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Current status and future of cannabis research

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Abstract and Figures

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.
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Clinical Researcher
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
April 2015
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
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
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
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
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
with distinct
Clinical Researcher
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
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
April 2015
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
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.
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
Clinical Researcher
April 2015
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Ethan B. R usso, MD, (erusso@ 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@ 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
Clinical Researcher
... A prescription cannabis product must be standardized, consistent and display a quality equal to any New Chemical Entity that has passed muster as a pharmaceutical (Russo, 2006a;Russo et al., 2015). It must also possess a practical and suitable delivery system that minimizes patient risk, including intoxication, other aspects of drug abuse liability (DAL) or serious adverse events, such as pulmonary sequelae. ...
... Interestingly, these lower doses with fewer side effects have also been observed to correlate to higher efficacy of therapeutic benefit in cancer pain control (Portenoy et al., 2012). Similar endorsements of the efficacy of "low-dose" cannabis therapy, and the "Start low, and go slow" philosophy have been forthcoming from herbal cannabis usage (by Dustin Sulak, D.O. and other clinicians) in the community (Russo et al., 2015). ...
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This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.
... The first of these is its very variable effects on different individuals." He went on to note several-fold variability in required doses, with markedly different tolerance, a lesson still applicable in current treatment (Russo et al. 2015). Corrigan's observations were subsequently republished the same year (Corrigan 1845b), and a decade later in France (Corrigan 1855). ...
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Cannabis or hemp has been employed medicinally in Ireland since at least the Anglo-Saxon era, more than 1000 years ago. Its use came to the fore, however when William B. O’Shaughnessy, an Irish physician in India, became familiar with the versatility of Indian hemp in the treatment of rheumatic diseases, tetanus, cholera and epilepsy in 1838. His knowledge, acquired through application of the scientific method combining ethnobotanical teachings, animal experimentation and clinical observations in humans, was quickly shared with colleagues in Ireland and England. This led in turn to rapid advances in therapeutics by Michael Donovan in neuropathic pain states, Dominic Corrigan in chorea and trigeminal neuralgia, Fleetwood Churchill in uterine hemorrhage, and Richard Greene in the use of cannabis as a prophylactic treatment of migraine. In each instance the observations of these past treatments are examined in light of 21st century advances in pathophysiology so that their rationale and scientific basis are clarified. The venerable Irish tradition of cannabis research is being carried on contemporaneously by numerous prominent scientists with the promise of important advancements yet to come.
... Furthermore, obstacles such as lack of suitable pure materials, federal government classification, and emotional feelings about cannabis by researchers, clinicians, and medical administrators have produced the current situation where the widespread use of cannabis by patients has preceded quality validation of cannabis use for epilepsy. This "cart before the horse" situation has created the need for the medical community to respond to cannabis use in the clinical setting [2]. ...
... More recent experience would suggest that lower THC dosing with a cannabis-based preparation, as opposed to pure THC, might yield different results with prospects for not only fewer adverse events, but increased efficacy as well. [92][93][94] Certainly, additional trials are warranted in this common and difficult clinical context. Given the current seemingly increased incidence and recognition of autistic spectrum disorders, it is useful to note their possible relationship with the ECS. ...
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Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocanna-binoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migrai-neurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.
... Cannabis and the cannabinoids have shown therapeutic value as a treatment for chronic pain, spasticity in multiple sclerosis, and chemotherapy induced nausea (Whiting et al., 2015), with a number of other conditions such as cancer, epilepsy, sleep disorders, and PTSD implicated as possible targets for cannabis-based treatments. Given the growing interest in cannabis-based treatments and expanding access to medicinal cannabis, these areas will more than likely see significant growth in the years ahead (Russo et al., 2015). ...
Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value.
... Cannabis (Cannabis sativa) has been an important tool in the herbalist's arsenal and the medical pharmacopoeia for millennia, but it has only been in the past 25 years that science has provided a better understanding of its myriad benefits. This began with the discovery of cannabinoid receptors (see Glossary) [CB 1 , CB 2 , and the ionotropic cannabinoid receptor, transient receptor potential vanilloid 1 (TRPV1)], followed by endogenous cannabinoids [or endocannabinoids, anandamide (AEA), and 2-arachidonoylglycerol (2-AG)] and their regulatory metabolic and catabolic enzymes [fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and others], the triad now known collectively as the endocannabinoid system (ECS) [1,2]. The ECS performs major regulatory homeostatic functions in the brain, skin, digestive tract, liver, cardiovascular system, genitourinary function, and even bone [1,3]. ...
Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review.
The cannabis industry is a new quasi‐legal industry. Growing, selling and using cannabis are still illegal in most countries. However, twenty‐four countries and thirty‐three U.S. states have approved cannabis for medical use, and five countries and eleven U.S. states allow recreational use. This research focuses on value‐added producers (VAPs), companies that process cannabis to manufacture ingestible, inhalable or topical products. Due to public health concerns, the VAP tier of the cannabis supply chain faces stringent regulatory focus and turbulence. Using multiple case studies of VAPs in an emerging cannabis industry, this research investigates how these companies’ primary supply chain decision makers make and implement strategic decisions in an environment characterized by fast changing regulations. While the public often perceives this new market as a way for new business owners to get‐rich‐quick, the results of this research paint a different picture. Neither significant corporate expertise and funding nor black‐market cannabis experience are necessarily predictors of success. Incorporating the underpinnings of dynamic managerial capabilities, namely managerial cognitive capital, human capital and social capital, this research investigates how VAP companies have managed their production and supply chains to ultimately thrive, survive or fail. Human and cognitive capital are important, but social capital that reaches beyond the supply chain is a distinguishing feature of firms that thrive in this non‐predictive environment.
Background: Ratios of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact metabolism and therapeutic effects of cannabis. Currently, no states with legalized medical or recreational cannabis consider ratios THC:CBD in regulations. Objective: Determine what THC:CBD ratios are selected for use in clinical cannabis trials and what is the rationale. Methods: This is a systematic literature review of Central, CINAHL, Embase, PsycInfo, and PubMed of the last 10 years of English language medical cannabis publications highlighting THC:CBD ratios. Included were clinical studies of products containing and listing both THC and CBD ratios, percentages, or weighted amounts. Case reports and series, abstracts, reviews, and meta-analysis were excluded. Non-human, non-therapeutic, or studies examining approved cannabis pharmaceuticals were excluded. Results: Four hundred and seventy-nine (479) unique references were found, of which 11 met inclusion criteria. THC:CBD ratios listed and/or calculated: 1:0, 22:1, 2:1, 1:1, 1:2, 1:6, 1:9, 1:20, 1:33, 1:50, and 0:1. Rationale for ratios selected was often not listed, or simply trivialized as the ratios available to patients in the area, or ratios that were pharmaceutically available throughout the study country. One study compared ratios of high and low THC:CBD, but did not specify the ratios. Conclusion: The medical and scientific communities have not drawn substantive conclusions nor thoroughly explored THC:CBD ratios for “best practice” treatment of different disease processes and their sequelae. While there is evidence that cannabis provides medical benefits, research is lacking on standardization of medical cannabis use in modern medical practices.
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Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.
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Substitution can be operationalized as the conscious choice to use one drug (legal or illicit) instead of, or in conjunction with, another due to issues such as: perceived safety; level of addiction potential; effectiveness in relieving symptoms; access and level of acceptance. This practice of substitution has been observed among individuals using cannabis for medical purposes. This study examined drug and alcohol use, and the occurrence of substitution among medical cannabis patients. Anonymous survey data were collected at the Berkeley Patient's Group (BPG), a medical cannabis dispensary in Berkeley, CA. (N = 350) The sample was 68% male, 54% single, 66% White, mean age was 39; 74% have health insurance (including MediCal), 41% work full time, 81% have completed at least some college, 55% make less than $40,000 a year. Seventy one percent report having a chronic medical condition, 52% use cannabis for a pain related condition, 75% use cannabis for a mental health issue. Fifty three percent of the sample currently drinks alcohol, 2.6 was the average number of drinking days per week, 2.9 was the average number of drinks on a drinking occasion. One quarter currently uses tobacco, 9.5 is the average number of cigarettes smoked daily. Eleven percent have used a non-prescribed, non OTC drug in the past 30 days with cocaine, MDMA and Vicodin reported most frequently. Twenty five percent reported growing up in an abusive or addictive household. Sixteen percent reported previous alcohol and/or drug treatment, and 2% are currently in a 12-step or other recovery program. Forty percent have used cannabis as a substitute for alcohol, 26% as a substitute for illicit drugs and 66% as a substitute for prescription drugs. The most common reasons given for substituting were: less adverse side effects (65%), better symptom management (57%), and less withdrawal potential (34%) with cannabis. The substitution of one psychoactive substance for another with the goal of reducing negative outcomes can be included within the framework of harm reduction. Medical cannabis patients have been engaging in substitution by using cannabis as an alternative to alcohol, prescription and illicit drugs.
Recent studies in our laboratory have shown that in mice, low doses of morphine in combination with Delta (9)-tetrahydrocannabinol (Delta (9)-THC) have a similar antinociceptive effect to high doses of morphine alone. After short-term administration of this combination, there is no behavioral tolerance to the opioid. Previous binding studies and Western analyses following chronic morphine exposure in rodent models indicate significant mu -receptor down-regulation, as well as decreased levels of receptor protein, in both brain and spinal cord regions. We hypothesized that combination-treated animals would show no receptor protein down-regulation. The levels of opioid (mu, delta, kappa) and cannabinoid (CB1) receptor protein were evaluated in mouse models of short-term exposure to Delta (9)-THC, morphine, or both drugs in combination. Western blot analysis revealed that all three types of opioid receptor protein are significantly decreased in morphine-tolerant mouse midbrain. This down-regulation was not seen in combination-treated animals. In the spinal cord, there was an up-regulation of mu-, delta-, and kappa- opioid receptor protein in combination-treated mice when compared with morphine-tolerant mice. There were no apparent changes in levels of CB1 receptor protein in midbrain regions, and there was an upregulation of CB1 protein in the spinal cord. The data presented here indicate that there is a correlation between morphine tolerance and receptor protein regulation. A combination of Delta (9)-THC and morphine retains high antinociceptive effect without causing changes in receptor protein that may contribute to tolerance.
In February, we invited you to share your opinion about the medicinal use of marijuana. We now present the polling results.
Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag single nucleotide polymorphisms (tSNPs) that account for most of CB1 coding region genetic variability. Patients underwent a high-resolution anatomic brain magnetic resonance scan and cognitive assessment. Almost a quarter of the sample met DSM marijuana abuse (14%) or dependence (8%) criteria. Effects of CNR1 tSNPs and marijuana abuse/dependence on brain volumes and neurocognition were assessed using ANCOVA, including co-morbid alcohol/non-marijuana illicit drug misuse as covariates. Significant main effects of CNR1 tSNPs (rs7766029, rs12720071, and rs9450898) were found in white matter (WM) volumes. Patients with marijuana abuse/dependence had smaller fronto-temporal WM volumes than patients without heavy marijuana use. More interestingly, there were significant rs12720071 genotype-by-marijuana use interaction effects on WM volumes and neurocognitive impairment; suggestive of gene-environment interactions for conferring phenotypic abnormalities in schizophrenia. In this comprehensive evaluation of genetic variants distributed across the CB1 locus, CNR1 genetic polymorphisms were associated with WM brain volume variation among schizophrenia patients. Our findings suggest that heavy cannabis use in the context of specific CNR1 genotypes may contribute to greater WM volume deficits and cognitive impairment, which could in turn increase schizophrenia risk.
To examine whether withdrawal after abstinence and cue-elicited craving were associated with polymorphisms within two genes involved in regulating the endocannabinoid system, cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH). Two single nucleotide polymorphisms (SNPs) in the CNR1 (rs2023239) and FAAH (rs324420) genes, associated previously with substance abuse and functional changes in cannabinoid regulation, were examined in a sample of daily marijuana smokers. Participants were 105 students at the University of Colorado, Boulder between the ages of 18 and 25 years who reported smoking marijuana daily. Participants were assessed once at baseline and again after 5 days of abstinence, during which they were exposed to a cue-elicited craving paradigm. Outcome measures were withdrawal and craving collected using self-reported questionnaires. In addition, urine samples were collected at baseline and on day 5 for the purposes of 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) metabolite analysis. Between the two sessions, THC-COOH metabolite levels decreased significantly, while measures of withdrawal and craving increased significantly. The CNR1 SNP displayed a significant abstinence x genotype interaction on withdrawal, as well as a main effect on overall levels of craving, while the FAAH SNP displayed a significant abstinence x genotype interaction on craving. These genetic findings may have both etiological and treatment implications. However, longitudinal studies will be needed to clarify whether these genetic variations influence the trajectory of marijuana use/dependence. The identification of underlying genetic differences in phenotypes such as craving and withdrawal may aid genetically targeted approaches to the treatment of cannabis dependence.
The administration of delta9THC intravenously as a premedicant to oral surgery resulted in acute pronounced elevations in anxiety states, a predominance of dysphoria over euphoria, and varying degrees of psychotic-like paranoiac thought. Neural effects that appeared to promote these effects included distortions of perception with sensory delusions, and heightened sensory receptiveness including antalgesic impressions of surgery; autonomic and visceral arousal greater than control or placebo levels; lack of overt behavioral signals of distress due to depersonalization; and time disintegration leading to fear-inducing misinformation about real surgical events. Introverted subjects who generally were inclined to rely on drug solutions to their problems tended to respond poorly to surgical pain and anxiety with delta9THC. These results, obtained from subjects considered to have levels of presurgical apprehension that were average or below average, suggest that the environment in which high doses of cannabinols are experienced is a potent factor in determining the quality of the emotional response. A surgical environment containing even the mild stress of outpatient oral surgery appears to have the potential to precipitate undesirable emotional responses among cannabinol-intoxicated patients. There is continued high-level social use of cannabinols inour society, with an estimate of 40% to 55% among the college-age group seen frequently by oral surgeons. Results of this study suggest that clinicians should be prepared to detect the subtle signs of marijuana intoxication to protect their patients from further psychophysiologic complications during surgery.
Abstract A within subjects design was used to assess the effects of smoking marihujana upon feelings of anxiety. Marihuana did not increase the intensity of an individual's feelings of anxiety. Instead, anxious subjects tended to become less anxious and more euphoric, while nonanxious individuals tended to become somewhat more anxious.