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Cannabis and Cannabinoids Pharmacology, Toxicology, and Therapeutic Potential

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REVIEW
published: 14 September 2016
doi: 10.3389/fphar.2016.00309
Frontiers in Pharmacology | www.frontiersin.org 1September 2016 | Volume 7 | Article 309
Edited by:
Rukiyah Van Dross-Anderson,
The Brody School of Medicine at East
Carolina University, USA
Reviewed by:
Eric Murillo-Rodriguez,
Anahuac Mayab University, Mexico
John D. Salamone,
University of Connecticut, USA
*Correspondence:
Ethan B. Russo
ethanrusso@comcast.net
Specialty section:
This article was submitted to
Experimental Pharmacology and Drug
Discovery,
a section of the journal
Frontiers in Pharmacology
Received: 13 May 2016
Accepted: 30 August 2016
Published: 14 September 2016
Citation:
Russo EB (2016) Current Therapeutic
Cannabis Controversies and Clinical
Trial Design Issues.
Front. Pharmacol. 7:309.
doi: 10.3389/fphar.2016.00309
Current Therapeutic Cannabis
Controversies and Clinical Trial
Design Issues
Ethan B. Russo *
PHYTECS, Los Angeles, CA, USA
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.
Keywords: cannabis, clinical trials, drug abuse liability, cognition, driving, vaporization, placebo, pesticides
INTRODUCTION
Is there a pathway that will lead to the return of cannabis to mainstream medicine? The answer is
clear, inasmuch as it has already commenced. It follows the same time-honored process that any
pharmaceutical must attain to receive regulatory approval: proof of biochemical uniformity and
stability along with safety and efficacy as proven by randomized clinical trials (RCT).
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. An additional requirement is a supply chain that ensures security that it is
being distributed to its intended target patients.
Russo Current Therapeutic Cannabis Controversies
The status quo of cannabis medicine for most patients still
involves the black market with its myriad risks and inherent lack
of quality control. In the future, the desirable alternative would be
a safe and effective evidence-based pharmaceutical solution that
physicians prescribe with confidence, that pharmacists endorse
and supply, and that government health services and third party
payers will cover.
Garden variety cannabis as bought on the street cannot meet
these criteria nor gain regulatory approval in most nations of the
world. The biochemical variability of one chemovar to another
is a primary challenge, while unregulated material may harbor
pesticide residues, molds, bacteria, or heavy metals that endanger
public health. The most common delivery system, smoking,
imposes similar risks: chronic cough, phlegm production,
bronchitis, and inhalation of pyrolytic by-products (Tashkin,
2013). Cannabis inhalation, whether by smoking or vaporizer
produces a rapid peak in serum and brain concentrations that
maximizes intoxication and possible reinforcement that are
risk factors for DAL (Schoedel et al., 2011). Other routes of
administration, e.g., transdermal patches and rectal suppositories
have not yet demonstrated practicality in later stage clinical trials
(Huestis, 2007).
A cannabis delivery system with reliable intermediate onset,
allows dose titration without pulmonary dangers, relieves
symptoms, and is biochemically uniform and defined would
engender confidence of all parties. The first preparation to
fulfill these criteria, currently in 27 nations around the globe,
is nabiximols (US Adopted name, also known as Sativex R
),
an oromucosal spray produced from whole cannabis extracts
whose effects begin in 15–40 min, allowing a therapeutic window
for control of symptoms without intoxication. In reality,
patients are not seeking altered states from their medicine, but
rather relief of pain or other complaints. Other cannabis-based
medicines that follow will necessarily be required to meet similar
benchmarks.
It is the widespread belief of most scientists and many
legal scholars that the only viable solution to the issues of
medicinal cannabis is a pharmaceutical approach. Only in
this way are regulatory standards fulfilled, and patient desires
satisfied in safety. Such an approach can remove the current
clandestine atmosphere surrounding cannabis and promote the
kind of open and mutual therapeutic doctor-patient relationship,
while maintaining legal status. Political efforts at legalization in
certain American states and various countries will necessitate
wrestling with issues of pharmaceutical cannabis preparations as
compared to allowable claims in a less regulated market for herbal
preparations.
While cannabis is usually thought of in relation to THC
content, and its agonistic effects at the CB1receptor, it requires
emphasis that humans express individual endocannabinoid
tone, that may be deficient under certain conditions, as
has been suggested in migraine, fibromyalgia, and irritable
bowel syndrome (Russo, 2004, 2016a), or alternatively may be
excessive in obesity and metabolic syndrome (Kunos, 2007).
Beyond THC, other cannabis components such as cannabidiol
and tetrahydrocannabivarin act as neutral antagonists at CB1
(McPartland et al., 2015) that along with dietary manipulations
with prebiotics and probiotics portend to provide potential
treatment interventions for the latter (Russo, 2016b).
CONTROVERSIES IN CANNABIS
DISPENSARIES, COFFEE SHOPS, AND
SELF-ADMINISTRATION
The singular controversy in this category is quality control. Short
of a biochemical analysis by a certified laboratory employing
verified phytocannabinoids standards, the cannabis consumer
can have no real idea of the composition or consistency of
the product that they purchase. “Strain names” are eminently
malleable, and are as simple to alter as writing a new label
to change one to match the most desirable chemovar du jour.
The wary consumer should also be alert to the possibility
of coliform and heavy metal contamination, areas that are
infrequently tested on the black market, and are unlikely to
have been completed on every batch (vide infra). This type
of laboratory analysis is not simple; one should keep in mind
that the lipophilic nature of cannabinoids was responsible for
a 150-year gap between the identification of morphine in
opium to that of tetrahydrocannabinol in cannabis (Gaoni and
Mechoulam, 1964). The problem is compounded by the facts that
technically almost all laboratories pursuing phytocannabinoid
analyses in the USA are doing so illegally, most without
benefit of a Schedule I license from the Drug Enforcement
Administration (DEA). Additionally, many phytocannabinoid
standards available commercially are reportedly suspect. There
is additional difficulty in attempting to analyze cannabis
confections, as the assays require ascertainment of cannabinoid
content from a complex food matrix (Vandrey et al., 2015).
Legal state requirements on cannabis analysis, and packaging
vary wildly from one jurisdiction to another, and are often
rudimentary. The author believes that full cannabinoid and
terpenoid profiles are necessary for proper decisions by
consumers in both the medical and markets (Russo, 2011). The
current vernacular nomenclature classifying cannabis chemovars
as “sativa” or “indica” is scientifically indefensible (see Piomelli
and Russo, 2016 for more detailed opinion). Rather, what
is necessary is more complete data on a given chemovar’s
biochemistry and attributable pharmacology. One sophisticated
approach to the issue combining those quantitative assays with
additional subjective data on scent, taste and effects, dubbed
PhytoFacts R
, has recently been described (Giese et al., 2015).
CAN A BOTANICAL AGENT BECOME A
PRESCRIPTION MEDICINE?
Plants have been the historical source of medicine for most of
human history, and continue to account for the base material
of an estimated 25% of modern pharmaceuticals (Tyler, 1993).
While the herbal market is unfathomable to many consumers
and their doctors in countries lacking suitable regulation of
the practice, it is now a proven fact that prescription drugs of
botanical origin can be approved as medicines in most nations.
This requires standardization based on sound science (Russo,
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Russo Current Therapeutic Cannabis Controversies
2001). Botanical medicines can even meet rigorous requirement
of the American FDA as has already occurred for one topical
agent (Veregen R
, an extract of green tea, Camellia sinensis),
and one single component botanical isolate taken internally,
Fulyzaq R
(crofelemer, from Croton lechleri). These approvals
were achieved by following a blueprint that was updated in
August 2015 (Food and Drug Administration, 2015; accessed
May 2016) Guidance for Industry:Botanical Drug Products:
http://www.fda.gov/downloads/drugs/guidancecompliance
regulatoryinformation/guidances/ucm458484.pdf.
REGULATORY HURDLES
Since botanical medicines represent combinations of
components, particular attention is necessary to product
composition, which may be defined through quality control
methods including spectroscopic and chromatographic
techniques, “chemical fingerprinting,” assays for certain
markers such as specific phytocannabinoids or terpenoids,
assays of bioactivity, controls on raw material and processes
in manufacture, and process validation with batch analysis
(Fan et al., 2006; Fischedick et al., 2010; Giri et al., 2010). If
components of an extract are not already “Generally Recognized
As Safe” (GRAS), clinical trials, safety-extension studies and
rigorous quality control requirements all must be met. A
botanical agent administered by a non-oral route, such as
inhalation, requires additional pharmacology and toxicology
documentation before initiation of RCTs.
The Botanical Guidance (Food and Drug Administration,
2015) defines that that a botanical raw material (BRM; i.e.,
crude herb) becomes a botanical drug substance (BDS) after
it is processed through extraction, mixing, excipient addition,
formulation and packaging in a manner that is defined,
exacting and precise. The BDS must be examined for its
pharmacokinetic (PK) and pharmacodynamic (PD) properties.
Additional regulatory requirements in a given country may
also include monitoring for contaminants due to heavy metals,
pesticides, bacteria and fungi. The FDA dictates long-term
animal toxicity studies in two species, and reproductive toxicity,
genotoxicity, and carcinogenicity investigations. Subsequent
human studies of effects on cardiac QTc, DAL, and trials
in human subjects with renal or hepatic insufficiency are
mandatory.
THE ISSUE OF HERBAL SYNERGY
Whether cannabis components beyond THC contribute to its
medicinal effects has been an issue of contention (Wachtel
et al., 2002; Ilan et al., 2005). Certainly, some have advocated
this concept of herbal synergy (McPartland and Russo, 2001;
Williamson, 2001; Wilkinson et al., 2003; Russo, 2011), which is
quite akin to combinatorial activity of endocannabinoids via “the
entourage effect” of active and inactive metabolites (Ben-Shabat
et al., 1998; Mechoulam and Ben-Shabat, 1999). Such synergy
would be apparent under conditions in which the activity of
a minor component complemented the major, diminished the
adverse event profile, or otherwise contributed to a preparation’s
stability or efficacy. The data supporting CBD as a synergist
to THC has been summarized in the past (Russo, 2006c),
including its anti-anxiety benefits (Zuardi et al., 1982), it anti-
psychotic effects (Zuardi et al., 1995; Leweke et al., 2005, 2012;
Morgan and Curran, 2008), its inhibition of THC metabolism
to the possibly more psychoactive 11-hydroxy-THC (Bornheim
and Grillo, 1998), inhibition of glutamate excitotoxicity and
ability to serve as an anti-oxidant (Hampson et al., 2000),
its anti-inflammatory and immunomodulatory activity in its
own right (Malfait et al., 2000; Costa et al., 2007). CBD and
other phytocannabinoids and terpenoids (McPartland and Russo,
2001) act in synergy with THC (Whittle et al., 2001) through
pharmacological potentiation, amelioration of adverse events,
summation, pharmacokinetic, and metabolic modulation (Russo,
2011). More recent investigations have added to this foundation,
demonstrating the ability of CBD to eliminate dose-response
ceiling to pain in an animal model (Gallily et al., 2014), how
the presence of cannabidiol allowed a statistically significant
difference in 30% pain improvement in opioid-resistant cancer
pain in humans as compared to placebo and a THC-rich cannabis
extract (Johnson et al., 2010), and the contributions of cannabis
terpenoids to herbal synergy in whole cannabis preparations
(Russo, 2011; McPartland and Russo, 2014).
PHARMACOKINETICS AND CANNABINOID
DOSE TITRATION
Among the challenges of formulating phytocannabinoids as
medicines are their lipid solubility and slow, often erratic
oral absorption. While it is sometimes suggested that cannabis
smoking permits accurate dose titration due to its rapid onset,
this approach likewise delivers high concentrations in a rapid
manner (Huestis, 2007). While this is the raison d’être of
recreational cannabis smoking, it is wholly unnecessary and,
quite arguably, undesirable to therapeutic applications, especially
treatment of chronic conditions. The risk of rapid intoxication
could be a likely factor in a putative cannabis-based medicine
being rejected for regulatory approval, as seems to have been
the case for inhaled THC products in the USA (Hart et al.,
2005). In contrast, outside of early dosage titration, most
Sativex patients experience no psychoactive effect, and report
subjective intoxication visual analog scales (VAS) of less than
10 out of 100, not statistically different to placebo. Such
results refute contentions that euphoria or other psychoactive
accompaniments are necessary for attainment of symptomatic
relief (Robson, 2011; Wade, 2012). Only one study of herbal
cannabis, employing 25 mg of material of 9.4% composition,
taken in a single inhalation was able to demonstrate a “sweet
spot” in which pain relief was attained without significant
accompanying intoxication (Ware et al., 2007).
A marked reduction in cannabis-associated adverse events was
observed in the Sativex development program when initial high
doses (up to 128 sprays/day) and rapid titration in early studies
were eschewed in favor of slower titration with lower allowances
(up to 12 sprays/day; Novotna et al., 2011). Interestingly, these
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Russo Current Therapeutic Cannabis Controversies
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).
In general, 2.5 mg of THC is a threshold dose for patients
without previous tolerance to cannabis, 5 mg is a moderate dose,
10 mg a large dose that may be problematic for naïve patients,
while 15 mg or more at a time risks psychiatric adverse events
(Grotenhermen, 2001; Sellers et al., 2013).
ANTI-INFLAMMATORY DRUGS AND
CYCLO-OXYGENASE (COX) INHIBITION
The adverse event profile with attendant morbidity and mortality
of non-steroidal anti-inflammatory drugs (NSAID) has been
of great public health concern. In essence, COX-1 agents may
precipitate gastric ulceration and hemorrhage, while COX-2
agents may increase myocardial infarction and cerebrovascular
accident risks (Fitzgerald, 2004; Topol, 2004). Apparently the
anti-inflammatory and analgesic effects of THC and CBD are
achieved independently of this mechanism, as they produce no
COX inhibition of either isozyme at physiologic doses (Stott
et al., 2005). In fact, cannabinoids have demonstrated inhibitory
effects on duodenal ulcer formation (Douthwaite, 1947), as has
the cannabis sesquiterpenoid/CB2agonist, beta-caryophyllene
(Tambe et al., 1996).
CANNABIS AND DRUG-DRUG
INTERACTIONS
Both THC and CBD are metabolized via the cytochrome P450
system. In in vitro and in vivo animal models undertaken by
GW Pharmaceuticals (data on file), inhibitory effects were only
seen at exposures significantly higher than the maximum dose-
equivalents utilized in human clinical trials and no relevant
induction of cytochrome P450 enzymes seen in vitro for human
CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Specific testing of
drug-drug interaction in human subjects was undertaken with
nabiximols (Stott et al., 2013), and no clinically relevant changes
in levels of CBD and THC with concomitant administration of
ketoconazole, rifampicin, or omeprazole. In extensive clinical
application including complex drug regimens with opioids,
tricyclic antidepressants, anticonvulsants, etc., no drug-drug
interactions have been observed that would contraindicate or
preclude use of nabiximols with any specific pharmaceutical,
although additive sedative effects are always possible (reviewed
in more detail Russo, 2006b). In nabiximols, these sedative
influences are seemingly counteracted by CBD (Nicholson et al.,
2004).
CBD can induce CYP2B isozymes, and in current
observational and clinical trial usage of CBD (Epidiolex R
)
in intractable epilepsy in children at very high doses up to
25 mg/kg/d, some elevation of the N-desmethyl clobazam
metabolite of the anticonvulsant clobazam have been observed,
producing sedation that has responded to dose reduction of the
latter drug without corresponding loss of anticonvulsant efficacy
(Devinsky et al., 2016). Caution is also advisable with utilization
of other benzodiazepines, and valproic acid.
BLINDING, PLACEBO, AND DESIGN
ISSUES IN CANNABIS RANDOMIZED
CLINICAL TRIALS
The ability to produce adequate blinding in clinical trials
of psychoactive drugs has been a difficult challenge in
pharmaceutical development. It has long been known that the
mere act of being in a clinical trial generates a certain degree
of subjective improvement, probably as a result of the extra
attention that the patient receives, and her/his desire to please
the clinical staff and contribute to the welfare of similarly affected
individuals. These placebo effects are aggravated when the RCT
lacks objective measures (as in many pain and mood trials), when
the drug in question is psychoactive (antidepressants et al.), or
when the agent in question has a reputation as “miraculous” (as
is certainly the case in public perception of cannabis). The latter
problem certainly applies to the current excitement regarding
cannabis treatment of epilepsy. In a recent observational study
of cannabidiol-rich cannabis chemovar use (Press et al., 2015),
the response rate for families moving to Colorado for treatment
of their children was 47% vs. only 22% for those already state
residents, and three times as great for those reporting >50%
response!
The placebo effect has become increasingly problematic over
time. In a landmark study with chilling implications (Tuttle et al.,
2015), it was documented that in the interval 1990–2013, placebo
responses in neuropathic pain studies increased significantly
(p=0.002), that while drug responses in pain in early studies
decreased an average of 34.7% from baseline and were stable over
time, producing 16.5% greater analgesia than placebo, or 1 point
decrease in NRS. By 2013, treatment advantage over placebo
decreased (p=0.0003) with only an 8.9% decrease in pain over
baseline. Additionally, placebo responses increased with sample
size (p=0.001), and study length (p=0.05), with the worst
differences by far in USA-based studies. The US FDA generally
requires 12-week duration RCTs in Phases II-III in accordance
with IMMPACT (Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials) Guidelines (Dworkin et al., 2005),
but this may be counterproductive to the success of the clinical
trial!
This hurdle of demonstrating salient differences of cannabis-
based medicines over placebo may have been adequately
surpassed by nabiximols (Wright et al., 2012) in some
instances. Nabiximols and its corresponding placebo are
seemingly indistinguishable in appearance, color and taste due
to the peppermint masking excipient. Approximately 50% of
nabiximols trial participants in earlier studies had prior exposure
to cannabis, but post-hoc analysis indicates no differences in
efficacy or side effect profile in cannabis-experienced vs. -
naïve subjects, and differential efficacy of Sativex to various MS
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Russo Current Therapeutic Cannabis Controversies
symptoms. Specifically, no statistical differences were observed
in the incidence of Euphoric Mood among patients with prior
experience of cannabis vs. those who were cannabis-naïve (3%
in each instance). No significant differences were noted for any
other psychiatric adverse events. No differences were noted in
the two groups with respect to efficacy of symptom control with
Sativex (supporting the efficacy of blinding), in contrast to the
CAMS study (Zajicek et al., 2003; Cannador extract vs. THC vs.
placebo), wherein treatment allocation was correctly guessed by
patients to a greater degree than expected. Virtually all clinical
studies of inhaled cannabis have produced salient differences in
psychoactive side effects in the verum group vs. placebo, with
the exception of the single inhalation study (vide supra; Ware
et al., 2007). Subsequent post-marketing studies of nabiximols
have similarly supported the efficacy of blinding (Notcutt, 2013;
Notcutt et al., 2012; Rekand, 2014).
Whereas, earlier studies of nabiximols in intractable spasticity
in multiple sclerosis produced variable differences from placebo
(Wade et al., 2004, 2010; Collin et al., 2010), more impressive
results were attained through the institution of a randomized
withdrawal study design (Novotna et al., 2011). In part A
(N=572), unbeknownst to patients, all received nabiximols
titrated upwards to clinical response or side effects. After 1
month, all patient came in for re-evaluation at a “resupply visit,
at which time, only those who had demonstrated a 20% or greater
improvement in numerical rating scales (NRS) of spasticity were
continued in the study. These patients were then randomized to
continue nabiximols at the prior number of sprays per day, or,
the corresponding number of placebo sprays. After an additional
12 weeks of treatment, spasticity NRS scores favored nabiximols
over placebo by a convincing margin (P=0.0002). Over the full
course of 16 weeks, mean spasticity improvement on nabiximols
was 48%.
Unfortunately, application of the same randomized
withdrawal study approach in a Phase III clinical trial of
nabiximols in cancer pain unresponsive to optimized opioids
failed to attain statistical significance (data on file, GW
Pharmaceuticals).
Other strategies that may reduce placebo effect in cannabis
RCTs would include limiting patient expectations: “This
experimental drug may or may not help you,” treating patients
in a neutral fashion, avoiding confounding ancillary benefits
to trial participation, such as concomitant physical therapy;
utilizing a delivery technique with slower pharmacokinetics
(oral as compared to inhalation); and, utilization of cannabis-
based preparations that limit THC-induced psychoactivity with
cannabidiol and terpenoid buffers (Russo, 2011).
CANNABIS, DRUG ABUSE LIABILITY, AND
DEA SCHEDULING
The issue of cannabis abuse and dependency remains quite
controversial. A cannabis dependency syndrome has been
posited (Budney et al., 2004), with an oft quoted figure of 9%
of ever cannabis users becoming dependent at some point. In
the USA, at least, these figures, which apply to “recreational”
usage must be tempered by the fact that greater than 50%
of patients admitted to substance abuse treatment programs
are there by legal mandate as an alternative to prosecution or
incarceration, and not always because of an actual addiction
to cannabis. Other authorities opine that cannabis has a DAL
lower than that of other legal and illicit agents (Hilts, 1994;
Roques, 1998; Nutt et al., 2007). The relative addictive potential
of a drug is ascertained by judging its attendant intoxication,
reinforcement, tolerance, withdrawal and dependency. DAL
requires additional determination of public health and legal data
on its degree of abuse and diversion. The advent of the Internet
has revolutionized promulgation of drug information to any
inquisitive potential consumer.
Herbal cannabis is scheduled in international and national
categories that generally designate it as addictive or dangerous,
having severe abuse potential, and lacking any recognized
medical utility. In contrast, Marinol R
, a synthetic form of THC
has been down-scheduled in countries where it is an approved
pharmaceutical, to a category denoting a lesser potential for
abuse or lower dependency risk, after documentation showed
rare abuse or diversion to the black market (Calhoun et al., 1998).
This precedent is one that could potentially be repeated with
cannabis-based medicines once their safety and appropriate DAL
risk is demonstrated.
Intoxication, as noted above, is rarely problematic in long-
term usage of nabiximols. The reinforcement properties of a
drug are mediated in part by the rapidity of its delivery (Samaha
and Robinson, 2005). Nabiximols’ onset of effects is 15–40 min,
with peak activity in a few hours. This is considerably slower
than most drugs of highest abuse potential. Smoked and injected
drugs produce greater reinforcement with higher peak serum
and brain levels (Samaha and Robinson, 2005). Nabiximols effect
onset is intermediate between that of inhalation and that of
oral administration. CBD modulates the psychoactivity of THC
(Russo, 2006a; Morgan and Curran, 2008; Morgan et al., 2010a,b).
Euphoric mood, while desirable to recreational cannabis users,
would be a possible risk for abuse in medical users, but has
been uncommonly observed with nabiximols (Wade et al., 2006,
2010; Robson, 2011). Given acutely, particularly in cannabis-
naïve individuals, THC may produce typical reactions such
as tachycardia, hypothermia, orthostatic hypotension, and dry
mouth, but these are subject to rapid tachyphylaxis in chronic
administration (Jones et al., 1976). The latter side effects have
become less prominent with slow titration of nabiximols (Russo
et al., 2008), and it has shown no dose tolerance with respect to its
therapeutic benefits in MS or treating cancer pain after prolonged
usage as long as several years (Wade et al., 2006; Notcutt et al.,
2012; Serpell et al., 2013).
Information from nabiximols RCTs and safety-extension
(SAFEX) studies does not indicate any particular evidence of
reinforcement. Euphoric mood is reported in nabiximols clinical
trials with under 2% incidence (GW Pharmaceuticals, 2011).
Tolerance is quickly established to various manifestations of
cannabinoid intoxication: tachycardia, hypothermia, orthostatic
hypotension, dry mouth, ocular injection, intraocular pressure
decreases, etc. (Jones et al., 1976). In over 15,000 patient-years of
experience, no dose tolerance to nabiximols has been observed,
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Russo Current Therapeutic Cannabis Controversies
however, while therapeutic efficacy is maintained (Wade et al.,
2006; Notcutt et al., 2012; Serpell et al., 2013) In SAFEX
studies in MS and peripheral neuropathic pain, nabiximols
doses have been steady or reduced after months or years of
administration (Serpell et al., 2013; Koehler, 2014). Symptomatic
pain control is maintained with slow continued improvement in
non-progressive disorders.
The existence or severity of a cannabis withdrawal syndrome
remains under debate (Smith, 2002; Budney et al., 2004). In
contrast to reported withdrawal sequelae in recreational users
(Solowij et al., 2002), 24 subjects with MS who volunteered
to discontinue nabiximols after a year or more suffered no
withdrawal symptoms meeting Budney criteria. While symptoms
such as pain recurred after some 7–10 days without Sativex,
symptom control was rapidly re-attained upon resumption
(Wade et al., 2006). Similar safety was noted in a clinical
randomized withdrawal trial in spasticity of MS (Notcutt et al.,
2012), wherein 36 patients previously improved on Sativex
showed no withdrawal symptoms of significance. Additionally, in
a study of 136 MS patients taking Sativex for a mean of 334 days,
sudden cessation, no withdrawal effects of associated adverse
events were reported (Serpell et al., 2013).
While herbal cannabis has lowest overall dependency risk
of commonly abused drugs (Hilts, 1994; Roques, 1998; Nutt
et al., 2007), that of nabiximols is apparently lower yet, due
to slower peak compared to smoking, low doses required for
therapeutic efficacy, virtual absence of intoxication in normal
usage, and freedom from withdrawal sequelae even after chronic
administration. Finally, no known abuse or diversion incidents
with nabiximols were reported (as of March 2013). Formal
DAL studies with nabiximols have demonstrated its drug abuse
potential to be equal to or less than that of Marinol, which is
Schedule III in the USA (Schoedel et al., 2011).
The situation is particularly puzzling for cannabidiol, which
seems to be a victim of guilt by association, in that it was
placed in Schedule I of the US Controlled Substances Act of
1970 along with cannabis and THC as a placeholder (United
States Commission on Marihuana and Drug Abuse, 1972),
and has remained there ever since, in spite of meeting no
criteria for intoxication, reinforcement, tolerance, withdrawal, or
dependency.
COGNITIVE ISSUES AND
NEUROPSYCHIATRIC SEQUELAE
Cognitive issues with cannabis usage have been reviewed in
the past (Russo et al., 2002; Fride and Russo, 2006) with more
recent data and analyses on an ongoing basis, many alleging
permanent sequelae and even structural changes on imaging
studies. A meta-analysis of these data is beyond the scope of
this highlights article, but readers are referred to a current
excellent systematic review (Walsh et al., 2016). Certain points
must be emphasized. Such studies are usually retrospective
analyses of recreational cannabis usage, most often at high
doses on a chronic basis. Often there is little premorbid data
on neuropsychological status, psychiatric status, socioeconomic
milieu, concomitant substance use and other pertinent potential
confounders. Additionally, one must seriously consider whether
dangers inherent to chronic cannabis usage, particularly in
high-risk situations (adolescents, pregnancy, etc.) are absolutely
relevant to medical application of cannabis under optimal
conditions with non-inhaled administration at low doses with
optimized preparations designed to reduce adverse events to the
greatest extent possible.
Impairment of short-term memory impairment has been
observed after heavy chronic recreational cannabis usage but
virtually disappears after a few weeks’ abstinence (Pope et al.,
2001). More recent studies are similarly encouraging with
regards to the reversibility of any cannabis-associated cognitive
sequelae. In brief, observed hippocampal volume changes after
cannabis usage were apparently reversible with cannabidiol
exposure or abstinence (Yucel et al., 2016). Lower grade-point
averages associated with persistent cannabis usage in high
school pupils lost statistical significance one controlling for
concomitant alcohol and tobacco usage (Meier et al., 2015).
Similarly, cannabis usage alone was not found responsible for
IQ or performance differences in teens compared to cigarette
smoking or other confounds (Mokrysz et al., 2016). A very
wise analysis points out that with recent developments in
cannabis policy, rational approaches would include adoption of
regulated markets with controls upon age of access to usage,
accurate information on dosing guidelines for consumers, and
availability of more balanced material with respect to cannabidiol
availability with lower relative THC content (Curran et al.,
2016).
Studies of cognitive issues in purely medical cannabis users are
comparatively quite few. Four patients in the Compassionate Use
Investigational New Drug program employing NIDA cannabis
for decades, and up to 10 grams/day of low potency cannabis
were systematically examined while maintaining their customary
daily intake (Russo et al., 2002). Mild difficulties were noted in
attention and concentration and with acquisition of complex
new verbal material, but without effect on higher level executive
function. No pertinent attributable imaging findings were
observed on MRI studies. One of the subjects continues to serve
at an executive level in an investment firm.
Halstead-Reitan battery components have been analyzed
from two nabiximols studies. In peripheral neuropathic pain
with allodynia (Nurmikko et al., 2005), no differences were
noted vs. placebo. In central neuropathic pain in MS (Rog
et al., 2005), four of five subtests failed to demarcate from
placebo. While the Selective Reminding Test did not deteriorate
significantly on Sativex during the study, placebo patients
improved unexpectedly (p=0.009).
Subsequently, a study of 55 MS with spasticity patients on
nabiximols vs. 52 on placebo revealed no significant differences
in cognitive ability after 1 year of treatment as measured by the
Paced Auditory Serial Addition Test (PASAT; Rekand, 2014).
Depression and anxiety have been possible sequelae of
recreational cannabis (reviewed Fride and Russo, 2006), but
slight improvements were noted with nabiximols in one study
(Rog et al., 2005) on Hospital Anxiety and Depression Scales.
No mood disorders have been evident in long-term usage.
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Cannabidiol appears very promising in this area, but no major
clinical investigations have commenced.
Whether cannabis has an causative role in schizophrenia
remains contentious (Muller-Vahl and Emrich, 2008), but is no
clear etiological relationship is evident based on epidemiological
data (Degenhardt et al., 2003; Macleod et al., 2006; Muller-Vahl
and Emrich, 2008; Hickman et al., 2009; Macleod and Hickman,
2010). One might assume that a greater risk would be evident as
a dose-related phenomenon. The low serum levels required for
nabiximols therapy, coupled with the anti-psychotic properties
of CBD (Zuardi and Guimaraes, 1997; Morgan and Curran, 2008;
Leweke et al., 2012), would hopefully minimize such risks. Once
more, the long-term adverse event profile of nabiximols would
seem to indicate few symptoms of paranoia, thought disorder or
similar changes (Wade et al., 2010; Robson, 2011; Notcutt et al.,
2012).
One study indicating safety and efficacy of cannabidiol in
psychosis equal to or greater than conventional treatment has
been published (Leweke et al., 2012), while another Phase II study
of CBD as Epidiolex with positive results vs. placebo has been
reported online and in the press.
IMMUNE FUNCTION
Deleterious effects of cannabinoids on immune function have
been reported in laboratory animals at doses 50–100 times the
psychoactive threshold in humans (Cabral, 2001). No changes
in leukocyte, CD4 or CD8 cell counts were documented in
the Compassionate Use IND subjects (Russo et al., 2002). MS
patients in the CAMS study of Cannador showed no immune
changes (Katona et al., 2005), nor were they reported with
smoked cannabis in a short-term HIV trial (Abrams et al., 2003).
Hematological parameters have been unaffected in all nabiximols
studies.
DRIVING SAFETY
While it is scientifically accepted that alcohol impairs driving
performance, and that blood ethanol levels may accurately assess
inherent risks, similar correlations to cannabis usage produce no
such clear profile.
Some retrospective studies of road crashes impute an
etiological relationship to recreational cannabis usage, while
others (Movig et al., 2004) have not supported a link, unless
cannabis was used along with alcohol. In a comprehensive
review (Hadorn, 2004), the overall impression was of a low risk
for cannabis in such accidents, and one less pronounced than
that associated with benzodiazepines and older antihistamine
formulations (Verster and Volkerts, 2004). A recent conference
report also supports these findings (Soderstrom et al., 2005).
The situation is even less clear with respect to driving and
medicinal cannabis. For Marinol, the manufacturer indicates
http://www.drugs.com/pro/marinol.html#s28 (accessed
February 2013): “Patients receiving MARINOL R
capsules
should be specifically warned not to drive, operate machinery, or
engage in any hazardous activity until it is established that they
are able to tolerate the drug and to perform such tasks safely.”
The Sativex Consumer information in Canada http://www.
bayer.ca/files/SATIVEX-PM-ENG-PT3-30MAR2012- 149598.
pdf (accessed February 2013) states:
Serious Warnings and Precautions.
THC, one of the principal active components of SATIVEX R
,
has numerous effects on the central nervous system such
as changes in mood, decreased mental performance and
memory and altered perceptions of reality. Symptoms such
as fainting and interference in the physical ability to
carry out complicated tasks have been seen in patients
taking SATIVEX R
. Therefore, you should not drive, operate
machinery or engage in activities that require unimpaired
judgment and coordination.
While taking SATIVEX R
you should not drink alcohol or take
other drugs which may have an effect on the central nervous
system such as sedatives or hypnotics, without consulting your
doctor, as these products have a further additive effect on some
of the symptoms listed above.
The CBD content of nabiximols may modulate THC effects
(Russo, 2011). In a Phase I trial of Sativex in normal subjects,
CBD promoted alertness and eliminated residual THC effects
the morning following bedtime dosing (Nicholson et al., 2004).
Additionally, post-hoc analysis of safety-extension patients with
MS taking Sativex for over 1 year indicate that in the 73% of 119
subjects completing a questionnaire, 59% noted an improvement
in total disability, 63% improved in at least one activity, 20%
reported a decreased need for equipment or assistance, 95%
noted positive changes in General Life Benefits, and 12–32% of
caretakers noted easier administration to demands of activities of
daily living.
Recently, nabiximols has been specifically tested for its
effects on driving in 33 female MS patients with moderate to
severe spasticity before and after 4–6 weeks of drug exposure
(Rekand, 2014). No significant differences were noted in
Visual Pursuit, Cognitrone, Reaction, Adaptive Tachistoscopic
Traffic Perception, or Overall scores, while Determination was
significantly improved by treatment (P=0.026). Similarly, a
survey of 196 patients in the Spanish patient registry revealed
complaints of decreased driving ability after treatment of
only 2.4%.
An expert panel (Grotenhermen et al., 2005) performed
a comprehensive analysis of the issue of cannabinoids and
driving with recommendations of as roadside sobriety tests, as
opposed to per se standards of inactive cannabinoid metabolites
that indicate past usage without accurate assessment of a
driver’s actual contemporaneous ability. The panel did endorse
the validity of measures of THC itself (Grotenhermen et al.,
2005, p. 7):
Based on the results of culpability studies and from meta-
analyses of experimental studies, per se laws for DUIC (driving
under the influence of cannabis) should specify a legal limit
for THC in blood serum of 7–10 ng/mL as a reasonable
choice for determining relative impairment by cannabis.
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This corresponds to THC concentration in whole blood- the
parameter commonly used in U.S. jurisdictions- or 3.5–5
ng/mL.
Of note, no studies demonstrated relevant impact of cannabis on
driving skills at plasma levels below 5 ng/ml of THC. The latter
benchmark value was incorporated into the legalization statute
approved by voters in Washington State in 2012, and Colorado
and Montana adopted this standard, as well.
A timely report sponsored by the American Automobile
association has re-examined the issue (Logan et al., 2016):
https://www.aaafoundation.org/sites/default/files/EvaluationOf
DriversInRelationToPerSeReport.pdf.
This study examined 602 drivers arrested for driving under
the influence (DUI) who tested positively for THC but no other
substances, as well as 349 people with no drugs in their system.
All the people had complete records as to their performance on
tests by a Drug Recognition Expert (DRE). Their examination
comprised physiological standards and psychophysical tests,
including the Standardized Field Sobriety Test (SFST) battery.
Also considered were data from an additional 4799 drivers testing
positive for cannabinoids for whom testing results were available.
Key findings included the following:
(1) DRE arrestees performed more poorly than drug-free
controls on walk-and-turn, one-leg-stand, and finger-to-
nose tests.
(2) Physical signs including red, bloodshot and watery eyes,
tremor of eyelids, lack of ocular convergence, and rebound
pupillary dilation were significantly more frequent in people
testing positive for cannabis.
(3) Data were analyzed for salient differences above and below
the 5 ng/mL standard, but this was significant solely for the
finger-to-nose test, wherein more misses were counted in the
group with higher serum levels.
(4) Data were additionally analyzed to ascertain if a different
value from 1 to 10 ng/mL produced consistency with SFST
results, but none was identified.
(5) Arrests for DUI included 70 percent with THC
concentrations below 5 ng/mL. While 23% of those
detained were positive solely for THC, the majority tested
positive for other drugs with or without alcohol.
Based on these data, laws including per se standards for impaired
drivers for cannabinoids should be re-examined and replaced
with roadside tests of impairment, followed by blood or other
corroboratory laboratory tests where a problem is suggested.
WHAT ABOUT THE CHILDREN?
The press frequently criticizes medicinal cannabis on the
basis that acquiescence to its availability promotes usage by
youth. To the contrary, analyses such as that undertaken
by the US Government Accounting Office (GAO) reveal
no increase in associated drug crimes or youth usage rates
after passage of state laws allowing medicinal cannabis (U.S.
General Accounting Office, 2002; O’Keefe and Earleywine, 2005).
Subsequent studies have failed to show any systematic increases,
and in fact, compelling epidemiological investigation suggests
a decrease in opioid overdose mortality in states that have
legalized medicinal cannabis usage (Bachhuber et al., 2014).
Additional support for opioid sparing comes from a recent
investigation and accompanying editorial revealing decreased
analgesic prescriptions in Medicare Part D in states where
cannabis was available for medical purposes (Bradford and
Bradford, 2016; Dyer, 2016).
There is no doubt that such concerns regarding youth usage
are well-intentioned, but once more, as in all of clinical medicine,
the recommendation of drug therapy requires informed consent
and a full consideration of costs and benefits. Two recent
studies of cannabis use in pregnancy seems to provide relative
reassurance of lack of data to support birth defects, significant
intrauterine growth retardation, or cognitive sequelae (Gunn
et al., 2016; Torres and Hart, 2016). Eventually, cannabis
based medicines will become available for serious pediatric
conditions, such as nausea and vomiting with in chemotherapy
and supportive oncology (Abrahamov and Mechoulam, 1995),
primary treatment of cancer (Foroughi et al., 2011), cystic fibrosis
(Fride, 2002), and severe neurologic impairment (Gottschling,
2011), and these concerns will require ongoing consideration.
SMOKING AND VAPORIZERS (ADAPTED
AND UPDATED FROM RUSSO AND
HOHMANN, 2013)
Available formal RCTs of smoked cannabis have all been Phase II
studies of quite short duration, and would have little sway among
regulators in most nations. The IMMPACT recommendations
for clinical trials in neuropathic pain, as one example (Dworkin
et al., 2005) suggest a 12-week course of study. The cumulative
cannabis exposure in herbal cannabis studies undertaken in
California totaled only 1106 patient-days, or 3 patient-years, as
analyzed in Russo and Hohmann (2013). In comparison, total
experience with Sativex including clinical trials, prescription
monitoring and named-patient supplies exceeded 30,000 patient-
years in 2014, with much lower rates of side effects (data on file,
GW Pharmaceuticals; Russo, 2006a, 2008).
The studies of smoked or vaporized cannabis to date have been
completed with cannabis-experienced patients in almost every
instance, usually as a protocol requirement. Whether the results
can be generalized to cannabis-naïve patients is open to serious
question.
Careful epidemiological studies support that cannabis
smoking induces chronic cough and bronchitis (Tashkin,
2005), but seemingly not emphysema (Tashkin et al., 1997) or
aerodigestive cancers (Hashibe et al., 2006). Lester Grinspoon
noted (Grinspoon and Bakalar, 1997, p. 250), “—the only
well-confirmed deleterious physical effect of marihuana is harm
to the pulmonary system.”
In Canada, mainstream and side stream smoke of cannabis
vs. tobacco smoke were compared (Moir et al., 2008). Their
cannabis sample’s smoke yielded ammonia (NH3) at a rate of 720
µg per 775 mg cigarette, 20 times higher than that in tobacco
smoke, possibly due to usage of synthetic nitrate fertilizers.
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Formaldehyde and acetaldehyde were generally less concentrated
in cannabis smoke than in tobacco, but butyraldehyde titers
were higher. Polycyclic aromatic hydrocarbons were qualitatively
similar. Levels of NO, NOx, hydrogen cyanide and aromatic
amines concentrations were 3–5 times higher in cannabis
smoke, with potential mutagenic and carcinogenic effects.
Possible genotoxicity has been posited to cannabis smoke due
to acetaldehyde production and production of possible DNA-
adducts (Singh et al., 2009).
Vaporization of cannabis is designed to heat to a temperature
that volatilizes THC and other components with the intent to
minimize combustion by-products (Figure 1; For reviews please
see Gieringer, 1996, 2001; Storz and Russo, 2003; Gieringer et al.,
2004; Hazekamp et al., 2006; Bloor et al., 2008; Van der Kooy
et al., 2008; Zuurman et al., 2008; Pomahacova et al., 2009).
The Volcano vaporizer was compared to smoking (Abrams
et al., 2007) in 18 customary cannabis smokers, after 2
days of abstinence. NIDA 900 mg cannabis (1.7, 3.4, 3.4,
and 6.8% THC) cigarettes were split in two, allowing one-
half each to be smoked or vaporized sequentially in double-
blind fashion. THC plasma concentrations were comparable
or slightly higher after vaporization than smoking. Exhaled
CO diminished very slightly in vapor, while it increased after
smoking (p<0.001). Visual analog scales of intoxication were
almost identical and increased with higher potency cannabis.
While it was claimed that since CO did not rise after
vaporization, there would be “little or no exposure to gaseous
combustion toxins” (p. 576), a quite remarkable assertion,
given that PAHs and other products of combustion were
not directly measured. It was also claimed that there were
no reported adverse events. While twelve 12 experimenters
preferred the Volcano, 2 liked smoking, and 2 had no
preference as to technique. The authors labeled the vaporizer,
“an acceptable system,” providing “a safer way to deliver
THC—”(p. 576).
The Volcano Medic R
with an upper temperature limit of
210C. is a licensed medical device in the European Union, and
in Canada since 2010 (No. 82405).
Subsequently, new innovations have appeared on the
vaporization scene. The Syqe vaporizer from Israel is a hand
held portable device designed to provide dose-metered single
inhalations from ground herbal Bedrocan cannabis from the
Netherlands (Eisenberg et al., 2014). This seemingly promising
approach produced salient issues, nevertheless:
(1) The observed maximum serum concentration of THC
(Cmax) of 38 ng/ml is still in the psychoactive range, and
would be an issue for regulators, as well as being possibly
problematic for THC-naïve patients.
(2) The selected patients with neuropathic pain were a biased
population by virtue of already being cannabis patients.
(3) Critics may point out that cannabis users will recognize the
high, and confabulate that with reduced pain (whether that
is true or not).
(4) The study was unblinded, which would have no weight in the
regulatory environment.
(5) A 12-h abstention from the patients’ customary therapeutic
cannabis usage was employed in the trials, and is not long
enough to eliminate residual effects on pain threshold from
prior use. In most RCTs of clinical application of cannabis, a
month of abstinence is mandated.
(6) The pain relief was very brief (about 90 min), and use of
this technology for a chronic pain patient would require
very frequent application, thereby increasing relative risks of
reinforcement and dependency. From a DAL standpoint, this
would be unacceptable to most regulators.
(7) The presence or absence of polyaromatic hydrocarbons was
not assayed, and would more likely be lower employing a
cannabis extract without extraneous plant material.
(8) A 20% device failure was observed without additional
explanation or qualification.
A recent study examined several newer vaporizer models (Lanz
et al., 2016), all of which produced effective decarboxylation
of the herbal Bedrocan cannabis base material. The highest
cannabinoid recovery rates in the vapor were produced by the
Arizer Solo R
, 67.5–82.7%, but once more, no specific assays were
performed for polyaromatic hydrocarbon residues.
As with smoked cannabis studies, clinical trials undertaken to
date with vaporizers have been small pilot studies of maximum 5
days’ duration, that will not likely portend regulatory acceptance
under the Botanical Guidance (Food and Drug Administration,
2004). Neither is it probable that the side effect of smoked
FIGURE 1 | Demonstration of the effects of vaporization of cannabis flower material at different temperatures employing the Volcano Digit Vaporizer
(Left to Right): Unheated dried cannabis, Post-vaporization at 175C, Post-vaporization at 195C, Post-vaporization at 230C.
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Russo Current Therapeutic Cannabis Controversies
or vaporized cannabis would pass regulatory muster. Even
if a perfect vaporizer were produced, standardization of the
cannabis employed and quantification of delivered doses would
be necessary for such approval, as well as total elimination of
potential carcinogens and mutagens (Russo, 2006a). For better or
worse, vaporizers have had little market penetration to date: an
Internet survey noted that only 2.2% of cannabis users primarily
utilized vaporization for cannabis consumption (Earleywine and
Barnwell, 2007), but this situation may be in flux.
Cognitive effects evident in smoked cannabis studies call
into question the reliability of blinding vs. placebo (vide
supra). It is instructive to compare adverse event profiles
for other drugs used for similar conditions: An analysis of
medications employed for chronic polyneuropathy revealed
that intolerable side-effects were not significantly different
in cohorts receiving gabapentinoids, tricyclic anti-depressants,
anticonvulsants, cannabinoids (including nabilone, Sativex) and
topical agents (Toth and Au, 2008). None of the adverse events
were serious.
CANNABIS CONCENTRATES: “DABS,
WAX, AND SHATTER”
The illegality of cannabis of the last few decades has catalyzed
selective breeding for ever more potent THC-predominant
chemovars, and preparations that further concentrate that
component. Whereas, techniques such as water hash or sieving
of cannabis could produce kif or hashish of up to 60% THC
(Clarke, 1998), chemical extractions with naphtha, petroleum
ether, butane and other solvents can push these figures to 90%
THC or more, with dangers of residual solvents (Romano and
Hazekamp, 2013), fires and explosions in kitchen laboratories.
A clean concentrate can be produced via supercritical CO2
extraction (Guy and Stott, 2005), but this requires technical
equipment and expertise.
These cannabis concentrates sport various names: dabs, wax,
shatter, and have spawned an entire new industry based on “vape
pens” (Figure 2). The appellation may be a misnomer, however,
as evidenced by the instant production of red hot elements in
most devices. Their ramifications can be dramatic, as evidenced
by increasing emergency visits for exploding lithium batteries
in the units, or sequelae of their use in the form of panic
reactions, toxic psychosis episodes, and orthostatic hypotension
with resultant falls and accompanying injury. Even surveyed
users acknowledge attendant greater tolerance and withdrawal
effects (Loflin and Earleywine, 2014). The extreme viscosity of
“wax” often necessitates the addition of propylene glycol and
glycerol as propellants for the devices to function. Whereas,
these substances are safe for oral usage in small amounts, recent
research on their application in E-cigarettes containing nicotine
reveals that when overheated, up to 2% of the mixture forms
formaldehyde, a Group I carcinogen, producing a cancer risk
estimated to be as much as 15 time that of chronic cigarette
smoking (Jensen et al., 2015).
Many of these preparations are questionable with respect
to their appropriateness to medicinal application. It is
hoped that these by-products of prohibition with their
advantage of clandestine transport of ever higher potency
materials will become less attractive in a legal, regulated
market.
CANNABIS CONTAMINANTS: HEAVY
METALS, MICROBES AND RECENT DATA
ON PESTICIDES
Cannabis is a bio-accumulator (McPartland et al., 2000) that
recruits heavy metals (lead, mercury, cadmium, and arsenic)
from the soil into the plant biomass. While this is an advantage
when rehabilitating contaminated soils with a hemp crop, it is
a distinct liability if medical grade cannabis is grown in such
media.
Similarly, foods and other materials to be ingested must be
free of microbial contamination. Potential pathogenic bacteria
may be introduced from the soil, fertilizer, or human handling
with inadequate hygiene (i.e., handwashing). While clean culture
without coliform bacterial infestation is certainly possible (Potter,
2009), some government-approved medicinal cannabis programs
have utilized gamma-irradiation of cannabis for its sterilization.
These raises some concerns of its own, while no residual
radiation is reported in such instances, it is the case that no
FIGURE 2 | Demonstration of a “vape-pen.” (A) Vape-pen unit (B) “Wax” in unit (C) Unheated coil (D) Coil becomes red hot in seconds after actuation.
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safety studies have been published to attest to the safety of
the technique for a smoked or vaporized product. Additionally,
gamma irradiation significantly reduced monoterpene content
in orange juice and cilantro (coriander herb; Fan and Gates,
2001; Fan and Sokorai, 2002). A recent report in this journal
examining the technique with cannabis has demonstrated
“minor” quantitative changes in terpenoid content, if not overall
profile (Hazekamp, 2016). The gamma irradiation did produce
a 10% decrement in β-caryophyllene in one cannabis chemovar,
and this certainly might affect the therapeutic effect of a
medical product given that this sesquiterpenes component is a
selective CB2full agonist (Gertsch et al., 2008) with important
anti-inflammatory and analgesic benefits (Russo, 2011, 2016b).
Even without such changes, a certain segment of health-
conscious consumers may choose to avoid such irradiated
preparations on moral grounds, and deserve full disclosure in this
regard.
Both the American Herbal Products Association (American
Herbal Products Association, 2014) and American Herbal
Pharmacopoeia (Upton et al., 2013) have developed guidelines
for cultivation and production of medicinal cannabis.
Contamination risk by bacteria and insects is greatest in
the indoor environment that has predominated in the black
market, is less in greenhouses, and less still in open air
cultivation.
An informal survey in 2014 of California laboratories
performing assays for residual pesticides on cannabis crops
observed an incidence of only 1–2% (Backes, 2014). This
author contacted other prominent California analytical
laboratories that observed that 15–35% of samples submitted
to them were positive, and that they had become hesitant
to publicize their service or list agents for which they could
assay, as they suspected that such information merely led
unscrupulous growers to seek out possibly more toxic agents
that were not included. A more formal published survey
of contamination in California demonstrated qualitative
presence of eight pesticides in 33% of samples (Raber et al.,
2015).
Washington State legalized medicinal cannabis in 1998, where
it remained largely unregulated until recently. Legalization
of recreational cannabis was passed by ballot initiative in
2012, but despite panel recommendations, no testing for
pesticide contamination was mandated. Subsequently, efforts
are underway to unify the prior medical market with the legal
one. No current method is available to certify organic cannabis
culture, and there are no Environmental Protection Agency
guidelines on acceptable pesticide levels for a smoked product.
Prior informal testing in Washington was undertaken by a
concerned medical purveyor yielded pesticide residues in 5–10%
of tested cannabis inflorescence samples. An alarming recent
study has demonstrated the passage of up to 70% of pesticides
spiked into herbal cannabis into the captured smoke (Sullivan
et al., 2013).
To more fully assess the current situation, 26 distinct
cannabis samples were purchased (24 concentrates, 2 cannabis
inflorescence) from legal stores in Washington and passed via
witnessed chain of evidence to a state certified legal licensed
laboratory (Trace Analytics, Spokane, WA; Russo, 2016c).
Samples were homogenized, and extracted using a modified
QuEChERS AOAC protocol. The supernatant was injected
for LCMS-MS analysis. Detection was carried out using a
Shimadzu LCMS-8050 triple quadrupole mass spectrometer with
a Shimadzu Prominence HPLC. Approximately 200 analytes
were measured with over 500 MRM transitions per run.
Out of the 26 Washington State samples, 22 tested positively
for pesticides (84.6%). Many harbored multiple contaminants,
attaining levels in the tens of thousands of parts per billion (ppb),
exceeding the upper limit of quantification. These included 24
distinct pesticide agents of every class (Table 1;McPartland
et al., 2000; Upton et al., 2013; Kegley et al., 2014): insecticides,
miticides, fungicides, an insecticidal synergist and growth
regulators, including organophosphates, organochlorides,
carbamates, etc. One tested cannabis extract, a candidate for
folding into the medical market in Washington, demonstrated
lower levels of azoxystrobin, triflumizole, and piperonyl
butoxide, with extreme levels of carbaryl, boscalid, bifenazate,
pyraclostrobin, fenpyroximate, and myclobutanil, with
documented associated toxicities as carcinogens, neurotoxins,
cholinesterase inhibitors, developmental and reproductive
toxins, and endocrine disruptors.
The unregulated commerce in cannabis with respect to
pesticide usage and lack of available organic certification have
resulted in widespread abuse of the legal cannabis market
system. Cannabis concentrates currently account for 50% of
legal sales in WA, and are also the basis for a burgeoning
commerce in cannabis edibles. These products present a
clear and present danger, particularly to young patients with
epilepsy and other neurological conditions. Future regulation
and monitoring with allowance for organic certification and
employment of integrated pest management techniques without
synthetic pesticides (McPartland et al., 2000) are required
approaches to rectify this looming public health threat.
These finding should serve as an indictment of individual
industrial oversights and unscrupulous practices, but should
not be taken as evidence that cannabis is too dangerous for
therapeutic application when proper standards are applied.
CONCLUSIONS
As the legal tide is turning on cannabis as a forbidden drug,
experiments are ongoing in the various states (and other
countries) as called for in Justice Brandeis’ “laboratories of
democracy.” Daunting problems remain for those attempting
to seek regulatory approval for smoked or vaporized cannabis
as a prescription product, whereas nabiximols, a standardized
oromucosal spray has achieved such approval in 27 nations
based on its ability to demonstrate biochemical consistency,
and safety and efficacy in randomized controlled trials.
Pure CBD (Epidiolex) also appears headed for regulatory
approval.
In contrast, the recreational market is facing numerous
challenges in quality control, and addressing myriad safety
concerns associated with newer, more potent preparations and
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TABLE 1 | Pesticides encountered in 26 cannabis samples in Washington State, with structure, chemical class, and potential toxicities.
Pesticide Structure Class/Usage Toxicity
Azoxystrobin Fungicide Questionable
developmental/reproductive
toxin and endocrine
disruptor
Bifenazate Miticide Slight acute toxicity,
potential ground water
contaminant, questionable
developmental/reproductive
toxin and endocrine
disruptor
Boscalid Fungicide Possible carcinogen;
Questionable
developmental/reproductive
toxin and endocrine
disruptor
Carbaryl Carbamate/Insecticide BAD ACTOR;
Cholinesterase inhibitor;
carcinogen;
developmental/reproductive
toxin; suspected endocrine
disruptor
Carbendazim Benzimidalole/Fungicide Possible carcinogen;
questionable ground water
contaminant; questionable
developmental/reproductive
toxin; suspected endocrine
disruptor
Clothianidin Neonicotinoid/Insecticide Questionable
developmental/reproductive
toxin; questionable
endocrine disruptor
Diazinon Organophosphate/Insecticide/Miticide Unlikely carcinogen;
cholinesterase inhibitor;
developmental/reproductive
toxin; suspected endocrine
disruptor
Diuron
(DCMU)
Herbicide/
Photosynthesis
inhibitor
Carcinogen;
developmental/reproductive
toxin; suspected endocrine
disruptor
(Continued)
Frontiers in Pharmacology | www.frontiersin.org 12 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
TABLE 1 | Continued
Pesticide Structure Class/Usage Toxicity
Ethoprophos Organophosphate/Insecticide/Nematicide BAD ACTOR: Carcinogen;
cholinesterase inhibitor;
potential ground water
contaminant; questionable
developmental/reproductive
toxin; questionable
endocrine disruptor
Etoxazole Miticide Questionable
developmental/reproductive
toxin and endocrine
disruptor
Fenpyroximate Insecticide/Miticide Questionable
developmental/reproductive
toxin; questionable
endocrine disruptor
Imidacloprid Neonicotinoid/Insecticide Questionable
developmental/reproductive
toxin and endocrine
disruptor
Malathion Organophosphate/Insecticide Cholinesterase inhibitor;
possible
developmental/reproductive
toxin; suspected endocrine
disruptor
Myclobutanil Triazole/Fungicide Developmental/reproductive
toxin; not cholinesterase
inhibitor
Permethrin Pyrethroid/Insecticide BAD ACTOR; Moderate
acute toxicity, Carcinogen,
potential ground water
contaminant, questionable
developmental/reproductive
toxin, suspected endocrine
disruptor
Piperonyl
butoxide
Pesticide synergist Possible carcinogen;
Questionable
developmental/reproductive
toxin; Suspected endocrine
disruptor
(Continued)
Frontiers in Pharmacology | www.frontiersin.org 13 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
TABLE 1 | Continued
Pesticide Structure Class/Usage Toxicity
Propargite Organochlorine/Miticide Carcinogen;
developmental/reproductive
toxin; Questionable
endocrine disruptor
Propiconazole Triazole/Fungicide Possible carcinogen;
developmental/reproductive
toxin; Suspected endocrine
disruptor
Pyraclostrobin Fungicide Questionable
developmental/reproductive
toxin; Questionable
endocrine disruptor
Pyriproxyfen Pyridine/Pesticide Questionable
developmental/reproductive
toxin; Questionable
endocrine disruptor
Triflumizole Fungicide Potential ground water
contaminant; Questionable
developmental/reproductive
toxin; Questionable
endocrine disruptor
Trifloxystrobin Fungicide Questionable
developmental/reproductive
toxin and endocrine
disruptor
Triticonazole Fungicide Questionable
developmental/reproductive
toxin; Questionable
endocrine disruptor
Zoxamide Fungicide Questionable
developmental/reproductive
toxin; questionable
endocrine disruptor
Data from: American Herbal Pharmacopoeia Cannabis Inflorescence (Loflin and Earleywine, 2014), PAN Pesticides Database:
http://www.pesticideinfo.org/Search_Products.jsp#ProdSearch (Fan and Sokorai, 2002), Hemp diseases and pests (Eisenberg et al., 2014). Assay results from Trace Analytics,
Spokane, WA. Structures from ACD/ChemSketch 2015.2.5.
Frontiers in Pharmacology | www.frontiersin.org 14 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
novel delivery techniques. Science may provide suitable data
for addressing these issues if commensurate research funding is
forthcoming to meet the urgent need.
AUTHOR CONTRIBUTIONS
ER was responsible for the investigation and drafting of this
review.
ACKNOWLEDGMENTS
The assistance of the Inter-Library Loan staff of Mansfield
Library of the University of Montana in providing research
materials is greatly appreciated. Dr. Gilbert Mobley provided
the funding for pesticide assays in Washington State. This work
was approved and supervised by Gordon Fagras, CEO of Trace
Analytics, Spokane, WA. Their contributions were essential to
the accomplishment of this investigation.
REFERENCES
Abrahamov, A., and Mechoulam, R. (1995). An efficient new cannabinoid
antiemetic in pediatric oncology. Life Sci. 56, 2097–2102. doi: 10.1016/0024-
3205(95)00194-B
Abrams, D. I., Hilton, J. F., Leiser, R. J., Shade, S. B., Elbeik, T. A., Aweeka, F.
T., et al. (2003). Short-term effects of cannabinoids in patients with HIV-1
infection. A randomized, placbo-controlled clinical trial. Ann. Intern. Med. 139,
258–266. doi: 10.7326/0003-4819-139-4-200308190-00008
Abrams, D. I., Vizoso, H. P., Shade, S. B., Jay, C., Kelly, M. E., and Benowitz, N.
L. (2007). Vaporization as a smokeless cannabis delivery system: a pilot study.
Clin. Pharmacol. Ther. 82, 572–578. doi: 10.1038/sj.clpt.6100200
American Herbal Products Association (2014). Recommendations for Regulators-
Cannabis Operations. Silver Spring, MD.
Bachhuber, M. A., Saloner, B., Cunningham, C. O., and Barry, C. L.
(2014). Medical cannabis laws and opioid analgesic overdose mortality in
the United States, 1999-2010. JAMA Intern. Med. 174, 1668–1673. doi:
10.1001/jamainternmed.2014.4005
Backes, M. (2014). Cannabis Pharmacy: The Practical Guide to Medical Marijuana.
New York, NY: Black Dog & Leventhal.
Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T., Rhee, M. H., Vogel, Z., et al. (1998).
An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-
arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31. doi:
10.1016/S0014-2999(98)00392-6
Bloor, R. N., Wang, T. S., Spanel, P., and Smith, D. (2008). Ammonia release from
heated ‘street’ cannabis leaf and its potential toxic effects on cannabis users.
Addiction 103, 1671–1677. doi: 10.1111/j.1360-0443.2008.02281.x
Bornheim, L. M., and Grillo, M. P. (1998). Characterization of cytochrome
P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-
hydroxyquinone as a P450 inactivator. Chem. Res. Toxicol. 11, 1209–1216. doi:
10.1021/tx9800598
Bradford, A. C., and Bradford, W. D. (2016). Medical marijuana laws reduce
prescription medication use in medicare part D. Health Aff. (Millwood) 35,
1230–1236. doi: 10.1377/hlthaff.2015.1661
Budney, A. J., Hughes, J. R., Moore, B. A., and Vandrey, R. (2004). Review of the
validity and significance of cannabis withdrawal syndrome. Am. J. Psychiatry
161, 1967–1977. doi: 10.1176/appi.ajp.161.11.1967
Cabral, G. (2001). “Immune system,” in Cannabis and Cannabinoids:
Pharmacology, Toxicology and Therapeutic Potential, eds F. Grotenhermen and
E. B. Russo (Binghamton, NY: Haworth Press), 279–287.
Calhoun, S. R., Galloway, G. P., and Smith, D. E. (1998). Abuse potential
of dronabinol (Marinol). J. Psychoactive Drugs 30, 187–196. doi:
10.1080/02791072.1998.10399689
Clarke, R. C. (1998). Hashish! Los Angeles, CA: Red Eye Press.
Collin, C., Ehler, E., Waberzinek, G., Alsindi, Z., Davies, P., Powell, K., et al.
(2010). A double-blind, randomized, placebo-controlled, parallel-group study
of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis.
Neurol. Res. 32, 451–459. doi: 10.1179/016164109X12590518685660
Costa, B., Trovato, A. E., Comelli, F., Giagnoni, G., and Colleoni, M. (2007).
The non-psychoactive cannabis constituent cannabidiol is an orally effective
therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur. J.
Pharmacol. 556, 75–83. doi: 10.1016/j.ejphar.2006.11.006
Curran, H. V., Freeman, T. P., Mokrysz, C., Lewis, D. A., Morgan, C. J., and
Parsons, L. H. (2016). Keep off the grass? Cannabis, cognition and addiction.
Nat. Rev. Neurosci. 17, 293–306. doi: 10.1038/nrn.2016.28
Degenhardt, L., Hall, W., and Lynskey, M. (2003). Testing hypotheses about the
relationship between cannabis use and psychosis. Drug Alcohol Depend. 71,
37–48. doi: 10.1016/S0376-8716(03)00064-4
Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J., et al.
(2016). Cannabidiol in patients with treatment-resistant epilepsy: an open-
label interventional trial. Lancet Neurol. 15, 270–278. doi: 10.1016/S1474-
4422(15)00379-8
Douthwaite, A. H. (1947). Choice of drugs in the treatment of duodenal ulcer. Br.
Med. J. 2, 43–47. doi: 10.1136/bmj.2.4514.43
Dworkin, R. H., Turk, D. C., Farrar, J. T., Haythornthwaite, J. A., Jensen, M. P.,
Katz, N. P., et al. (2005). Core outcome measures for chronic pain clinical trials:
IMMPACT recommendations. Pain 113, 9–19. doi: 10.1016/j.pain.2004.09.012
Dyer, O. (2016). US states that allow medical marijuana see drop in prescriptions
for other drugs, study finds. BMJ 354:i3942. doi: 10.1136/bmj.i3942
Earleywine, M., and Barnwell, S. S. (2007). Decreased respiratory symptoms
in cannabis users who vaporize. Harm Reduct. J. 4:11. doi: 10.1186/1477-
7517-4-11
Eisenberg, E., Agintz, M., and Almog, S. (2014). The pharmacokinetics, efficacy,
safety, and ease of use of a novel portable metered-dose inhaler in patients with
chronic neuropathic pain: A Phase 1a study. J. Pain Palliat. Care Pharmacother.
28, 216–225. doi: 10.3109/15360288.2014.941130
Fan, X., and Gates, R. A. (2001). Degradation of monoterpenes in orange juice by
gamma radiation. J. Agric. Food Chem. 49, 2422–2426. doi: 10.1021/jf0013813
Fan, X., and Sokorai, K. J. (2002). Changes in volatile compounds of gamma-
irradiated fresh cilantro leaves during cold storage. J. Agric. Food Chem. 50,
7622–7626. doi: 10.1021/jf020584j
Fan, X.-H.,Cheng, Y.-Y.,Ye, Z.-L., Lin, R.-C., and, Qian, Z.-Z. (2006). Multiple
chromatographic fingerprinting and its application to the quality control
of herbal medicines. Anal. Chim. Acta 555, 217–224. doi: 10.1016/
j.aca.2005.09.037
Fischedick, J. T., Hazekamp, A., Erkelens, T., Choi, Y. H., and Verpoorte, R. (2010).
Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids
for chemotaxonomic and drug standardization purposes. Phytochemistry 71,
2058–2073. doi: 10.1016/j.phytochem.2010.10.001
Fitzgerald, G. A. (2004). Coxibs and cardiovascular disease. N. Engl. J. Med. 351,
1709–1711. doi: 10.1056/NEJMp048288
Food and Drug Administration (2004). Guidance for Industry: Botanical Drug
Products. U.D.o.H.a.H. Services, US Government.
Food and Drug Administration (2015). Botanical Drug Development Guidance
for Industry. U.S.D.o.H.a.H. Services, Food and Drug Administration
(Washington, DC).
Foroughi, M., Hendson, G., Sargent, M. A., and Steinbok, P. (2011). Spontaneous
regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role
of Cannabis inhalation. Childs. Nerv. Syst. 27, 671–679. doi: 10.1007/s00381-
011-1410-4
Fride, E. (2002). Cannabinoids and cystic fibrosis: a novel approach. J. Cannabis
Ther. 2, 59–71. doi: 10.1300/J175v02n01_03
Fride, E., and Russo, E. B. (2006). “Neuropsychiatry: Schizophrenia, depression,
and anxiety,” in Endocannabinoids: The Brain and Body’s Marijuana and
Beyond, eds E. Onaivi, T. Sugiura, and V. Di Marzo (Boca Raton, FL: Taylor
& Francis), 371–382.
Gallily, R., Yekhtin, Z., and Hanus, L. (2014). Overcoming the bell-
shaped dose-response of cannabidiol by using cannabis extract enriched
in cannabidiol. Pharmacol. Pharm. 6, 75–85. doi: 10.4236/pp.2015.
62010
Frontiers in Pharmacology | www.frontiersin.org 15 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
Gaoni, Y., and Mechoulam, R. (1964). Isolation, structure and partial synthesis
of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647. doi:
10.1021/ja01062a046
Gertsch, J., Leonti, M., Raduner, S., Racz, I., Chen, J. Z., Xie, X. Q., et al. (2008).
Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. U.S.A. 105,
9099–9104. doi: 10.1073/pnas.0803601105
Gieringer, D. (1996). Marijuana waterpipe and vaporizer study. MAPS Bull. 6,
59–66.
Gieringer, D. (2001). Cannabis “vaporization": a promising strategy for smoke
harm reduction. J. Cannabis Ther. 1, 153–170. doi: 10.1300/J175v01n03_10
Gieringer, D., St. Laurent, J., and Goodrich, S. (2004). Cannabis vaporizer
combines efficient delivery of THC with effective suppression of pyrolytic
compounds. J. Cannabis Ther. 4, 7–27. doi: 10.1300/J175v04n01_02
Giese, M. W., Lewis, M. A., Giese, L., and Smith, K. M. (2015). Development and
validation of a reliable and robust method for the analysis of cannabinoids and
terpenes in cannabis. J. AOAC Int. 98, 1503–1522. doi: 10.5740/jaoacint.15-116
Giri, L., Andola, H. C., Purohit, V. K., Rawat, M. S. M., Rawal, R. S., and Bhatt,
I. D. (2010). Chromatographic and spectral fingerprinting standardization of
traditional medicines: an overview as modern tools. Res. J. Phytochem. 4,
234–241. doi: 10.3923/rjphyto.2010.234.241
Gottschling, S. (2011). Cannbinoide bei Kindern. Gute Erfahrungen bei
Schmerzen, Spastik und in der Onkologie. Angewandte Schmerztherapie und
Palliativmedizin. 55–57.
Grinspoon, L., and Bakalar, J. B. (1997). Marihuana, The Forbidden Medicine. New
Haven: Yale University Press.
Grotenhermen, F. (2001). “Practical hints,” in Cannabis and Cannabinoids:
Pharmacology, Toxicology and Therapeutic Potential, eds F. Grotenhermen and
E. B. Russo (Binghamton, NY: Haworth Press), 345–353.
Grotenhermen, F., Leson, G., Berghaus, G., Drummer, O., Krueger, H. P., Longo,
M., et al. (2005). “Developing science-based per se limits for driving under the
influence of cannabis (DUIC),” in Findings and Recommendations by an Expert
Panel, Nova- Institut, Hürth, Germany, 49.
Gunn, J. K., Rosales, C. B., Center, K. E., Nuñez, A., Gibson, S. J., Christ, C.,
et al. (2016). Prenatal exposure to cannabis and maternal and child health
outcomes: a systematic review and meta-analysis. BMJ Open 6:e009986. doi:
10.1136/bmjopen-2015-009986
Guy, G. W., and Stott, C. G. (2005). “The development of Sativex- a natural
cannabis-based medicine,” in Cannabinoids as Therapeutics, ed R. Mechoulam
(Basel: Birkhäuser Verlag), 231–263.
GW Pharmaceuticals (2011). Investigator Brochure Sativex Oromucosal Spray.
Salisbury: GW Pharmaceuticals, 170.
Hadorn, D. (2004). “A review of cannabis and driving skills,” in Medicinal Uses
of Cannabis and Cannabinoids, eds G. W. Guy, B. A. Whittle, and P. Robson
(London: Pharmaceutical Press), 329–368.
Hampson, A. J., Grimaldi, M., Lolic, M., Wink, D., Rosenthal, R., and Axelrod, J.
(2000). Neuroprotective antioxidants from marijuana. Ann. N.Y. Acad. Sci. 899,
274–282. doi: 10.1111/j.1749-6632.2000.tb06193.x
Hart, C. L., Haney, M., Vosburg, S. K., Comer, S. D., and Foltin, R. W.
(2005). Reinforcing effects of oral 19-THC in male marijuana smokers in a
laboratory choice procedure. Psychopharmacology (Berl.) 181, 237–243. doi:
10.1007/s00213-005-2234-2
Hashibe, M., Morgenstern, H., Cui, Y., Tashkin, D. P., Zhang, Z. F., Cozen, W.,
et al. (2006). Marijuana use and the risk of lung and upper aerodigestive tract
cancers: results of a population-based case-control study. Cancer Epidemiol.
Biomarkers Prev. 15, 1829–1834. doi: 10.1158/1055-9965.EPI-06-0330
Hazekamp, A. (2016). Evaluating the effects of gamma-irradiation for
decontamination of medicinal cannabis. Front. Pharmacol. 7:108. doi:
10.3389/fphar.2016.00108
Hazekamp, A., Ruhaak, R., Zuurman, L., van Gerven, J., and Verpoorte, R. (2006).
Evaluation of a vaporizing device (Volcano) for the pulmonary administration
of tetrahydrocannabinol. J. Pharm. Sci. 95, 1308–1317. doi: 10.1002/jps.20574
Hickman, M., Vickerman, P., Macleod, J., Lewis, G., Zammit, S., Kirkbride, J., et al.
(2009). If cannabis caused schizophrenia–how many cannabis users may need
to be prevented in order to prevent one case of schizophrenia? England and
Wales calculations. Addiction 104, 1856–1861. doi: 10.1111/j.1360-0443.2009.
02736.x
Hilts, P. J. (1994). Is nicotine addictive? It depends on whose criteria you use. New
York Times, New York, pp. C3.
Huestis, M. A. (2007). Human cannabinoid pharmacokinetics. Chem. Biodivers. 4,
1770–1804. doi: 10.1002/cbdv.200790152
Ilan, A. B., Gevins, A., Coleman, M., ElSohly, M. A., and de Wit, H.
(2005). Neurophysiological and subjective profile of marijuana with varying
concentrations of cannabinoids. Behav. Pharmacol. 16, 487–496. doi:
10.1097/00008877-200509000-00023
Jensen, R. P., Luo, W., Pankow, J. F., Strongin, R. M., and Peyton, D. H. (2015).
Hidden formaldehyde in e-cigarette aerosols. N. Engl. J. Med. 372, 392–394.
doi: 10.1056/NEJMc1413069
Johnson, J. R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E. D., Potts,
R., and Fallon, M. T. (2010). Multicenter, double-blind, randomized,
placebo-controlled, parallel-group study of the efficacy, safety, and
tolerability of THC:CBD extract and THC extract in patients with
intractable cancer-related pain. J. Pain Symptom Manage. 39, 167–179.
doi: 10.1016/j.jpainsymman.2009.06.008
Jones, R. T., Benowitz, N., and Bachman, J. (1976). Clinical studies of
cannabis tolerance and dependence. Ann. N.Y. Acad. Sci. 282, 221–239. doi:
10.1111/j.1749-6632.1976.tb49901.x
Katona, S., Kaminski, E., Sanders, H., and Zajicek, J. (2005). Cannabinoid influence
on cytokine profile in multiple sclerosis. Clin. Exp. Immunol. 140, 580–585. doi:
10.1111/j.1365-2249.2005.02803.x
Kegley, S. E., Hill, B. R., Orme, S., and Choi, A. H. (2014). PAN Pesticide Database.
Oakland, CA: Pesticide Action Network.
Koehler, J. (2014). Who benefits most from THC:CBD spray? Learning from
clinical experience. Eur. Neurol. 71(Suppl. 1), 10–15. doi: 10.1159/0003
57743
Kunos, G. (2007). Understanding metabolic homeostasis and imbalance: what is
the role of the endocannabinoid system? Am. J. Med. 120, S18–S24; discussion
S24. doi: 10.1016/j.amjmed.2007.06.007
Lanz, C., Mattsson, J., Soydaner, U., and Brenneisen, R. (2016). Medicinal cannabis:
in vitro validation of vaporizers for the smoke-free inhalation of cannabis. PLoS
ONE 11:e0147286. doi: 10.1371/journal.pone.0147286
Leweke, F. M., Koethe, D., Gerth, C. W., Nolden, B., Mauss, C., Schreiber, D., et al.
(2005). “Cannabidiol as an antipsychotic: a double-blind, controlled clinical
trial on cannabidiol vs. amisulpride in acute schizophrenia,” in Symposium
on the Cannabinoids, International Cannabinoid Research Society (Clearwater,
FL), 48.
Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C.,
et al. (2012). Cannabidiol enhances anandamide signaling and alleviates
psychotic symptoms of schizophrenia. Transl. Psychiatry 2:e94. doi: 10.1038/tp.
2012.15
Loflin, M., and Earleywine, M. (2014). A new method of cannabis ingestion:
the dangers of dabs? Addict. Behav. 39, 1430–1433. doi: 10.1016/
j.addbeh.2014.05.013
Logan, B., Kacinko, S. L., and Beirness, D. J. (2016). An Evaluation of Data from
Drivers Arrested for Driving Under the Influence in Relation to per se Limits
for Cannabis (May 2016). Washington, DC: American Automobile Association
Foundation for Traffic Safety.
Macleod, J., and Hickman, M. (2010). How ideology shapes the evidence and the
policy: what do we know about cannabis use and what should we do? Addiction
105, 1326–1330. doi: 10.1111/j.1360-0443.2009.02846.x
Macleod, J., Davey Smith, G., and Hickman, M. (2006). Does cannabis use cause
schizophrenia? Lancet 367, 1055. doi: 10.1016/S0140-6736(06)68468-7
Malfait, A. M., Gallily, R., Sumariwalla, P. F., Malik, A. S., Andreakos, E.,
Mechoulam, R., et al. (2000). The nonpsychoactive cannabis constituent
cannabidiol is an oral anti-arthritic therapeutic in murine collagen-
induced arthritis. Proc. Natl. Acad. Sci. U.S.A. 97, 9561–9566. doi:
10.1073/pnas.160105897
McPartland, J. M., and Russo, E. B. (2001). Cannabis and cannabis extracts:
greater than the sum of their parts? J. Cannabis Ther. 1, 103–132. doi:
10.1300/J175v01n03_08
McPartland, J. M., and Russo, E. B. (2014). “Non-phytocannabinoid constituents
of cannabis and herbal synergy,” in Handbook of Cannabis, ed R. G. Pertwee
(Oxford, UK: Oxford University Press), 280–295.
McPartland, J. M., Clarke, R. C., and Watson, D. P. (2000). Hemp Diseases and
Pests: Management and Biological Control. Wallingford, UK: CABI.
McPartland, J. M., Duncan, M., Di Marzo, V., and Pertwee, R. G. (2015). Are
cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the
Frontiers in Pharmacology | www.frontiersin.org 16 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
endocannabinoid system? A systematic review. Br. J. Pharmacol. 172, 737–753.
doi: 10.1111/bph.12944
Mechoulam, R., and Ben-Shabat, S. (1999). From gan-zi-gun-nu to anandamide
and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat. Prod. Rep. 16,
131–143. doi: 10.1039/a703973e
Meier, M. H., Hill, M. L., Small, P. J., and Luthar, S. S. (2015). Associations
of adolescent cannabis use with academic performance and mental health: a
longitudinal study of upper middle class youth. Drug Alcohol Depend. 156,
207–212. doi: 10.1016/j.drugalcdep.2015.09.010
Moir, D., Rickert, W. S., Levasseur, G., Larose, Y., Maertens, R., White, P., et al.
(2008). A comparison of mainstream and sidestream marijuana and tobacco
cigarette smoke produced under two machine smoking conditions. Chem. Res.
Toxicol. 21, 494–502. doi: 10.1021/tx700275p
Mokrysz, C., Landy, R., Gage, S. H., Munafò, M. R., Roiser, J. P., and Curran,
H. V. (2016). Are IQ and educational outcomes in teenagers related to their
cannabis use? A prospective cohort study. J. Psychopharmacol. 30, 159–168. doi:
10.1177/0269881115622241
Morgan, C. J., and Curran, H. V. (2008). Effects of cannabidiol on schizophrenia-
like symptoms in people who use cannabis. Br. J. Psychiatry 192, 306–307. doi:
10.1192/bjp.bp.107.046649
Morgan, C. J., Freeman, T. P., Schafer, G. L., and Curran, H. V. (2010a).
Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol
in humans smoking their chosen cannabis. Neuropsychopharmacology 35,
1879–1885. doi: 10.1038/npp.2010.58
Morgan, C. J., Schafer, G., Freeman, T. P., and Curran, H. V. (2010b).
Impact of cannabidiol on the acute memory and psychotomimetic effects
of smoked cannabis: naturalistic study. Br. J. Psychiatry 197, 285–290. doi:
10.1192/bjp.bp.110.077503
Movig, K. L., Mathijssen, M. P., Nagel, P. H., Van Egmond, T., De Gier, J. J.,
Leufkens, H. G., et al. (2004). Psychoactive substance use and the risk of
motor vehicle accidents. Accid. Anal. Prev. 36, 631–636. doi: 10.1016/S0001-
4575(03)00084-8
Müller-Vahl, K. R., and Emrich, H. M. (2008). Cannabis and schizophrenia:
towards a cannabinoid hypothesis of schizophrenia. Expert Rev. Neurother. 8,
1037–1048. doi: 10.1586/14737175.8.7.1037
Nicholson, A. N., Turner, C., Stone, B. M., and Robson, P. J. (2004). Effect of
delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-
morning behavior in young adults. J. Clin. Psychopharmacol. 24, 305–313. doi:
10.1097/01.jcp.0000125688.05091.8f
Notcutt, W., Langford, R., Davies, P., Ratcliffe, S., and Potts, R. (2012).
A placebo-controlled, parallel-group, randomized withdrawal study of
subjects with symptoms of spasticity due to multiple sclerosis who are
receiving long-term Sativex(R) (nabiximols). Mult. Scler. 18, 219–228. doi:
10.1177/1352458511419700
Notcutt, W. G. (2013). A questionnaire survey of patients and carers of patients
prescribed Sativex as an unlicensed medicine. Prim. Health Care Res. Dev. 14,
192–199. doi: 10.1017/S1463423612000333
Novotna, A., Mares, J., Ratcliffe, S., Novakova, I., Vachova, M., Zapletalova, O.,
et al. (2011). A randomized, double-blind, placebo-controlled, parallel-group,
enriched-design study of nabiximols(Sativex( R
)), as add-on therapy, in
subjects with refractory spasticity caused by multiple sclerosis. Eur. J. Neurol.
18, 1122–1131. doi: 10.1111/j.1468-1331.2010.03328.x
Nurmikko, T. J., Serpell, M. G., Hoggart, B., Toomey, P. J., and Morlion, B. J.
(2005). A multi-center, double-blind, randomized, placebo-controlled trial of
oro-mucosal cannabis-based medicine in the treatment of neuropathic pain
characterized by allodynia. Neurology 64, A374.
Nutt, D., King, L. A., Saulsbury, W., and Blakemore, C. (2007). Development of
a rational scale to assess the harm of drugs of potential misuse. Lancet 369,
1047–1053. doi: 10.1016/S0140-6736(07)60464-4
O’Keefe, K., and Earleywine, M. (2005). Marijuana Use by Young People: The
Impact of State Medical Marijuana Laws. Washington, DC: Marijuana Policy
Project, 19.
Piomelli, D., and Russo, E. B. (2016). The Cannabis sativa versus Cannabis indica
debate: an interview with Ethan Russo, MD. Cannabis Cannabinoid Res. 1,
44–46. doi: 10.1089/can.2015.29003.ebr
Pomahacova, B., Van der Kooy, F., and Verpoorte, R. (2009). Cannabis smoke
condensate III: the cannabinoid content of vaporised Cannabis sativa.Inhal.
Toxicol. 21, 1108–1112. doi: 10.3109/08958370902748559
Pope, H. G. Jr., Gruber, A. J., Hudson, J. I., Huestis, M. A., and Yurgelun-Todd,
D. (2001). Neuropsychological performance in long-term cannabis users. Arch.
Gen. Psychiatry 58, 909–915. doi: 10.1001/archpsyc.58.10.909
Portenoy, R. K., Ganae-Motan, E. D., Allende, S., Yanagihara, R., Shaiova, L.,
Weinstein, S., et al. (2012). Nabiximols for opioid-treated cancer patients with
poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose
trial. J. Pain 13, 438–449. doi: 10.1016/j.jpain.2012.01.003
Potter, D. J. (2009). The Propagation, Characterisation and Optimisation of
Cannabis sativa L. as a Phytopharmaceutical. Pharmaceutical Sciences, King’s
College, London, 224.
Press, C. A., Knupp, K. G., and Chapman, K. E. (2015). Parental reporting of
response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy
Behav. 45, 49–52. doi: 10.1016/j.yebeh.2015.02.043
Raber, J. C., Elzinga, S., and Kaplan, C. (2015). Understanding dabs: contamination
concerns of cannabis concentrates and cannabinoid transfer during the act of
dabbing. J. Toxicol. Sci. 40, 797–803. doi: 10.2131/jts.40.797
Rekand, T. (2014). THC:CBD spray and MS spasticity symptoms: data from latest
studies. Eur. Neurol. 71(Suppl. 1), 4–9. doi: 10.1159/000357742
Robson, P. (2011). Abuse potential and psychoactive effects of delta-9-
tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a
new cannabinoid medicine. Expert Opin. Drug Saf. 10, 675–685. doi:
10.1517/14740338.2011.575778
Rog, D. J., Nurmiko, T., Friede, T., and Young, C. (2005). Randomized
controlled trial of cannabis based medicine in central neuropathic pain due
to multiple sclerosis. Neurology 65, 812–819. doi: 10.1212/01.wnl.0000176753.
45410.8b
Romano, L. L., and Hazekamp, A. (2013). Cannabis oil: chemical evaluation of an
upcoming cannabis-based medicine. Cannabinoids 1, 1–11.
Roques, B. (1998). Problèmes Posés Par la Dangerosité des Drogues. Paris: Sécretaire
d’Etat à la Santé.
Russo, E. B. (2001). Handbook of Psychotropic Herbs: A Scientific Analysis of Herbal
Remedies for Psychiatric Conditions. Binghamton, NY: Haworth Press.
Russo, E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept
explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable
bowel syndrome and other treatment-resistant conditions? Neuroendocrinol
Lett. 25, 31–39.
Russo, E. B. (2006c). A tale of two cannabinoids: the therapeutic rationale
for combining tetrahydrocannabinol (THC) and cannabidiol (CBD). Med.
Hypotheses 66, 234–246. doi: 10.1016/j.mehy.2005.08.026
Russo, E. B. (2006a). “The solution to the medicinal cannabis problem,” in Ethical
Issues in Chronic Pain Management,ed M. E. S chatman (Boca Raton, FL: Taylor
& Francis), 165–194.
Russo, E. B. (2006b). “The role of cannabis and cannabinoids in pain management,
in Weiner’s Pain Management: A Practical Guide for Clinicians, eds B. E. Cole
and M. Boswell (Boca Raton, FL: CRC Press), 823–844.
Russo, E. B. (2008). Cannabinoids in the management of difficult to treat pain.
Ther. Clin. Risk Manag. 4, 245–259.
Russo, E. B. (2011). Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163,
1344–1364. doi: 10.1111/j.1476-5381.2011.01238.x
Russo, E. B. (2016a). Clinical endocannabinoid deficiency reconsidered: current
research supports the theory in migraine, fibromyalgia, irritable bowel, and
other treatment-resistant syndromes. Cannabis Cannabinoid Res. 1, 154–165.
doi: 10.1089/can.2016.0009
Russo, E. B. (2016b). Beyond cannabis: plants and the endocannabinoid system.
Trends Pharmacol. Sci. 37, 594–605. doi: 10.1016/j.tips.2016.04.005
Russo, E. B. (2016c). “Pesticide contamination of cannabis in the legal market,
26th Annual Conference on the Cannabinoids, International Cannabinoid
Research Society (Bukovina), 66.
Russo, E. B., and Hohmann, A. G. (2013). “Role of cannabinoids in pain
management,” in Comprehensive Treatment of Chronic Pain by Medical,
Interventional and Behavioral Approaches, eds T. Deer, and V. Gordin (New
York, NY: Springer), 181–197.
Russo, E. B., Etges, T., and Stott, C. G. (2008). “Comprehensive adverse
event profile of Sativex,” in 18th Annual Symposium on the Cannabinoids.,
International Cannabinoid Research Society (Aviemore), 136.
Russo, E. B., Mathre, M. L., Byrne, A., Velin, R., Bach, P. J., Sanchez-Ramos, J.,
et al. (2002). Chronic cannabis use in the Compassionate Investigational New
Frontiers in Pharmacology | www.frontiersin.org 17 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
Drug Program: an examination of benefits and adverse effects of legal clinical
cannabis. J. Cannabis Ther. 2, 3–57. doi: 10.1300/J175v02n01_02
Russo, E. B., Mead, A. P., and Sulak, D. (2015). “Current status and future of
cannabis research,” in Clinical Researcher. 58–63. doi: 10.14524/CR-15-0004
Samaha, A. N., and Robinson, T. E. (2005). Why does the rapid delivery of
drugs to the brain promote addiction? Trends Pharmacol. Sci. 26, 82–87. doi:
10.1016/j.tips.2004.12.007
Schoedel, K. A., Chen, N., Hilliard, A., White, L., Stott, C., Russo, E., et al. (2011). A
randomized, double-blind, placebo-controlled, crossover study to evaluate the
subjective abuse potential and cognitive effects of nabiximols oromucosal spray
in subjects with a history of recreational cannabis use. Hum. Psychopharmacol.
26, 224–236. doi: 10.1002/hup.1196
Sellers, E. M., Schoedel, K., Bartlett, C., Romach, M., Russo, E. B., Stott, C. G.,
et al. (2013). A multiple-dose, randomized, double-blind, placebo-controlled,
parallel-group QT/QTc study to evaluate the electrophysiologic effects of
THC/CBD Spray. Clin. Pharmacol. Drug Dev. 2, 285–294. doi: 10.1002/
cpdd.36
Serpell, M. G., Notcutt, W., and Collin, C. (2013). Sativex long-term use: an open-
label trial in patients with spasticity due to multiple sclerosis. J. Neurol. 260,
285–295. doi: 10.1007/s00415-012-6634-z
Singh, R., Sandhu, J., Kaur, B., Juren, T., Steward, W. P., Segerbäck, D., et al. (2009).
Evaluation of the DNA damaging potential of cannabis cigarette smoke by the
determination of acetaldehyde derived N2-ethyl-2-deoxyguanosine adducts.
Chem. Res. Toxicol. 22, 1181–1188. doi: 10.1021/tx900106y
Smith, N. T. (2002). A review of the published literature into cannabis withdrawal
symptoms in human users. Addiction 97, 621–632. doi: 10.1046/j.1360-
0443.2002.00026.x
Soderstrom, C. A., Dischinger, P. C., Kufera, J. A., Ho, S. M., and Shepard,
A. (2005). “Crash culpability relative to age, and sex for injured drivers
using alcohol, marijuana or cocaine,” in Association for the Advancement of
Automotive Medicine (Cambridge, MA).
Solowij, N., Stephens, R. S., Roffman, R. A., Babor, T., Kadden, R., Miller, M.,
et al. (2002). Cognitive functioning of long-term heavy cannabis users seeking
treatment. JAMA 287, 1123–1131. doi: 10.1001/jama.287.9.1123
Storz, M., and Russo, E. B. (2003). An interview with Markus Storz. J. Cannabis
Ther. 3, 67–78. doi: 10.1300/J175v03n01_04
Stott, C. G., Guy, G. W., Wright, S., and Whittle, B. A. (2005). “The effects
of cannabis extracts Tetranabinex & Nabidiolex on human cyclo-oxygenase
(COX) activity,” in Symposium on the Cannabinoids, International Cannabinoid
Research Society (Clearwater, FL).
Stott, C., White, L., Wright, S., Wilbraham, D., and Guy, G. (2013). A Phase I,
open-label, randomized, crossover study in three parallel groups to evaluate the
effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics
of THC/CBD oromucosal spray in healthy volunteers. SpringerPlus 2:236. doi:
10.1186/2193-1801-2-236
Sullivan, N., Elzinga, S., and Raber, J. C. (2013). Determination of pesticide residues
in cannabis smoke. J. Toxicol. 2013:378168. doi: 10.1155/2013/378168
Tambe, Y., Tsujiuchi, H., Honda, G., Ikeshiro, Y., and Tanaka, S. (1996). Gastric
cytoprotection of the non-steroidal anti-inflammatory sesquiterpene, beta-
caryophyllene. Planta Med. 62, 469–470. doi: 10.1055/s-2006-957942
Tashkin, D. P. (2005). Smoked marijuana as a cause of lung injury. Monaldi Arch.
Chest Dis. 63, 93–100. doi: 10.4081/monaldi.2005.645
Tashkin, D. P. (2013). Effects of marijuana smoking on the lung. Ann. Am. Thorac.
Soc. 10, 239–247. doi: 10.1513/AnnalsATS.201212-127FR
Tashkin, D. P., Simmons, M. S., Sherrill, D. L., and Coulson, A. H. (1997).
Heavy habitual marijuana smoking does not cause an accelerated decline
in FEV1 with age. Am. J. Respir. Crit. Care Med. 155, 141–148. doi:
10.1164/ajrccm.155.1.9001303
Topol, E. J. (2004). Failing the public health–rofecoxib, Merck, and the FDA. N.
Engl. J. Med. 351, 1707–1709. doi: 10.1056/NEJMp048286
Torres, C. A., and Hart, C. L. (2016). Prenatal Cannabis Exposure and Cognitive
Function: A Critical Review. College on Problems of Drug Dependency, Palm
Springs, CA, 142.
Toth, C., and Au, S. (2008). A prospective identification of neuropathic pain in
specific chronic polyneuropathy syndromes and response to pharmacological
therapy. Pain 138, 657–666. doi: 10.1016/j.pain.2008.04.023
Tuttle, A. H., Tohyama, S., Ramsay, T., Kimmelman, J., Schweinhardt, P.,
Bennett, G. J., et al. (2015). Increasing placebo responses over time
in U.S. clinical trials of neuropathic pain. Pain 156, 2616–2626. doi:
10.1097/j.pain.0000000000000333
Tyler, V. E. (1993). “Phytomedicines in Western Europe: potential impact on
herbal medicine in the United States,” in Human Medicinal Agents from
Plants, ACS Symposium, No. 534, eds A. D. Kinghorn and M. F. Balandrin
(Philadelphia: American Chemical Society), 25–37.
United States Commission on Marihuana and Drug Abuse (1972). Marihuana: A
Signal of Misunderstanding. First Report,U.S. Government Publishing Office,
Washington.
Upton, R., Craker, L., ElSohly, M., Romm, A., Russo, E., and Sexton, M. (2013).
Cannabis Inflorescence: Cannabis spp.: Standards of Identity, Analysis and
Quality Control. Scotts Valley, CA: American Herbal Pharmacopoeia.
U.S. General Accounting Office (2002). Marijuana:Early Experiences with Four
States’ Laws that Allow Use For Medical Purposes. Washington, DC: United
States General Accounting Office, 63.
Van der Kooy, F., Pomahacova, B., and Verpoorte, R. (2008). Cannabis
smoke condensate I: the effect of different preparation methods
on tetrahydrocannabinol levels. Inhal. Toxicol. 20, 801–804. doi:
10.1080/08958370802013559
Vandrey, R., Raber, J. C., Raber, M. E., Douglass, B., Miller, C., and Bonn-Miller,
M. O. (2015). Cannabinoid dose and label accuracy in edible medical cannabis
products. JAMA 313, 2491–2493. doi: 10.1001/jama.2015.6613
Verster, J. C., and Volkerts, E. R. (2004). Antihistamines and driving ability:
evidence from on-the-road driving studies during normal traffic. Ann.
Allergy Asthma Immunol. 92, 294–303; quiz 303–355. doi: 10.1016/S1081-
1206(10)61566-9
Wachtel, S. R., ElSohly, M. A., Ross, R. A., Ambre, J., and de Wit, H. (2002).
Comparison of the subjective effects of delta9-tetrahydrocannabinol and
marijuana in humans. Psychopharmacology 161, 331–339. doi: 10.1007/s00213-
002-1033-2
Wade, D. (2012). Evaluation of the safety and tolerability profile of Sativex: is it
reassuring enough? Expert Rev. Neurother. 12, 9–14. doi: 10.1586/ern.12.12
Wade, D. T., Collin, C., Stott, C., and Duncombe, P. (2010). Meta-analysis
of the efficacy and safety of Sativex (nabiximols), on spasticity in people
with multiple sclerosis. Mult. Scler. 16, 707–714. doi: 10.1177/13524585103
67462
Wade, D. T., Makela, P., Robson, P., House, H., and Bateman, C. (2004). Do
cannabis-based medicinal extracts have general or specific effects on symptoms
in multiple sclerosis? A double-blind, randomized, placebo-controlled study
on 160 patients. Mult. Scler. 10, 434–441. doi: 10.1191/1352458504ms
1082oa
Wade, D. T., Makela, P. M., House, H., Bateman, C., and Robson, P. J. (2006).
Long-term use of a cannabis-based medicine in the treatment of spasticity
and other symptoms in multiple sclerosis. Multiple Scler. 12, 639–645. doi:
10.1177/1352458505070618
Walsh, Z., Gonzales, R., Crosby, K., Carroll, C., and Bonn-Miller, M. O. (2016).
Medical cannabis and mental health: a systematic review. Clin. Psychol. Rev.
Ware, M., Wang, W., Shapiro, S., Ducruet, T., Robinson, A., Gamsa, A., et al.
(2007). “Smoked cannabis for chronic neuropathic pain: results of a pilot
study,” in 17th Annual Symposium on the Cannabinoids (Saint-Sauveur, QC:
International Cannabinoid Research Society), 31.
Whittle, B. A., Guy, G. W., and Robson, P. (2001). Prospects for new
cannabis-based prescription medicines. J. Cannabis Ther. 1, 183–205. doi:
10.1300/J175v01n03_12
Wilkinson, J. D., Whalley, B. J., Baker, D., Pryce, G., Constanti, A., Gibbons, S.,
et al. (2003). Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for
all its effects? J. Pharm. Pharmacol. 55, 1687–1694. doi: 10.1211/0022357022304
Williamson, E. M. (2001). Synergy and other interactions in phytomedicines.
Phytomedicine 8, 401–409. doi: 10.1078/0944-7113-00060
Wright, S., Duncombe, P., and Altman, D. G. (2012). Assessment of blinding
to treatment allocation in studies of a cannabis-based medicine (Sativex(R))
in people with multiple sclerosis: a new approach. Trials 13:189. doi:
10.1186/1745-6215-13-189
Yücel, M., Lorenzetti, V., Suo, C., Zalesky, A., Fornito, A., Takagi, M. J.,
et al. (2016). Hippocampal harms, protection and recovery following regular
cannabis use. Transl. Psychiatry 6, e710. doi: 10.1038/tp.2015.201
Zajicek, J., Fox, P., Sanders, H., Wright, D., Vickery, J., Nunn, A., et al. (2003).
Cannabinoids for treatment of spasticity and other symptoms related to
Frontiers in Pharmacology | www.frontiersin.org 18 September 2016 | Volume 7 | Article 309
Russo Current Therapeutic Cannabis Controversies
multiple sclerosis (CAMS study): multicentre randomised placebo-controlled
trial. Lancet 362, 1517–1526. doi: 10.1016/S0140-6736(03)14738-1
Zuardi, A. W., and Guimaraes, F. S. (1997). “Cannabidiol as an anxiolytic
and antipsychotic,” in Cannabis in Medical Practice:A Legal, Historical and
Pharmacological Overview of the Therapeutic Use of Marijuana, ed M. L. Mathre
(Jefferson, NC: McFarland), 133–141.
Zuardi, A. W., Morais, S. L., Guimarães, F. S., and Mechoulam, R. (1995).
Antipsychotic effect of cannabidiol [letter]. J. Clin. Psychiatry 56, 485–486.
Zuardi, A. W., Shirakawa, I., Finkelfarb, E., and Karniol, I. G. (1982). Action
of cannabidiol on the anxiety and other effects produced by delta 9-THC in
normal subjects. Psychopharmacology 76, 245–250. doi: 10.1007/BF00432554
Zuurman, L., Roy, C., Schoemaker, R. C., Hazekamp, A., den Hartigh, J., Bender, J.
C., et al. (2008). Effect of intrapulmonary tetrahydrocannabinol administration
in humans. J. Psychopharmacol. 22, 707–716. doi: 10.1177/02698811080
89581
Conflict of Interest Statement: The author declares that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2016 Russo. This is an open-access article distributed under the terms
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Frontiers in Pharmacology | www.frontiersin.org 19 September 2016 | Volume 7 | Article 309
... 1,2 Three structural features characterize the general chemical skeleton of phytocannabinoid: a central resorcinol core accompanied by an alkyl side chain and monoterpene unit ( Figure 1). 3,4 Depending on the biosynthesis, 5,6 cannabinoids with varying alkyl chain length such as C 5 (olivetoids), C 3 (varionoids), C 1 (orcoids), and C 0 (resorcinoid) are found in planta 3,7−9 and have recently attracted much attention in medical research. ...
... 30,31 The first preclinical studies of this biphenyl compound for the treatment of wide-angle glaucoma and Epidermolysis bullosa have shown some promising results. 3,4,9 This rare cannabinoid has been synthesized via aromatization of THC-C 5 (4a). 23 However, Razdan et al. 32 found that not all isomers with a THC scaffold can convert into CBN-C 5 . ...
Article
Efficient syntheses of eight key cannabinoids were established and optimized. Predominant cannabinoids such as cannabigerol (CBG-C5) and cannabidiol (CBD-C5) were prepared from olivetol via regioselective condensation. Further treatments of CBD led to Δ9-tetrahydrocannabinol (THC-C5), Δ8-iso-tetrahydrocannabinol (iso-THC-C5), and cannabinol (CBN-C5). Alternatively, a [3 + 3] annulation between olivetol and citral yielded the minor cannabinoid cannabichromene (CBC-C5), which was converted into two very rare polycycles, cannabicyclol (CBL-C5) and cannabicitran (CBT-C5), in a one-pot reaction. Finally, all eight syntheses were extended by utilizing resorcinol and two phenolic analogues, achieving a cannabinoid group with more than 30 compounds through a facile synthesis strategy.
... Despite heavy prohibition legislation in the US, cannabis was still recommended by the medical community in the 1930s and 40s until the Marihuana Tax Act made it almost impossible to grow, sell, and prescribe due to the strong risk of incarceration [16]. A full history of cannabis and the use of cannabinoids in migraine treatment is well-documented elsewhere [17]. ...
... Two resources for up-todate information on state-specific laws include Americans for Safe Access [12] and the National Conference of State Legislatures [11]. Important differences among state cannabis programs include allowable delivery forms, qualifying medical conditions, and third-party testing requirements [17]. ...
Article
Full-text available
Purpose of Review Public acceptance of Cannabis sativa L. (cannabis) as a therapeutic option grows despite lags in both research and clinician familiarity. Cannabis—whether as a medical, recreational, or illicit substance—is and has been commonly used by patients. With ongoing decriminalization efforts, decreased perception of harms, and increased use of cannabis in the treatment of symptoms and disease, it is critical for clinicians to understand the rationale for specific therapies and their medical and practical implications for patients. In view of the opioid crisis, overall patient dissatisfaction, and lack of adherence to current chronic pain and headache therapies, this review provides up-to-date knowledge on cannabis as a potential treatment option for headache pain. Recent Findings Research into the use of cannabinoids for disease treatment have led to FDA-approved drugs for seizures, nausea, and vomiting caused by cancer chemotherapy; and for decreased appetite and weight loss in people with HIV/AIDS. For a wide variety of conditions and symptoms (including chronic pain), cannabis has gained increasing acceptance in society. The effects of cannabidiol (CBD) and tetrahydrocannabinol (THC) in pain pathways have been significantly elucidated. An increasing number of retrospective studies have shown a decrease in pain scores after administration of cannabinoids, as well as long-term benefits such as reduced opiate use. Yet, there is no FDA-approved cannabis product for headache or other chronic pain disorders. More is being done to determine who is likely to benefit from cannabis as well as to understand the long-term effects and limitations of the treatment. Summary Cannabis can refer to a number of products derived from the plant Cannabis sativa L. Relatively well-tolerated, these products come in different configurations, types, and delivery forms. Specific formulations of the plant have been shown to be an effective treatment modality for chronic pain, including headache. It is important for clinicians to know which product is being discussed as well as the harms, benefits, contraindications, interactions, and unknowns in order to provide the best counsel for patients.
... Cannabis has psychoactive properties, primarily associated with the cannabinoid THC that produces euphoria, and is widely consumed in Canada for both medical and nonmedical purposes. 1 The 2017 Canadian Tobacco Alcohol and Drugs (CTADS) found that 15% (4.4 million) of Canadians (aged ‡ 15 years) reported using cannabis in the past year, 2 a 22% increase from 3.6 million Canadians who endorsed use in 2015. 3 In general, individuals who endorse use of cannabis for nonmedical purposes are more likely to be male and younger. ...
Article
Objectives: To examine the proportion of individuals using cannabis for medical purposes who reported nonmedical use of cannabis after it became legal to do so. Materials and Methods: We acquired data from the Population Assessment for Tomorrow's Health, the Cannabis Legalization Surveillance Study on a subpopulation of participants residing in Hamilton, Ontario, Canada, who reported using cannabis for medical purposes. Specifically, we acquired data 6 months before, and again 6 months after, legalization of cannabis for nonmedical purposes. We constructed a logistic regression model to explore the association between potential explanatory factors and endorsing exclusively nonmedical use after legalization and reported associations as odds ratios and 95% confidence intervals. Results: Our sample included 254 respondents (mean age 33±13; 61% female), of which 208 (82%) reported both medical and nonmedical use of cannabis (dual motives) before legalization for nonmedical purposes, and 46 (18%) reported cannabis use exclusively for medical purposes. Twenty-five percent (n=63) indicated they had medical authorization to use medical cannabis, of which 37 (59%) also endorsed nonmedical use. After legalization of nonmedical cannabis, ∼1 in 4 previously exclusive cannabis users for medical purposes declared dual use (medical and nonmedical), and ∼1 in 4 previously dual users declared exclusively nonmedical use of cannabis. No individual with medical authorization reported a change to exclusively nonmedical use after legalization. Our adjusted regression analysis found that younger age, male sex, and lacking authorization for cannabis use were associated with declaring exclusively nonmedical use of cannabis after legalization. Anxiety, depression, impaired sleep, pain, and headaches were among the most common complaints for which respondents used cannabis therapeutically. Most respondents reported using cannabis as a substitute for prescription medication at least some of the time, and approximately half reported using cannabis as a substitute for alcohol at least some of the time. Conclusions: In a community sample of Canadian adults reporting use of cannabis for medical purposes, legalization of nonmedical cannabis was associated with a substantial proportion changing to either dual use (using cannabis for both medical and nonmedical purposes) or exclusively nonmedical use. Younger men without medical authorization for cannabis use were more likely to declare exclusively nonmedical use after legalization.
... The use of cannabis for female reproductive complaints has a long ethnopharmacological history, but little modern clinical evidence in the literature. The earliest records associated with cannabis use therapeutically are associated with the Chinese, Indian, and Egyptian cultures before the Common Era [23][24][25], with the earliest Chinese pharmacopoeia, the Shen-nung pen ts'ao ching, ascribing cannabis use for rheumatic pain and disorders of the female reproductive system [24,25]. Historical medical evidence of cannabis being used to manage dysmenorrhea dates back to the 1800s, with Reynolds recommending its use in The Lancet in 1890 [26]. ...
Article
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Objective: This study sought to investigate the perceptions, barriers, and drivers associated with medicinal cannabis use among Australian women with primary dysmenorrhea. A qualitative study via virtual focus groups involving 26 women experiencing regular, moderate, or greater menstrual pain explored categories including cost, associated stigma, current drug driving laws, community and workplace ethics, and geographical isolation within the context of patient access under current Australian laws and regulations. Results: A qualitative descriptive analysis identified that dissatisfaction with current management strategies such as over-the-counter analgesic usage was the key driver for wanting to use medicinal cannabis. A number of significant barriers to use were identified including patient access to medical prescribers, medical practitioner bias, current drug driving laws, geographic location, and cost. Community and cultural factors such as the history of cannabis as an illicit drug and the resulting stigma, even when prescribed by a medical doctor, still existed and was of concern to our participants. Conclusion: Whilst medicinal cannabis is legal in all states and territories within Australia, several barriers to access exist that require government regulatory attention to assist in increasing patient adoption, including possible subsidisation of cost. The high cost of legal, medicinal cannabis was a key factor in women's choice to use illicit cannabis. Overall, the concerns raised by our participants are consistent with the broader findings of a recent Australian Senate inquiry report into barriers to patient access to medicinal cannabis in Australia, suggesting many of the issues are systematic rather than disease-specific. Given the interest in use of medicinal cannabis amongst women with primary dysmenorrhea, clinical trials in this area are urgently needed.
... Cannabis, Cannabis sativa, is a herbaceous flowering plant that has been used as a natural therapeutic agent since ancient times. 3 In 1842, cannabis was introduced into modern medicine for its analgesic, sedative, anti-inflammatory, antispasmodic and 4 Cannabinoids are a group of chemicals that are derived from the Cannabis plant, which can directly alter mental state when consumed, which can indirectly lead to physical changes. Of the hundreds of cannabinoids known, the two compounds that have been researched the most are CBD and THC, with THC being a psychoactive compound, whereas CBD is non-psychoactive. ...
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... 5 Cannabis was available in the US pharmacies since 1845 and was available in British pharmacies for over a century, 6 however, because of the rise of concerns by its psychotropic effects, it was removed from the US Pharmacopeia in 1941. 7 In 1976, the United States Controlled Substances Act classified cannabis as a Schedule I drug, meaning it had no acceptable medical use and high potential for abuse. 1 During the last decade, interest in cannabis in medicine has been increasing, and several countries, including United States and Canada, have produced their own legislation about marihuana and cannabis-based medicines. 8 In 2017, 38 states and the District of Columbia allowed medical use of cannabis, and 8 states and the District of Columbia have legalized its recreational use. ...
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The world market has been introduced with cannabis industry since long ago before the start of the Common Era. Since a century ago, this industry has been overwhelmed with controversial legal battles and debates. However, recently, the legitimate cannabis market has been growing rapidly and is highly potential to significantly boost the world's economy. This intensive review is organised to elaborate on the indirect cost and profit potentials associated with the industrial-scale cannabis and hemp cultivation and processing as well as its formulation for cosmetics applications. The search for new alternatives for hemp and to help local farmers expanding their current practices is highly on demand for the improvement of the worldwide hemp markets. Summarizing all the data from various studies and countries, this review presents a comprehensive discussion focusing on cosmetics applications starting from the therapeutic potentials of the cannabis and hemp, regulatory resources, its safety and effectiveness, mechanism in treating skin diseases and the future prospect of cannabis in cosmetics industries. The current stigma of the world hemp industry has somehow prevented farmers from switching to large scale cultivation of the cannabis. It is proposed for the state governments to allocate high economic incentives especially for the farmers to willingly taking the challenge in introducing cannabis into their agriculture practices. These additional investment and in-depth research focus could lead to a positive competition to the current products in multiple industries.
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Contents at a glance At a time when cannabis legalisation is spreading across an increasing number of jurisdictions globally, this book cuts across the noise and presents a factual account of issues faced by regulators in the real-world context of Colorado. It can be read as an evidence-based handbook for regulators and should be a first port of call for anyone interested in the legalisation of cannabis. In January 2014, Colorado implemented a commercial cannabis market for pleasure - the first jurisdiction globally to implement a regulated, adult-use cannabis supply chain from seed-to-sale. It was reported as an historic occasion that presaged a grand social and economic experiment in drug legalisation. Including analysis of hundreds of pages of government documents, almost 1000 media articles, and interviews in the field with over 30 senior government officials, industry executives, and front-line public health representatives, this book is the definitive account of real-world cannabis policy implementation. The cannabis academic public health literature is examined prodigiously including its potential for harm and benefit together with alternative regulatory approaches. The book also features a number of papers published in academic journals based on the PhD research of the author. The commodification of cannabis vs the craft approach together with the entanglement of the medical and recreational markets are two of many topical themes discussed in detail. Multiple recommendations relevant for other jurisdictions considering the legalisation of cannabis are presented. Recognising the limitations of harm reduction approaches that cannot conceptually conceive beneficial aspects of cannabis consumption, a new framework, the spectrum of wellness is proposed as an alternative in Appendix 1 of the book.
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