Current status and future of cannabis research

Abstract

Cannabis sativa has a long history of medicinal use and contains phytocannabinoids that demonstrate therapeutic activity in preclinical models of numerous disease states. Widespread clinical use of cannabis has preceded the evidence base. Randomized controlled trials are needed to understand the safety, efficacy, and optimal dosages of standardized cannabis preparations. In addition to regulatory and legal challenges,certain botanical and pharmacologic factors that complicate the collection and interpretation of clinical data on the efficacy of cannabinoid therapies are reviewed.

Full text

Clinical Researcher
58
April 2015
Current Status and Future
of Cannabis Research
Cannabis is a versatile herb that can produce
a variety of medicinal preparations with distinct
pharmacologic propert ies, depending on the con-
tent of cannabinoids and other phytochemicals,
many of which possess synergistic eects.4 e
best known plant cannabinoid is tetrahydrocan-
nabinol (THC), the primary psychoactive agent in
cannabis, responsible for the preponderance of
the cannabis “high”; however, it is also a powerful
analgesic,5 muscle relaxant,6 and antinausea
agent,7 among myriad ot her eects. Coming to
greater recognition is its analogue sister, can-
nabidiol (CBD), which distinguishes itself by its
lack of intoxicat ion and its ability to complement
the pain relief, antiemetic, anticonvulsant,8 and
other benets of THC, while modulating and
attenuating its associated side eects (anxiety,
tachycardia, et al.).4,9–13
Although cannabis is primarily viewed by the public as a recreational drug or
agent of abuse, its medical application spans recorded history.1,2 Evolution has
yielded a cannabis plant that produces a family of some 100 chemicals called
phytocannabinoids (“plant cannabinoids”), many of which have distinct and
valuable therapeutic eects.3,4
PEER REVIEWED | Ethan B. Russo, MD
Alice P. Mead, JD, LLM | Dustin Sulak, DO
[DOI:10.14524/CR-15-0004]

April 2015
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Clinical Researcher
To gain regulator y approval of a cannabis-based
product, pursuing the dietary supplement/botani-
cal path—as opposed to the pharmaceutical one—
may be an opt ion for certain preparations. Dietary
supplements rarely contain substances w ith abuse
potential, and manufacturers and vendors of such
products can make only “structure and function”
claims (e.g., “promotes heart health”), rather than
medical claims. erefore, it is probably unlikely
that cannabis preparations with a notable amount
of THC could be treated as dietar y supplements.
However, nonpsychoactive cannabinoids, such
as CBD could be descheduled (i.e., removed from
the federal Controlled Substances Act [CSA]) and
developed and marketed as botanical supplements.
Cannabis exerts its eects through a variety
of receptor and nonreceptor mechanisms. All
vertebrates tested to date harbor an endoge-
nous cannabinoid system (ECS),14 a regulator of
physiological homeostasis whose function has
been summarized as “rela x, eat, sleep, forget,
and protect.”15 e ECS has three components:
endocannabinoids, biosy nthetic and catabolic
enzymes, and two cannabinoid receptors—CB1,
the “psychoactive” neuromodulator that is the most
abundant G-protein coupled receptor in the brain,
and CB2, a nonpsychoactive immunomodulatory
and anti-inammatory receptor most abundant in
the periphery.14,16
Although various surveys support the idea that
the American public already accepts the medical
utility of cannabis and is acting upon that belief
in ever higher numbers, t he U.S. Food and Drug
Administrat ion (FDA) requires more rigorous
proof. Additionally, a sur vey of Colorado family
physicians found that; “Despite a high prevalence
of use in Colorado, most family physicians are
not convinced of marijuana’s health benets and
believe its use carries risks. Nearly all agreed on the
need for further medical education about medical
marijuana.”17
If cannabis-based medicines are to overcome
prejudice and gain greater trust from physicians,
their production must be standardized and their
contents proven safe and ecacious in randomized
clinical trials (RCTs) that follow accepted scientic
method and are the sine qua non of regulator y bod-
ies such as the FDA18 However, botanical cannabis
is highly inconsistent and variable in its chemical
composition.
Procedures for standardization of plant-based
medicines have been formally presented in the
U.S., providing an FDA blueprint for their reg-
ulator y approval in the “Guidance for Indust ry:
Botanical Drug Products.”19 Meanwhile, although
cannabis smok ing may not be epidemiologically
linked to lung cancer,20 it is responsible for chronic
cough, sputum, and cytological changes,21,2 2 which
render smoked cannabis an impossible candidate
for approval as a prescription product in most
jurisdictions.
Anecdotal claims for ecacy of crude cannabis
hold no sway for t he FDA.18 ere is a relative
paucity of published RCT data for inhaled cannabis:
the ex isting trials for pai n total only three pat ient-
years of data, whereas the corresponding gu re for
nabiximols (Sativex®, GW Pharmaceuticals), a stan-
dardized oromucosal extract spray combining THC,
CBD, and other cannabis components, exceeds
6,000 pat ient-years of data in published studies of
pain, or a two t housand-fold dierence.5 e latter
is also approved in 26 countries for treatment of
spasticity in multiple sclerosis, and is current ly
completing clinical t rials for opioid-resistant cancer
pain in the U.S. and elsewhere.23–25 is agent has
ful lled criteria of sa fety and consistency, and has
not been abused or diver ted to any degree in more
than 30,000 patient-years of recorded usage.
Regulatory Challenges and Solutions
e FDA has responsibility for assessing human
research and evaluating data from clinical
studies. Such research is initiated by an individual
researcher in an investigator-initiated trial (IIT) or
by a pharmaceutical company. In both situations,
an Investigational New Drug (IND) application
containing one or more protocols must be pre-
sented to, and allowed by, the FDA.26
For industry-sponsored programs, the FDA
requires a range of nonclinical/preclinical studies
and then clinical trials to demonstrate that the
product meets the FDA’s exacting standards of
quality, safety, and ecacy in a particular patient
population.
e FDA has claried that it will allow bot h IITs
and RCT development programs w ith cannabis
or cannabis-derived products. Exa mples of such
IITs have been completed and published.2 7,2 8 An
indust ry-sponsored development program is a lso
progressing w ith a cannabis-derived product.29
Finally, FDA has promu lgated “expanded access”
regulations in the Code of Federal Regulations
in 21 CFR sections 312.310, 312.315, and 312.320,
allow ing seriously ill patients who lack conventiona l
treat ment options and clinical tria l opportunities
to be treated with an invest igational product on a
compassionate access basis. More tha n 300 children
Cannabis is a
versatile herb that
can produce a
variety of medicinal
preparations
with distinct
pharmacologic
properties.

Clinical Researcher
60
April 2015
with var ious types of medication-resistant epilep-
sies have been allowed by FDA to receive treatment
with a cannabis-derived (but puried) CBD product
under such expanded access programs.30
Studies involv ing herbal cannabis must obtain
the material from the National Institute on Drug
Abuse (NIDA), which is the sole federally lawful
source of research-grade cannabis. NIDA has
contracted with the University of Mississippi to
grow cannabis (of various cannabinoid ratios and
potencies) for research.31, 32
FDA has approved at least two products based
on botanical extracts; however, FDA has not
previously approved any raw botanical/herbal
material as a prescription medicine. Such material
would face regulatory challenges, such as achiev-
ing adequate purity, displaying batch-to-batch
standardization, and identif ying an appropriate
method of delivery (i.e., one that would supply a
precise and reproducible dose without t he produc-
tion of toxic by-products).
Cannabis, THC, and products containing
botanically or synthetically derived cannabinoids
found in the cannabis plant are classied under
Schedule I of the federal CSA. e CSA contains
ve schedules corresponding to a substance’s
abuse potential and medical usefulness.
Schedule I and II substances are subject to strict
security, recordkeeping, and other measures. Sub-
stances in Schedule I have “no currently accepted
medical use in the U.S.” and a high potential for
abuse. Substances in Schedule II also have a high
potential for abuse, but have an “accepted medical
use,” a phrase given specic meaning by the
federal Drug Enforcement Administration (DEA)
and upheld by federal courts:
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 ecacy;
4. The drug must be accepted by qualied
experts; and
5. The scientic evidence must be widely
available.33
If FDA approves a cannabis-derived product,
such approval constitutes “accepted medical
use,” and that product will then be moved to a less
stringent schedule. A lthough a substance and a
product containing t hat substance are in the same
schedule, “dierential” scheduling is possible. For
example, Marinol, a product comprising synthetic
THC in sesame oil, is classied in Schedule III,
whereas other forms of THC remain in Schedule I.34
is may serve as precedent if a cannabis-
derived product is FDA approved and rescheduled,
although cannabis may remain in Schedule I.
Cannabis’s (and THC’s) Schedule I status
means there are additional hurdles to overcome
to conduct research in the U.S. As provided in
21 CFR sect ion 1301.13, a physician who holds a
DEA registration (license) to prescribe controlled
substances in Schedules II–V may conduct research
within t hose schedules as a “coincident activit y”
to his or her existing registration, with no further
approval from the DEA.
However, to conduct research with a Schedule
I substance, an investigator must secure a Sched-
ule I research registration from DEA (which is
substance- and protocol-specic), and (often) a
Schedule I research license from the state-
controlled drugs agency. ese addit ional steps can
add three to six months to the time required before
an investigator can begin the research project.
A specic medical product cannot be pre-
scribed by physicians and dispensed by pharma-
cists unless the FDA has approved t hat product
(the “compounding pharmacy” exception is very
limited). erefore, even if cannabis were moved
to Schedule II, physicians could not automatically
prescribe it direct ly to patients. Although the NIDA
single-source supply is the only domestic source,
cannabis-derived products may be manufactured
in Europe or elsewhere, and the nished product
may be imported into the U.S. for research or
ultimately for commercial distribution follow ing
FDA approva l.35
Current Status of Clinical
Cannabinoid Medicine
Due to the obstacles involved in human clinical
research using cannabis, widespread use in the
clinical setting has preceded well-established data
on dosage, delivery systems, safety, and ecacy. In
states that have legalized medical cannabis, about
0.77% of the population use cannabis with the
recommendation of a medical provider.36
The FDA has
claried that it will
allow both IITs and
RCT development
programs with
cannabis or
cannabis-derived
products.

April 2015
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Clinical Researcher
Cannabinoids are considered nonlethal
and have a w ide range of eective and tolerated
dosages. Many patients use medical cannabis in a
harm-reduction paradigm to decrease or discon-
tinue the use of prescribed and illicit substances.37
Also, the growing number of medical providers
accepting cannabis as a viable treatment option38
may attest to obser ved or suspected clinical
ecacy. Meanwhile, observational studies can
inform the emerging clinica l practice of cannabi-
noid medicine, while guiding the development of
clinical experimental design.39
One of this article’s authors has obser ved
clinical responses in his patient populat ion in oral
doses beginning as low as 0.1 mg cannabinoids/
kg body weight/day, whereas some nd optimal
benets at doses as high as 25 mg/kg/day. is
wide dosing range is complicated by a biphasic
dose-response curve, where lower doses may
exhibit greater ecac y and tolerabilit y than higher
doses, as seen in a clinical trial of nabiximols for
poorly controlled chronic pain in opioid-treated
cancer patients.24
Another clinical trial of inhaled cannabis
for neuropathic pain found low-potency (3.5%
THC) and high-potency (7% THC) cannabis to
have equivalent analgesic properties.27 Biphasic
dose-response eects may be due to subjects’
sensitization to cannabinoids at lower doses and
tolerance building at higher doses. is hypoth-
esis is supported by preclinical studies in which
administrat ion of exogenous cannabinoids both
upregulate endocannabinoid system function at
acute and lower doses via increased endocannabi-
noid production,40 cannabinoid receptor expres-
sion,41 and cannabinoid receptor anity,42 and
downregulate endocannabinoid system function
upon persistent agonism via membrane receptor
endosome internalization.43
Bidirectional eects are often related to dos-
age,44,45 with high doses of cannabinoids potentially
causing symptoms usually ameliorated by lower
dosages. e mindset of the cannabis user and
setting in which the cannabis use takes place also
inuence bidirectional eects; anxious subjects
tend to become less anxious and more euphoric,
nonanxious individuals tend to become somewhat
more anxious,46 and stressful environments can
precipitate adverse emotional responses.47
Polymorphisms have been associated w ith vari-
able responses to cannabis, including protective
eects on development of cannabis dependence in
adolescents,48 intensity of withdrawal and craving
during cannabis abstinence,49 and white matter
volume decits and cognitive impairments in
schizophrenic heav y cannabis users.50
Cannabis use histor y also complicates clinical
response, with cannabis-naïve pat ients demon-
strating more frequent adverse eects51 and regular
users demonstrating less psychotomimetic, per-
ceptual altering, amnestic, and endocrine eects.52
Another factor to note is that physicians
often lack training in using botanical medicines,
and endocannabinoid physiology is still absent
from most medical school curricula. Many legal
cannabis patients receive permission to use
cannabis from their physician, but must rely on
formula selection and dosing instructions provided
by cannabis growers or dispensar y sta with little
training or experience.
Properly interpreting observational data on
medical cannabis patients requires an understand-
ing of the chemical composition and potency of the
cannabis preparations used, and of the phar-
macokinetics of the deliver y system employed.
Laboratories oering third-party chemical analysis
of herbal cannabis preparations under industry-
published standards53 can be found in most states
that allow the use of medical cannabis.54
Conclusion
e endocan nabinoid system regulates physiologic
homeostasis and is an exciting target for disease
management and hea lth promotion. Cannabis-
based preparations are poised to become an
accepted option in mainstream medicine, w ith
broad support from preclinical models, pat ient testi-
monials, and more recently, human clinical t rials.
However, numerous regulatory, botanical, and
pharmacologic factors challenge the collection
and interpretation of clinical data on the ecacy
of cannabinoid therapies. e understanding of an
individual’s optimal dosing and delivery method of
cannabinoids for various ailments is still emerging,
and must be g uided by both obser vational and
experimental data.
Clinical researchers can overcome the chal-
lenges inherent in cannabinoid therapeut ics
and help elucidate solutions for a wide variety of
prevalent health challenges.
Acknowledgments
e authors would like to express sincere thanks to
Tyler Strause, Brendon Strause, and Linda Strause,
PhD, for their excellent support and review in
preparing this article.
Although various surveys support the idea that the American public already accepts the
medical utility of cannabis and is acting upon that belief in ever higher numbers, the U.S.
Food and Drug Administration (FDA) requires more rigorous proof.
Due to the obstacles
involved in human
clinical research using
cannabis, widespread
use in the clinical
setting has preceded
well-established data
on dosage, delivery
systems, safety, and
ecacy.

Clinical Researcher
62
April 2015
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Ethan B. R usso, MD, (erusso@
phytecs.com) is medical
director o f PHYTECS and past
president of the International
Cannabinoid Research Society.
Alice P. Mead, JD, LL M, is vice
president, U.S. Professional
Relations, GW Pharmaceuticals.
Dustin S ulak, DO, (drsulak@
gmail.com) is founder and
medical director of Integr8
Health, Falmouth, Maine.
Clear the Mud: Current and
Future of Cannabis Research.
The authors of this article will be
joined by Sean McAllister, PhD, to
speak at a two-hour session presented
during the ACRP Global Conference in
Salt Lake City on Sunday, April 26 from
8:30 AM to 10:30 AM. Learn rsthand
where they see this new and “explod-
ing” industry going. They will discuss
the current and future of cannabis
research from the perspective of a
pharmaceutical physician, regulatory
and legal expert, basic researcher, and
practicing physician.
April 2015
63
Clinical Researcher