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Metabolism of Classical Cannabinoids and the
Synthetic Cannabinoid JWH-018
MK Su
1
, KA Seely
2
, JH Moran
2,3
and RS Hoffman
1
Although the putative pharmacological targets of synthetic
cannabinoids (SCBs) abused in “K2” and “Spice” are similar to
D
9
-tetrahydrocannabinol (D
9
-THC), it remains unclear why
SCB toxicity is similar yet different from marijuana. There are
obvious potency and efficacy differences, but also important
metabolic differences that help explain the unique adverse
reactions associated with SCBs. This brief review discusses the
limited research on the metabolism of the SCB JWH-018 and
contrasts that with the metabolism of D
9
-THC.
INTRODUCTION
Synthetic cannabinoids (SCBs) are a class of illicit drugs often
laced on an herbal matrix and smoked like marijuana. Packages
are deceptively labeled with names like “K2” or “Spice” and
phrases like “not for human consumption” (Figure 1). Although
often portrayed as “synthetic marijuana,” SCBs are unique chemi-
cals distinctly different from marijuana. Whereas some similar-
ities exist, both the chemical composition and toxicological
properties of SCBs are different when compared to marijuana.
Quality control of K2 manufacturing is nonexistent, and end
users never know what they are consuming. Dosages and drug
mixtures vary from product to product and lot to lot. Despite
legislation banning specific SCBs and their analogs, “street chem-
ists” remain financially motivated to continuously alter SCB
structures to evade regulations and detection in standardized
drug tests. More than 50 specific SCBs have been identified thus
far in the United States, but most are classified biochemically as
aminoalkylindoles, cyclohexylphenols, benzoylindoles, or analogs
of D
9
-THC.
The aminoalkylindole family of SCBs and other structurally
related drugs are the dominant forms used in US illicit drug
markets. JWH-018 (1-penthyl-3-(1-napthoyl)indole) represents
one of the first aminoalkylindoles detected in K2 products seized
in the United States, and most of what is known about SCB
toxicity comes from cases involving JWH-018 toxicity. Even
though confounding factors, such as concomitant use of other
drugs, likely contribute to adverse reactions associated with SCB
use. Early clinical reports demonstrate an association with central
nervous system effects including, psychosis, seizures, anxiety, agita-
tion, irritability, memory changes, sedation, and confusion; cardi-
ovascular effects, including tachycardia, chest pain, dysrhythmias,
myocardial ischemia; and gastrointestinal effects, including nausea
and vomiting.
1
Less toxicologic information exists on potential
long-term effects of SCBs. However, tolerance, dependence, and
withdrawal are described in heavy, daily SCB users.
1
Furthermore,
because SCBs modulate release of gamma-aminobutyric acid,
glutamate, dopamine, and serotonin, prolonged use of SCBs may
alter emotional processing, cognitive functioning, and other neu-
ropsychiatric processes.
1
The specific actions of SCBs and D
9
-THC are mediated via
human cannabinoid receptors (Figure 2). Two human cannabi-
noid receptors have been identified and are G-protein coupled
receptors. The cannabinoid type-1 (CB1) receptors are predomi-
nately found in the central nervous system and responsible for
the psychoactive properties of marijuana and SCBs. The cannabi-
noid type-2 (CB2) receptors are primarily localized to the periph-
ery and not thought to be involved in psychoactive responses.
Because SCBs and D
9
-THC share the same pharmacological
targets, these drugs might be expected to induce similar psychoac-
tive and physiological responses. Most disconcerting is the sever-
ity, frequency, and unpredictable nature of SCBs. Efficacy and
potency differences certainly explain some of the differential
effects. For example, D
9
-THC is considered a partial agonist of
the CB1 receptor, whereas SCBs are generally regarded as full
agonists. In other words, partially vs. fully activating the CB1
receptor may correlate with the level of “high” experience with
SCBs. Thus, the level of “high” experience with marijuana is
likely to be considered low to moderate when compared directly
to SCBs. Binding potency of D
9
-THC and SCBs is also an
important determinant of relative toxicity, especially considering
the risk of overdosing. For comparison, the JWH-018 affinity for
1
Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, New York, USA;
2
Arkansas Department of Health, Public Health Laboratory, Little Rock, Arkansas, USA;
3
Department of Pharmacology & Toxicology, College of Medicine,
University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Correspondence: MK Su (su.mark.k@gmail.com)
Received 20 January 2015; accepted 12 March 2015; advance online publication 18 March 2015. doi:10.1002/cpt.114
562 VOLUME 97 NUMBER 6 | JUNE 2015 | www.wileyonlinelibrary/cpt
DISCOVERY
the CB1 receptor is about 15 times greater than D
9
-THC.
2
Although serum concentrations are hard to predict, most report
the effects of SCBs are shorter in duration than D
9
-THC,
1
which
could lead to rapid re-dosing and unintentional side effects that
may involve secondary organs with slower clearance rates when
compared to the brain. Thus, efficacy and potency differences
suggest that risk for overdosing is greater with SCBs.
Metabolic differences that alter pharmacokinetic and pharma-
codynamic properties of SCBs and D
9
-THC also need to be
considered while evaluating the relative toxicity of SCBs.
Delta
9
-THC is extensively metabolized by cytochrome P450
enzymes before conjugation and urinary excretion (Figure 2).
Specifically, D
9
-THC is oxidized via the hepatic and intestinal
isoforms CYP2C9 and CYP3A4 to form the active psychoactive
metabolite, 11-hydroxy D
9
-THC and other nonbiologically
active intermediates.
2
The 11-hydroxy D
9
-THC metabolite is
short-lived and further oxidized to produce biologically inactive
intermediates.
2
Direct oxidation of 11-hydroxy D
9
-THC forms
11-nor-9-carboxy-D
9
-THC, which is conjugated at the carboxyl
position to form the O-ester glucuronide, the major metabolite
found in human urine.
2
In contrast to D
9
-THC, most metabolites of SCBs retain signif-
icant biological activity at CB1 receptors (Figure 2). However,
little information is available on the pharmacokinetic properties
and metabolites of SCBs. Nonetheless, several studies investigating
Figure 1 Representative packaging and deceptive phrases like “not for
consumption” commonly found used for “K2” products. Photograph cour-
tesy of Cindy L. Moran at the Arkansas State Crime Laboratory.
Figure 2 A schematic representation that summarizes what is known about JWH-018 (upper) and D
9
-tetrahydrocannabinol (THC) (lower) metabolism,
excretion, and potential downstream interactions with cannabinoid type-1 (CB1) receptors (“1” indicates agonism, “2” indicates antagonism). CYP2C9
metabolism of JWH-018 produces several species that retain affinity and intrinsic activity at CB1 receptors. CYP2C9 metabolism of D
9
-THC results in the
production of a single active metabolite. Conjugation with glucuronic acid results in mixed affects with JWH-018 metabolites, and no affinity or activity
with D
9
-THC metabolites. Glucuronic acid conjugates of JWH-018 metabolites and D
9
-THC are excreted in urine.
DISCOVERY
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 6 | JUNE 2015 563
JWH-018 and other SCBs – aminoalkylindoles, cyclohexylphe-
nols, and benzoylindoles that share structural similarities – show
that SCBs are oxidized by cytochrome P450 enzymes
3
and then
conjugated with glucuronic acid via UDP-glucuronosyltransferases
(UGTs).
2,4
CYP2C9 and CYP1A2 are the primary cytochrome
P450 isoforms involved in the oxidation of JWH-018.
3
Unlike
D
9
-THC, CYP3A4 has little activity toward SCBs and does not
participate in the detoxification of JWH-018 when ingested.
Likewise, CYP1A2 may be important for metabolism for SCBs
inhaled via smoking,
2
because CYP1A2 is a highly inducible
isoform found abundantly in the lung. CYP3A4, CYP2C9, and
CYP1A2 are minimally expressed in neuronal tissue and likely
play no role in the metabolism of SCBs or D
9
-THC within the
central nervous system.
The relative contribution of CYP2D6 in D
9
-THC metabolism
is not known, but because this isoform is active toward SCBs, it
may play a significant role in regulating brain concentrations of
SCBs and their active metabolites.
2–4
Although CYP2D6 repre-
sents only 1–5% of the cytochrome P450 liver content, there are
considerable concentrations of this isoform found in the cerebral
cortex, hippocampus, and cerebellum. Interestingly, these areas
are known to possess high expression of CB1 receptors.
2
Further
studies are required to fully elucidate the neuronal metabolism of
SCBs and the total contribution of CYP2D6.
All of the identified cytochrome P450 enzymes involved in the
metabolism of SCBs are known to have genetic polymorphisms
that may significantly increase individual susceptibilities to SCB
toxicity. When measured by caffeine urinary metabolic ratios, a
wide range of CYP1A2 expression and activity exists.
4
There are
significant racial differences among gene expression and environ-
mental factors, such as cigarette smoking use, that are known to
induce CYP1A2 activity. In addition, CYP2C9 has more than
35 allelic variants and the two most common variants,
CYP2C9*2 and CYP2C9*3, are associated with reduced activity
of CYP2C9.
4
There is also interethnic variation in the expression
of CYP2D6 where both poor and ultra-rapid metabolizers are
described.
4
After cytochrome P450 oxidation, glucuronidation is the next
step of SCB metabolism (Figure 2). Analysis of urine specimens
from individuals who used JWH-018 demonstrates high concen-
trations of glucuronide metabolites. A study using recombinant
UGTs determined the major isoforms involved in the metabo-
lism of JWH-018 in the liver are UGT1A1, UGT1A9, and
UGT2B7.
5
Several extrahepatic isoforms, UGT1A3, UGT1A10,
UGT1A7, and UGT2B7, also have significant activity. UGT1A7
is expressed in the lung, and UGT1A3 and UGT2B7 are
expressed in the brain.
5
Studies conclude that human UGT1A3
and UGT2B7 are the predominant isoforms responsible for
metabolism of JWH-018.
5
Because both the cytochrome P450
and UGT enzymes are expressed in the human brain, central
nervous system activity of these isoforms may regulate the con-
centrations of SCBs binding to and activating CB1 receptors.
2
In addition to characterizing the specific enzymes involved in
SCB metabolism, it is equally important to characterize the bio-
logical significance of active intermediates. With the exception of
11-hydroxy D
9
-THC, most D
9
-THC metabolites lack significant
biological activity (Figure 2). Thus, D
9
-THC oxidation and sub-
sequent conjugation is generally regarded as a classical detoxifica-
tion metabolic pathway. On the other hand, SCB metabolites
retain significant activity that may contribute to the development
of severe reactions. Several SCB metabolites and oxidized deriva-
tives are agonists, neutral antagonists, and/or inverse agonists at
CB1 receptors (Figure 2).
2
In particular, the omega-hydroxyl
metabolite of JWH-018 metabolite is bioavailable, found in
human blood, and an agonist at CB1 receptors with an affinity
similar to D
9
-THC. Interestingly, the glucuronic acid conjugate
of an omega-hydroxyl metabolite of JWH-018 retains affinity for
CB1 receptors but acts as a neutral antagonist (Figure 2).
2
The
conjugate is primarily found in urine, and further study is
required to determine if this metabolic-derived antagonist con-
tributes to JWH-018 tolerance. In addition, tolerance and cross-
tolerance has been noted in individuals who chronically abuse
D
9
-THC and SCBs,
6
potentially because of CB1 receptor desen-
sitization and down-regulation.
SCBs are increasingly abused, can cause significant human tox-
icity, and represent a public health concern. Because SCB abuse
is a relatively new phenomenon, little information is available to
explain adverse reactions. Early clinical studies and mechanistic-
based studies are beginning to shed light on why the toxicologic
profiles of marijuana and SCBs are similar yet strikingly different.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
V
C2015 American Society for Clinical Pharmacology and Therapeutics
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DISCOVERY
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