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Forum
Cannabidiol Claims
and Misconceptions
Ethan B. Russo1,*
Once a widely ignored phytocan-
nabinoid, cannabidiol now attracts
great therapeutic interest, espe-
cially in epilepsy and cancer. As
with many rising trends, various
myths and misconceptions have
accompanied this heightened pub-
lic interest and intrigue. This forum
article examines and attempts to
clarify some areas of contention.
Cannabidiol
Cannabidiol (CBD) is a 21-carbon terpe-
nophenolic compound exclusive to can-
nabis after its decarboxylation from a
cannabidiolic acid precursor (Figure 1). It
is a pharmacological agent of wondrous
diversity, an absolute archetypal ‘dirty
drug’, encompassing analgesic, anti-
inflammatory, antioxidant, antiemetic,
antianxiety, antipsychotic, anticonvulsant,
198 Trends in Pharmacological Sciences, March 2017, Vol. 38, No. 3
and cytotoxic effects (confined to malig-
nant cell lines), which are mediated by a
wide variety of signaling mechanisms
including activity on cannabinoid recep-
tors, 5-HT1A, GPR55, GPR18, TRPV1,
and other transient receptor potential
channels (see [1,2] for more comprehen-
sive reviews).
The newfound interest in CBD has been
accompanied by an alarming number of
mischaracterizations that will be the focus
of this forum article. These include appar-
ent confusion as to the correct assignation
of CBD’s psychopharmacological activity,
particularly alleged sedative effects, its
mechanism of action as an antagonist at
the CB1 receptor, its legal status in com-
merce, and its metabolic fate in human
administration. Better understanding of
these issues will be of great importance
for patients, recreational consumers,
physicians, and legislators as they further
consider the role and disposition of this
versatile phytocannabinoid.
Misconception: Cannabidiol Is
Non-psychoactive and Non-
psychotropic
CBD is frequently mischaracterized in lay,
electronic, and scientific sources as ‘non-
psychoactive’ or ‘non-psychotropic’ in
comparison to tetrahydrocannabinol
(THC), but these terms are inaccurate,
given its prominent pharmacological ben-
efits on anxiety, schizophrenia, addiction,
and possibly even depression. More
accurately, CBD should be preferably
labeled as ‘non-intoxicating’, and lacking
associated reinforcement, craving, com-
pulsive use, etc., that would indicate a
significant drug abuse liability [1].
Misconception: CBD Is Sedating
Some early anecdotal literature cited a low
incidence of sedation after CBD adminis-
tration, and contemporaneously, this side
effect is frequently attributed to CBD.
However, low to moderate doses are dis-
tinctly alerting, as proven in its ability to
counteract sedative effects of THC, delay
sleep time as documented via
electroencephalography, and reduce
THC-associated ‘hangover’ [3]. Numer-
ous modern studies, even those with sin-
gle doses of 600 mg of oral CBD, in
normal subjects have been free of seda-
tive effects [4]. By contrast, CBD as Epi-
diolex (an investigational cannabis extract
with traces of THC, other cannabinoids,
and terpenoids) employed in very high
doses of 25 mg/kg/day or more to treat
intractable epilepsy has produced seda-
tion under conditions of polypharmacy,
especially linked to elevated levels of N-
desmethylclobazam when co-adminis-
tered with clobazam, which resolves well
after reduction of the dose of the latter [5].
Whereas pure CBD is not sedating, many
CBD-containing drug and hemp chemo-
vars do display this liability. This is not
attributable to CBD concentration per
se, but rather to the predominance of
myrcene in high titer in many commercial
varieties. Myrcene, a monoterpenoid, dis-
plays a prominent narcotic-like profile that
is seemingly responsible for the ‘couch-
lock’ phenomenon frequently associated
with modern cannabis phenomenology
[1]. Selective breeding of low myrcene
chemovars reduces or eliminates this lia-
bility, yielding cannabis plants or extracts
that are more suitable to the patient who
must also work or study (Figure 2).
Misconception: CBD Is a CB1
Antagonist Like Rimonabant
Rimonabant, also called SR141617 or
Acomplia, is a synthetic CB1 inverse ago-
nist that was marketed briefly in Europe to
treat obesity and metabolic syndrome. It
was removed from the market due to
numerous serious associated adverse
events, including anxiety, suicidal ideation,
nausea, and even de novo cases of multi-
ple sclerosis [2]. This situation produced a
chilling effect on development programs
for other CB1 inverse agonists and even
extended to harsh scrutiny of the natural
compounds, CBD and tetrahydrocanna-
bivarin, which, in contradistinction, act as
neutral antagonists at CB1. The mecha-
nism of action of CBD seems, rather, to
 Capitate
glandular
Trichomes
GW Pharmaceucals

Hemp field
University
of Kentucky Precursors
Cannabis flower GW Pharmaceucals
OH OH OPO3OPO3
COOH COOH
+
Geranyl phosphate: olivetolate geranyltransferase
HO
HO
Olivetolic acid (5-pentyl resorcinolic acid) Geranyl pyrophosphate

Cannabigerolic acid Pure CBD crystals OH

OH Hepac OH
CBDA synthase

metabolism
7-hydroxy-cannabidiol
OH Decarboxylaon
via heat, light,
COOH
or aging OH
OH Strong acid
OH

Cannabidiolic acid Cannabidiol (in vitro only) O

Delta-9-tetrahydrocannabinolic acid
synthase (THC)

Figure 1. Cannabidiol (CBD) Production, Biosynthesis, and Metabolism. CBD is biosynthesized in hemp or drug chemovars of Cannabis sativa, and is
produced in greatest concentration in capitate glandular trichomes in the unfertilized female flowering tops of the plant. Its main precursors are olivetolic acid and geranyl
pyrophosphate, which produce cannabigerolic acid and then cannabidiolic acid (CBDA) via catalysis by CBDA synthase, an enzyme co-dominant with D9-tetrahy-
drocannabinolic acid synthase. Subsequently, decarboxylation via light exposure, heating, or aging results in CBD. In vivo, first-pass hepatic metabolism produces 7-
hydroxy-cannabidiol, whose specific pharmacology has yet to be ascertained. While exposure to strong acids can produce an isomerization of CBD to tetrahy-
drocannabinol (THC), this reaction does not occur in vivo in humans (all images by E.B.R.).

stem from negative allosteric modulation
of CB1 [6], particularly in the presence of
THC, and it produces none of the rimo-
nabant-type adverse events [2].
Misconception: CBD Is Legal in
All 50 States
In keeping with its versatile pharmacology
without associated drug abuse liability or
serious side effects, CBD is an unsched-
uled drug in most nations. This is not the
case in the USA, where, pharmacology
notwithstanding, CBD has been a for-
bidden Schedule I agent with its own Drug
Enforcement Administration (DEA) num-
ber, and designation as a THC analog.
In spite of this continuing prohibition,
domestic commerce in CBD in one form
or another is rampant in storefronts and on
the Internet, frequently accompanied by
claims that its extraction from hemp refuse
is a legal process. While currently tolerated
without federal prosecution as of this writ-
ing, such practices may concentrate pes-
ticides and other agricultural toxins [7],
and are explicitly illegal under the Con-
trolled Substances Act of 1970 [8],
wherein, although possession of hemp
stalks and certain other plant parts are
not expressly forbidden, chemical extrac-
tion of those parts clearly is. This ‘excep-
tion to the exception’ is clear in text of the
Act. An additional confound of American
law is that, at a time when Epidiolex
becomes an approved pharmaceutical
agent and is necessarily assigned to a less
restricted schedule, this same status will
not extend to CBD from other sources,
which must remain in Schedule I until
meeting similar standards of efficacy,
safety, and consistency. Only reclassifica-
tion of CBD by the Food and Drug Admin-
istration and DEA, or an act of Congress,
would alter this scheduling discrepancy
and continuing anomaly.
Misconception: CBD Turns into
THC in the Body
This false claim has been frequently
invoked online, and has gained currency,
and perhaps even credibility, after publi-
cation of a recent article [9], in which it was
demonstrated that CBD could be con-
verted into THC after prolonged exposure
to ‘simulated’ gastric acid. While this
isomerization reaction has been known
for decades, first reported with putative

Trends in Pharmacological Sciences, March 2017, Vol. 38, No. 3 199

 PhytoFacts™ Lemon CBD placebo-controlled study of CBD in Hun-
tington disease, 14 patients were admin-
istered oral doses of 10 mg/kg/day
Class: LXX3G (approximately 700 mg) over 6 weeks
Cannabinoids: 12.5% Type: Flower [11]. Mean plasma levels of CBD were
General

Terpenoids: 2.0% Species: SATIVAx

Harvest date: Not specified 5.9–11.2 ng/mL, but no plasma levels of
Moisture: 10.9% Sample info: 150619PP11 THC (down to picogram sensitivity) were
Test date: 16/03/09
Test ID #: ABDC-160309_120 found in any assays. Similarly, a more
recent randomized controlled study
Total examined single oral doses of 600 mg
Cannabinoid Weight%
Cannabinoids

THC
CBDA 11.9% of CBD or 10 mg of THC in 16 healthy
1.0
THCA 0.2% males [12]. Whereas THC was highly sta-
THCV 0.1%
THC 0.1% tistically significantly productive of adverse
Total CBC 0.1% events such as anxiety, dysphoria, posi-
CBD CBD 0.1%
46.6 CBG 0.1%
tive psychotic symptomatology, sedation,
Rao of top two cannabinoids and intoxication, CBD was well tolerated
without such THC manifestations. More
Relaxaon Focus
germane to this debate, neither THC nor
Sweet
Entourage effects∗

Tropical Fruity
its primary hepatic metabolite, 11-
Aroma & flavor

hydroxy-THC, was noted after CBD

Spicy Citrusy
administration. Effectively, there seems
Comfort Energy to be no compelling evidence that CBD
Camphor Floral
undergoes cyclization or bioconversion to
Earthy Herbal
THC in humans.
Piney
Calm Inspiraon
Key: Aroma Flavor Concluding Remarks
CBD is an intriguing agent of unparalleled
∗This varies with individual, close, and me.

Terpinolene pharmacological diversity that is neverthe-

α-phellandrene less surprisingly benign in all its observed
β-ocimene 0.11%
Carene effects. Its use has become widespread in
Limonene 0.77%
γ-terpinene certain geographical areas, particularly in
PhytoPrint™

α-pinene 0.15% ‘legal’ states in the USA, and it is on the

α-terpinene
β-pinene 0.12% threshold of becoming an approved phar-
Fenchol
0.06% maceutical agent in intractable epilepsies.
Camphene
α-terpineol
0.04% Given this current nouvelle richesse fol-
α-humulene 0.19%
β-caryophyllene 0.34%
lowing its long history of obscurity, it is
Linalool0.08% incumbent upon the scientific and medical
Caryophyllene oxide
0.00%
Myrcene 0.13% communities to understand better the
mechanisms of action of CBD, its limita-
tions, and particularly the myths and mis-
Figure 2. PhytoFacts of Type III Cannabidiol (CBD)-Predominant Non-sedating Chemovar ‘Lemon conceptions that its meteoric rise in
CBD’. The PhytoFacts analysis of the chemovar reveals it to be a Type III, CBD-predominant plant, with THC- popularity have engendered.
to-CBD ratio of 46.6:1, with high titers of limonene, caryophyllene, humulene, and alpha-pinene, but relatively
1
low myrcene content. Such a chemovar would be expected to be non-sedating, with good efficacy as an anti- PHYTECS, 20402 81st Avenue SW, Vashon, WA 98070,
inflammatory analgesic, also applicable to depression, anxiety, and treatment of addiction [1]. (Report courtesy USA

of NaPro Research, https://phytofacts.info/). THC, tetrahydrocannabinol.

*Correspondence: ethanrusso@comcast.net (E.B. Russo).
http://dx.doi.org/10.1016/j.tips.2016.12.004

end products by Roger Adams in 1940,
and with definitive structures by Yehiel
Gaoni and Raphael Mechoulam in the
1960s, there is no evidence whatsoever
that the reaction occurs in vivo in humans
[10]. First, no known enzyme exists that
can catalyze such a bioconversion. In
addition, pharmacokinetic and metabo-
lism studies in human clinical trials refute
such a reaction. In a double-blind
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