ArticlePDF AvailableLiterature Review

Metabolism of Classical Cannabinoids and the Synthetic Cannabinoid JWH-018



While the putative pharmacological targets of synthetic cannabinoids (SCBs) abused in "K2" and "Spice" are similar to Δ(9) -tetrahydrocannabinol (Δ(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 Δ(9-) THC. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
Metabolism of Classical Cannabinoids and the
Synthetic Cannabinoid JWH-018
, KA Seely
, JH Moran
and RS Hoffman
Although the putative pharmacological targets of synthetic
cannabinoids (SCBs) abused in “K2” and “Spice” are similar to
-tetrahydrocannabinol (D
-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
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
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.
Less toxicologic information exists on potential
long-term effects of SCBs. However, tolerance, dependence, and
withdrawal are described in heavy, daily SCB users.
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.
The specific actions of SCBs and D
-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
-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
-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
-THC and SCBs is also an
important determinant of relative toxicity, especially considering
the risk of overdosing. For comparison, the JWH-018 affinity for
Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, New York, USA;
Arkansas Department of Health, Public Health Laboratory, Little Rock, Arkansas, USA;
Department of Pharmacology & Toxicology, College of Medicine,
University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Correspondence: MK Su (
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
the CB1 receptor is about 15 times greater than D
Although serum concentrations are hard to predict, most report
the effects of SCBs are shorter in duration than D
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
-THC also need to be
considered while evaluating the relative toxicity of SCBs.
-THC is extensively metabolized by cytochrome P450
enzymes before conjugation and urinary excretion (Figure 2).
Specifically, D
-THC is oxidized via the hepatic and intestinal
isoforms CYP2C9 and CYP3A4 to form the active psychoactive
metabolite, 11-hydroxy D
-THC and other nonbiologically
active intermediates.
The 11-hydroxy D
-THC metabolite is
short-lived and further oxidized to produce biologically inactive
Direct oxidation of 11-hydroxy D
-THC forms
-THC, which is conjugated at the carboxyl
position to form the O-ester glucuronide, the major metabolite
found in human urine.
In contrast to D
-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
-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
-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
-THC metabolites. Glucuronic acid conjugates of JWH-018 metabolites and D
-THC are excreted in urine.
JWH-018 and other SCBs – aminoalkylindoles, cyclohexylphe-
nols, and benzoylindoles that share structural similarities – show
that SCBs are oxidized by cytochrome P450 enzymes
and then
conjugated with glucuronic acid via UDP-glucuronosyltransferases
CYP2C9 and CYP1A2 are the primary cytochrome
P450 isoforms involved in the oxidation of JWH-018.
-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,
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
-THC within the
central nervous system.
The relative contribution of CYP2D6 in D
-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.
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.
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.
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.
There is also interethnic variation in the expression
of CYP2D6 where both poor and ultra-rapid metabolizers are
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
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.
Studies conclude that human UGT1A3
and UGT2B7 are the predominant isoforms responsible for
metabolism of JWH-018.
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.
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
-THC, most D
-THC metabolites lack significant
biological activity (Figure 2). Thus, D
-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).
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
-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).
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
-THC and SCBs,
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.
The authors declared no conflict of interest.
C2015 American Society for Clinical Pharmacology and Therapeutics
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564 VOLUME 97 NUMBER 6 | JUNE 2015 | www.wileyonlinelibrary/cpt
... The most common effects of the cardiovascular system due to the use of SCs are tachycardia and increased blood pressure (BP) (9). Cases with myocardial infarction and QT prolongation have also been reported (10)(11)(12). ...
... It is detected at lower levels than the rats in the ALD group. One of the possible explanations of these results is that it is oxidized by CYP2C9 and CYP1A2 cytochrome P450 isoforms in drug metabolism and it was thought that the increase in metabolites and the storage of substance-metabolites in the organs were due to the effect of UGT2B7 found in hepatic tissue and UGT1A3 main function isoforms found in extraheptic tissue in the conjugation step (11). The HRs of the rats increased statistically significantly in the groups in which JWH-018 was administered subacutely, compared to the groups in which it was administered acutely. ...
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The use of JWH-018, which is among the abused bonsai in the world and in our country due to its psychostimulant effect, is increasing day by day. Here, we evaluated the pharmacologic, cardiologic, biochemical, and histopathological effects of acute and subacute administration of low and high doses of JWH-018 in rats. The concentrations of JWH-018 and its metabolites in the heart were analyzed by liquid chromatography-mass spectrometry. JWH-018 administration caused many cardiac pathologies including dysregulation of the heart rate, and low blood pressure, also induced cardiac arrhythmia, branch blocks, and ischemic ECG changes depending on the drug dosage and the duration of treatment. Echocardiography did not show any significant structural or functional changes among the groups. The level of serum pro-brain natriuretic peptide which is an indication of impaired cardiac capabilities become observed to be elevated in a long-time excessive dose JWH-018 used group. Histopathologic findings consistent with acute myocardial ischemia were detected in the hearts of all groups. Loss of cross-talk of myocardial fibrils, and prominent eosinophilic contraction bands were early signs of acute myocardial infarction (4th and 12th hours), which were more common in subacute groups and associated with ischemia. Desmin staining was observed as increased in subacute groups and there were marked contraction band dyneins. There is growing pharmacological and pathological evidence of impairment, cardiac effects, and tissue injury attributable to this emerging class of drugs.
... One author estimates that the risk of an emergency room visit is approximately 30-fold higher with SCs than with cannabis [88]. There is evidence that being a partial or a full agonist of the CB1 receptor along with their binding affinities may correlate with the level of exaggerated psychoactivity [89]. Both SCs and THC activate CB1 receptors which trigger the psychotomimetic effects. ...
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Cannabinoids (phytocannabinoids and synthetic cannabinoids) are most often used during adolescence and given the changing norms, enhanced potency, reduced societal perceptions of risk and multitude forms of products for consumption, clinicians need to be become more cognizant of cannabinoid products and their effects. The aim of this narrative review is to briefly discuss acute toxicities and a few chronic toxicities associated with cannabinoids that clinicians are likely to treat. In addition, cannabinoid toxicokinetics and toxicodynamics as it pertains to the clinical effects will be discussed as well as the route of exposure and the clinical implications for therapeutics. Although the neurodevelopmental effects of naturally occurring endocannabinoids will be briefly mentioned, it is beyond the scope of this review to discuss in detail. Regardless, clinicians, parents and patients should be aware of the potential implications that exogenous cannabinoids (cannabis) may have in altering the normative trajectory of brain maturation in pediatric patients.
... 8 D 9 -THC is mostly metabolized by the cytochrome P450 enzymes for conjugation and urinary excretion. 9 The metabolism of D 9 -THC is nonlinear; the chemical has a long terminal elimination phase due to its dissemination in tissues, which in turn is related to the differences in the frequency of its usage. 10 However, because of the existence of many different types of SCs, it is difficult to determine a standard mechanism for their metabolism and excretion. ...
Background: Synthetic cannabinoids (SCs) users appeared to have heightened risk for cardiac arrhythmias, however, current line of research is insufficient in terms of demonstrating both conventional and novel electrocardiographic arrhythmia risk indicators in this population. Objective(s): We aimed to investigate P-wave dispersion (Pwd), corrected QT interval (QTc), QTc dispersion (QTcd), Tpeak-Tend (Tp-e), Tp-e/QT ratio, corrected JT interval (JTc) and JTc dispersion (JTcd), which are shown among the risk factors for emergence of an arrhythmia, among SCs users, suggestive of possible adverse effects of SCs on the cardiac rhyhtm. Methods: Forty-one male SCs user patients who met DSM-5 substance use disorder criteria and 41 healthy male controls included in the study. Substance-related characteristics were recorded. Electrocardiography recordings under standardized procedure of all participants were performed and arrhythmia risk markers were calculated from electrocardiograms. Results: Age and heart rate per minute did not significantly differ between the groups. SCs user group had significantly higher Pwd, QTc, QTcd, Tp-e, Tp-e/QTc ratio, JTc and JTc dispersion values compared to controls. Among risk markers, only Pwd was significantly correlated with duration of SCs use. Conclusions: Alterations in electrocardiogram-derived markers of arrhythmia, which are acquired through an easy and cheap method, should be evaluated for the prediction and prevention of severe cardiac conditions in patients with SCs use.
... Se trata de un preparado con varias hierbas secas embadurnadas con cannabinoides sintéticos, la gran mayoría de la familia de los JWH's (JWH-018, CP-47,497, CP-47,497-C8 y HU-210) que se fuman, aunque en principio no llevan ni tabaco ni marihuana. Estos compuestos comprenden más de 100 sustancias de distintas estructuras químicas que tienen en común su acción sobre el receptor cannabinoide CB1 pero, a diferencia del THC que es un agonista parcial, estas suelen ser agonistas totales y mucho más potentes que el THC, por lo que los efectos psicoactivos son más potentes pero de menor duración por lo que la redosificación y sobredosis son más probables (Su, Seely, Moran y Hoffman, 2015). Al publicitarse como hierbas naturales, se pretende minimizar la sensación de peligro (Dolengevich-Segal, Gómez-Arnau, Rodríguez-Salgado, Rabito-Alcón y Correas-Lauffer, 2014). ...
... 32,34 Other CYPs that are implicated in pCB metabolism are CYP1A1, 1A2, 2D6, 3A5, and 3A7. [36][37][38] For this study, we selected pCBs which would provide the representative example of CYP2D6-pCB interactions. CBD and THC were selected since they are the two major cannabinoid components in cannabis and also because both have been implicated as P450 inhibitors. ...
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Bağımlılık yapıcı madde kullanımı, tüm dünyada ciddi bir halk sağlığı sorunudur. Birleşmiş Milletler Uyuşturucu ve Suç Ofisi (UNODC) dünyadaki yetişkin nüfusun yaklaşık yüzde 5’inin, 2015’te en az bir kez madde kullandığını belirtmektedir. Daha da endişe verici olan ise, bu madde kullanıcılarının yaklaşık 29.5 milyonunun ya da başka bir ifadeyle küresel yetişkin nüfusun binde 6’sının madde kullanım bozukluklarından etkilenmesidir. Bu durum madde kullanımının, sorunlar oluşturmaya başladığı ve tedavi gerektirebilecek noktada zarar verdiği anlamına gelmektedir. Madde kullanımının neden olduğu zararın büyüklüğünü değerlendirmemiz için, madde kullanımının neden olduğu erken ölüm ve sakatlık nedeniyle 2015 yılında dünya genelinde kaybedilen tahmini 28 milyon yıllık “sağlıklı” yaşamın göz önünde bulundurulması gerekmektedir. Özellikle gelişmekte olan ülkelerde çeşitli önlemlerin alınmasına rağmen madde kullanımı gittikçe artmaktadır. Madde kullanım biçimleri geniş bir yelpaze üzerinde yer alır. Çalışmaların birçoğunda bir kişinin madde kullanmadığı kabul edildiğinde kastedilen kişinin yaşantısında hiç madde kullanmadığı veya son bir yıl içinde hiç kullanmadığıdır. Kullanım bozukluğu tanısı koyarken sadece madde kullanımının olup olmadığını sorgulamak, tanısal değerlendirme için yeterli değildir. Bu sebeple madde kullanımına eşlik eden/edebilecek sorunları da göz önünde bulundurmak gerekmektedir. Bir maddenin sorunsuz olarak kullanımı (sosyal kullanım) bazı şartlara bağlıdır. Burada önemli ölçütlerden birisi kullanımla ilgili olarak kişinin sorun yaşamaması ve/veya bu kullanım biçiminin devam etmesi durumunda ileride kişinin madde kullanımı ile ilişkili bir sorunla karşı karşıya kalmayacak olmasıdır. Bu bakış açısından bakıldığında, kullanımında sorun oluştuğuna yönelik yüksek düzeyde kanıtların bulunduğu maddelerin düşük düzeylerdeki kullanımları dahi sosyal kullanım olarak değerlendirilemez. Örneğin, günde 2-3 sigara içmek sağlık sorunlarına yol açabilirken, hafta sonu partide ekstazi kullanmak hem sağlık, hem de adli sorunlara yol açabilir. Yasal olarak kısıtlanmış olan maddelerin kısıtlama ölçütlerine uyulmadan kullanımı da sosyal kullanım olarak değerlendirilmemelidir. Madde kullanım biçimine yönelik adlandırmalarda da kötüye kullanım, zararlı kullanım, bağımlılık, madde kullanım bozukluğu gibi farklılıklar bulunmaktadır. Madde kullanım biçiminin sorun olabilmesi için kişinin ya madde kullanımından dolayı sıkıntı/ huzursuzluk yaşaması ya da madde kullanma biçiminin sosyal/ mesleki işlevselliğini bozması gerekmektedir. Madde kullanımı kişinin özdenetimini etkileyip, özgüllüğünü ortadan kaldırmak suretiyle farklı tutum ve davranışların oluşmasına yol açmakta, uzun dönemde biyolojik ve psikolojik temelde gelişen kapsamlı sorunlara dönüşmektedir. Ana sorun madde kullanımı sorunu olup, biyolojik olduğu kadar bireysel, ruhsal ve toplumsal unsurların etkileşmesiyle tümleşik bir yapı haline gelir. Dolayısıyla sorun2 çok yönlü tanımlanmalı ve değerlendirilmelidir. Bu değerlendirme bir yandan etiyolojinin belirlenmesini, diğer yandan tanı, tedavi, önleme ve rehabilitasyon gibi temel unsurları barındırmalıdır. Elinizdeki bu kitapçık, acil servislere başvuran madde kullanan hastaların fark edilmesi, tanı konulması, ilgili birimlerle irtibatın sağlanması, tedavi gereken durumların tespiti, hastanın doğru yönlendirilmesi amacıyla hazırlanmış acil çalışanları için bir rehber niteliğindedir. Ayrıca madde kullanım bozukluklarına yol açan ve sık karşılaşılan maddeler hakkında genel bilgiler, tedavi öncelikleri ve Türkiye’deki madde kullanım bozukluğu durumu hakkında kısa ve güncel bilgiler vermektedir.
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K2, a synthetic cannabinoid (SC), is an emerging drug of abuse touted as "legal marijuana" and marketed to young teens and first-time drug users. Symptoms associated with K2 use include extreme agitation, syncope, tachycardia, and visual and auditory hallucinations. One major challenge to clinicians is the lack of clinical, pharmacological, and metabolic information for the detection and characterization of K2 and its metabolites in human samples. Information on the metabolic pathway of SCs is very limited. However, previous reports have shown the metabolites of these compounds are excreted primarily as glucuronic acid conjugates. Based on this information, this study evaluates nine human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of 1-naphthalenyl-1(1-pentyl-1H-indol-3-yl)-methanone (JWH-018) and (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073), the two most common SCs found in K2 products. Conjugates were identified and characterized using liquid chromatography/tandem mass spectrometry, whereas kinetic parameters were quantified using high-performance liquid chromatography-UV-visible methods. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 were shown to be the major enzymes involved, showing relatively high affinity with K(m) ranging from 12 to 18 μM for some hydroxylated K2s. These UGTs also exhibited a high metabolic capacity for these compounds, which indicates that K2 metabolites may be rapidly glucuronidated and eliminated from the body. Studies of K2 metabolites will help future development and validation of a specific assay for K2 and its metabolites and will allow researchers to fully explore their pharmacological actions.
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Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances.
Abuse of synthetic cannabinoids (SCs), such as [1-naphthalenyl-(1-pentyl-1H-indol-3-yl]-methanone (JWH-018) and [1-(5-fluoropentyl)-1H-indol-3-yl]-1-naphthalenyl-methanone (AM2201), is increasing at an alarming rate. Although very little is known about the metabolism and toxicology of these popular designer drugs, mass spectrometric analysis of human urine specimens after JWH-018 and AM2201 exposure identified monohydroxylated and carboxylated derivatives as major metabolites. The present study extends these initial findings by testing the hypothesis that JWH-018 and its fluorinated counterpart AM2201 are subject to cytochrome P450 (P450)-mediated oxidation, forming potent hydroxylated metabolites that retain significant affinity and activity at the cannabinoid 1 (CB(1)) receptor. Kinetic analysis using human liver microsomes and recombinant human protein identified CYP2C9 and CYP1A2 as major P450s involved in the oxidation of the JWH-018 and AM2201. In vitro metabolite formation mirrored human urinary metabolic profiles, and each of the primary enzymes exhibited high affinity (K(m) = 0.81-7.3 μM) and low to high reaction velocities (V(max) = 0.0053-2.7 nmol of product · min(-1) · nmol protein(-1)). The contribution of CYP2C19, 2D6, 2E1, and 3A4 in the hepatic metabolic clearance of these synthetic cannabinoids was minimal (f(m) = <0.2). In vitro studies demonstrated that the primary metabolites produced in humans display high affinity and intrinsic activity at the CB(1) receptor, which was attenuated by the CB(1) receptor antagonist (6aR,10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (O-2050). Results from the present study provide critical, missing data related to potential toxicological properties of "K2" parent compounds and their human metabolites, including mechanism(s) of action at cannabinoid receptors.