marijuana use
(Compton and Berning, 2015).
The DEA also notes recent studies examining unintentional exposures
of children to marijuana (Wang et al., 2013; 2014). Wang et al. (2013)
reviewed emergency department (ED) visits at a children's hospital in
Colorado from January 1, 2005 to December 31, 2011. As stated by the
authors, in 2000 Colorado passed Amendment 20 which allowed for the use
of marijuana. Following the passage of ``a new Justice Department
policy'' instructing ``federal prosecutors not to seek arrest of
medical marijuana users and suppliers as long as they conform to state
laws'' (as stated in Wang et al., 2013), 14 patients in Colorado under
the age of 12 were admitted to the ED for the unintended use of
marijuana over a 27 month period. Prior to the passage of this policy,
from January 1, 2005 to September 30, 2009 (57 months), there were no
pediatric ED visits due to unintentional marijuana exposure (Wang et
al., 2013). The DEA also notes a larger scale evaluation of pediatric
exposures using the National Poison Data System (Wang et al., 2014).
That study reported that there were 985 unintentional marijuana
exposures in children (9 years and younger) between January 1, 2005 to
December 31, 2011. The authors stratified the ED visits by states with
laws allowing medical use of marijuana, states transitioning to
legalization for medical use, and states with no such laws. Out of the
985 exposures, 495 were in non-legal states (n=33 states), 93 in
transitional states (n=8 states), and 396 in ``legal'' states (n=9
states). The authors reported that there was a twofold increase (OR =
2.1) in moderate or major effects in children with unintentional
marijuana use and a threefold increase (OR = 3.4) in admissions to
critical care units in states allowing medical use of marijuana, in
comparison to non-legal states.
Risks Associated With Chronic Use of Marijuana
The HHS noted that a major risk from chronic marijuana use is a
distinctive withdrawal syndrome, as described in the 2013 DSM-5. The
HHS analysis also quoted the following description of risks associated
with marijuana [cannabis] abuse from the DSM-5:
Individuals with cannabis use disorder may use cannabis
throughout the day over a period of months or years, and thus may
spend many hours a day under the influence. Others may use less
frequently, but their use causes recurrent problems related to
family, school, work, or other important activities (e.g., repeated
absences at work; neglect of family obligations). Periodic cannabis
use and intoxication can negatively affect behavioral and cognitive
functioning and thus interfere with optimal performance at work or
school, or place the individual at increased physical risk when
performing activities that could be physically hazardous (e.g.
driving a car; playing certain sports; performing manual work
activities, including operating machinery). Arguments with spouses
or parents over the use of cannabis in the home, or its use in the
presence of children, can adversely impact family functioning and
are common features of those with cannabis use disorder. Last,
individuals with cannabis use disorder may continue using marijuana
despite knowledge of physical problems (e.g. chronic cough related
to smoking) or psychological problems (e.g. excessive sedation or
exacerbation of other mental health problems) associated with its
use. (HHS 2015, page 34).
The HHS stated that chronic marijuana use produces acute and
chronic adverse effects on the respiratory system, memory and learning.
Regular marijuana smoking can produce a number of long-term pulmonary
consequences, including chronic cough and increased sputum (Adams and
Martin, 1996), and histopathologic abnormalities in bronchial
epithelium (Adams and Martin, 1996).
Marijuana as a ``Gateway Drug''
The HHS reviewed the clinical studies evaluating the gateway
hypothesis in marijuana and found them to be limited. The primary
reasons were: (1) Recruited participants were influenced by social,
biological, and economic factors that contribute to extensive drug
abuse (Hall and Lynskey, 2005), and (2) most studies testing the
gateway drug hypothesis for marijuana use the determinative measure any
use of an illicit drug rather than applying DSM-5 criteria for drug
abuse or dependence (DSM-5, 2013).
The HHS cited several studies where marijuana use did not lead to
other illicit drug use (Kandel and Chen, 2000; von Sydow et al., 2002;
Nace et al., 1975). Two separate longitudinal studies with adolescents
using marijuana did not demonstrate an association with use of other
illicit drugs (Kandel and Chen, 2000; von Sydow et al., 2002).
It was noted by the HHS that, when evaluating the gateway
hypothesis, differences appear when examining use versus abuse or
dependence of other illicit drugs. Van Gundy and Rebellon (2010)
reported that there was a correlation between marijuana use in
adolescence and other illicit drug use in early adulthood, but when
examined in terms of drug abuse of other illicit drugs, age-linked
stressors and social roles were confounders in the association.
Degenhardt et al. (2009) reported that marijuana use often precedes use
of other illicit drugs, but dependence involving drugs other than
marijuana frequently correlated with higher levels of illicit drug
abuse. Furthermore, Degenhardt et al. (2010) reported that in countries
with lower prevalence of marijuana usage, use of other illicit drugs
before marijuana was often documented.
Based on these studies among others, the HHS concluded that
although many individuals with a drug abuse disorder may have used
marijuana as one of their first illicit drugs, this does not mean that
individuals initiated with marijuana inherently will go on to become
regular users of other illicit drugs.
Factor 7: Its Psychic or Physiological Dependence Liability
Physiological (Physical) Dependence in Humans
The HHS stated that heavy and chronic use of marijuana can lead to
physical dependence (DSM-5, 2013; Budney and Hughes, 2006; Haney et
al., 1999). Tolerance is developed following repeated administration of
marijuana and withdrawal symptoms are observed as following
discontinuation of marijuana usage (HHS, 2015).
The HHS mentioned that tolerance can develop to some of marijuana's
effects, but does not appear to develop with respect to the
psychoactive effects. It is believed that lack of tolerance to
[[Page 53839]]
psychoactive effects may relate to electrophysiological data
demonstrating that chronic [Delta]\9\-THC administration does not
affect increased neuronal firing in the ventral tegmental area, a brain
region that plays a critical role in drug reinforcement and reward (Wu
and French, 2000). Humans can develop tolerance to marijuana's
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981).
Tolerance to some behavioral effects appears to develop with heavy and
chronic use, but not with occasional usage. Ramaekers et al. (2009)
reported that following acute administration of marijuana, occasional
marijuana users still exhibited impairments in tracking and attention
tasks whereas performance of heavy users on the these tasks was not
affected. In a follow-up study with the same subjects that participated
in the study by Ramaekers et al. (2009), a neurophysiological
assessment was conducted where event-related potentials (ERPs) were
measured using electroencephalography (EEG) (Theunissen et al., 2012).
Similar to the earlier results, the heavy marijuana users (n = 11;
average of 340 marijuana uses per year) had no changes in their ERPs
with the acute marijuana exposure. However, occasional users (n = 10;
average of 55 marijuana uses per year) had significant decreases in the
amplitude of an ERP component (categorized as P100) on tracking and
attention tasks and ERP amplitude change is indicative of a change in
brain activity (Theunissen et al., 2012).
The HHS indicated that down-regulation of cannabinoid receptors may
be a possible mechanism for tolerance to marijuana's effects (Hirvonen
et al., 2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994;
Oviedo et al., 1993).
As indicated by the HHS, the most common withdrawal symptoms in
heavy, chronic marijuana users are sleep difficulties, decreased
appetite or weight loss, irritability, anger, anxiety or nervousness,
and restlessness (Budney and Hughes, 2006; Haney et al., 1999). As
reported by HHS, most marijuana withdrawal symptoms begin within 24-48
hours of discontinuation, peak within 4-6 days, and last for 1-3 weeks.
The HHS pointed out that the American Psychiatric Association's
(APA's) Diagnostic and Statistical Manual of Mental Disorders--5 (DSM-
5) included a list of withdrawal symptoms following marijuana
[cannabis] use (DSM-5, 2013). The DEA notes that a DSM-5 working group
report indicated that marijuana withdrawal symptoms were added to DSM-5
(they were not previously included in DSM-IV) because marijuana
withdrawal has now been reliably presented in several studies (Hasin et
al., 2013). In short, marijuana withdrawal signs are reported in up to
one-third of regular users and between 50% and 90% of heavy users
(Hasin et al., 2013). According to DSM-5 criteria, in order to be
characterized as having marijuana withdrawal, an individual must
develop at least three of the seven symptoms within one week of
decreasing or stopping the heavy and prolonged use (DSM-5, 2013). These
seven symptoms are: (1) Irritability; anger or aggression, (2)
nervousness or anxiety, (3) sleep difficulty, (4) decreased appetite or
weight loss, (5) restlessness, (6) decreased mood, (7) somatic symptoms
causing significant discomfort (DSM-5, 2013).
Psychological (Psychic) Dependence in Humans
High levels of psychoactive effects such as positive reinforcement
correlate with increased marijuana abuse and dependence (Scherrer et
al., 2009; Zeiger et al., 2010). Epidemiological marijuana use data
reported by NSDUH, MTF, and TEDS support this assertion as presented in
the HHS 2015 review of marijuana and updated by the DEA. According to
the findings in the 2014 NSDUH survey, an estimated 9.2 million
individuals 12 years and older used marijuana daily or almost daily (20
or more days within the past month). In the 2015 MTF report, daily
marijuana use (20 or more days within the past 30 days) in 8th, 10th,
and 12th graders is 1.1%, 3.0%, and 6.0%, respectively.
The 2014 NSDUH report stated that 4.2 million persons were
classified with dependence on or abuse of marijuana in the past year
(representing 1.6% of the total population age 12 or older, and 59.0%
of those classified with illicit drug dependence or abuse) based on
criteria specified in the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition (DSM-IV). Furthermore, of the admissions to
licensed substance abuse facilities, as presented in TEDS, marijuana/
hashish was the primary substance of abuse for; 18.3% (352,297) of 2011
admissions; 17.5% (315,200) of 2012 admissions; and 16.8% (281,991) of
2013 admissions. Of the 281,991 admissions in 2013 for marijuana/
hashish as the primary substance, 24.3% used marijuana/hashish daily.
Among admissions to treatment for marijuana/hashish as the primary
substance in 2013, 27.4% were ages 12 to 17 years and 29.7% were ages
20 to 24 years.
Factor 8: Whether the Substance is an Immediate Precursor of a
Substance Already Controlled Under the CSA
Marijuana is not an immediate precursor of another controlled
substance.
Determination
After consideration of the eight factors discussed above and of the
HHS's Recommendation, the DEA finds that marijuana meets the three
criteria for placing a substance in schedule I of the CSA under 21
U.S.C. 812(b)(1):
1. Marijuana has a high potential for abuse.
The HHS concluded that marijuana has a high potential for abuse
based on a large number of people regularly using marijuana, its
widespread use, and the vast amount of marijuana that is available
through illicit channels.
Marijuana is the most abused and trafficked illicit substance in
the United States. Approximately 22.2 million individuals in the United
States (8.4% of the United States population) were past month users of
marijuana according to the 2014 NSDUH survey. A 2015 national survey
(Monitoring the Future) that tracks drug use trends among high school
students showed that by 12th grade, 21.3% of students reported using
marijuana in the past month, and 6.0% reported having used it daily in
the past month. In 2011, SAMHSA's Drug Abuse Warning Network (DAWN)
reported that marijuana was mentioned in 36.4% of illicit drug-related
emergency department (ED) visits, corresponding to 455,668 out of
approximately 1.25 million visits. The Treatment Episode Data Set
(TEDS) showed that 16.8% of non-private substance-abuse treatment
facility admissions in 2013 were for marijuana as the primary drug.
Marijuana has dose-dependent reinforcing effects that encourage its
abuse. Both clinical and preclinical studies have demonstrated that
marijuana and its principle psychoactive constituent, [Delta]\9\-THC,
possess the pharmacological attributes associated with drugs of abuse.
They function as discriminative stimuli and as positive reinforcers to
maintain drug use and drug-seeking behavior. Additionally, use of
marijuana can result in psychological dependence.
2. Marijuana has no currently accepted medical use in treatment in
the United States.
The HHS stated that the FDA has not approved an NDA for marijuana.
The HHS noted that there are opportunities for scientists to conduct
clinical research with marijuana and there are active INDs for
marijuana, but marijuana
[[Page 53840]]
does not have a currently accepted medical use in the United States,
nor does it have an accepted medical use with severe restrictions.
FDA approval of an NDA is not the sole means through which a drug
can be determined to have a ``currently accepted medical use'' under
the CSA. Applying the five-part test summarized below, a drug has a
currently accepted medical use if all of the following five elements
have been satisfied. As detailed in the HHS evaluation and as set forth
below, none of these elements has been fulfilled for marijuana:
i. The drug's chemistry must be known and reproducible
Chemical constituents including [Delta]\9\-THC and other
cannabinoids in marijuana vary significantly in different marijuana
strains. In addition, the concentration of [Delta]\9\-THC and other
cannabinoids may vary between strains. Therefore the chemical
composition among different marijuana samples is not reproducible. Due
to the variation of the chemical composition in marijuana strains, it
is not possible to derive a standardized dose. The HHS does advise that
if a specific Cannabis strain is cultivated and processed under
controlled conditions, the plant chemistry may be consistent enough to
derive standardized doses.
ii. There must be adequate safety studies
There are not adequate safety studies on marijuana for use in any
specific, recognized medical condition. The considerable variation in
the chemistry of marijuana results in differences in safety,
biological, pharmacological, and toxicological parameters amongst the
various marijuana samples.
iii. There must be adequate and well-controlled studies proving
efficacy
There are no adequate and well-controlled studies that determine
marijuana's efficacy. In an independent review performed by the FDA of
publicly available clinical studies on marijuana (FDA, 2015), FDA
concluded that these studies do not have enough information to
``currently prove efficacy of marijuana'' for any therapeutic
indication.
iv. The drug must be accepted by qualified experts
At this time, there is no consensus of opinion among experts
concerning the medical utility of marijuana for use in treating
specific recognized disorders.
v. The scientific evidence must be widely available
The currently available data and information on marijuana is not
sufficient to address the chemistry, pharmacology, toxicology, and
effectiveness. The scientific evidence regarding marijuana's chemistry
with regard to a specific cannabis strain that could be formulated into
standardized and reproducible doses is not currently available.
3. There is a lack of accepted safety for use of marijuana under
medical supervision.
Currently, there are no FDA-approved marijuana products. The HHS
also concluded that marijuana does not have a currently accepted
medical use in treatment in the United States or a currently accepted
medical use with severe restrictions. According to the HHS, the FDA is
unable to conclude that marijuana has an acceptable level of safety in
relation to its effectiveness in treating a specific and recognized
disorder due to lack of evidence with respect to a consistent and
reproducible dose that is contamination free. The HHS indicated that
marijuana research investigating potential medical use should include
information on the chemistry, manufacturing, and specifications of
marijuana. The HHS further indicated that a procedure for delivering a
consistent dose of marijuana should also be developed. Therefore, the
HHS concluded that marijuana does not have an acceptable level of
safety for use under medical supervision.
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