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Expert Pharmacologist
Jul 6, 2021
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JWH-018 (Naphthalene-1-yl(1-pentyl-1H-indol-3-yl)methanone)- is a synthetic cannabinoid of naphtalenoid class, which is a full agonist of CB1 and partial agonist of CB2-receptors. It has similar mechanism of action to that of THC, different in certain aspect, which will be mentioned below. This compound action imitates effects of endocannabinoids, which are produced in the body naturally. For example, it imitates biologically active 2-AG and АЕА, which change transmission of nerve signals. This underlies its anesthetic effect. The compound can be found in the following mixtures: ‘Atomic Bomb’, ‘Dragon’, ‘Monkees Go Bananas’, ‘Rockstar’, ‘Spike 99’, ‘Ultra’ and ‘Wasted’. Sometimes the compound is called AM-678. It is one of the first aminoalkaloids, found in K2 products, seized in the USA. 1-Pentyl-3-(1-naphthoyl) indole is a DEA Schedule I controlled substance. This compound was synthesized in 1995 by John W. Huffman (JWH name comes from his initials). He was a professor of organic chemistry at Clemson University, who worked with his colleagues on the synthesis process of 470 analogs and metabolites of THC in order to study its interactions with cannabinoid receptors in the brain. Huffman knows JWH-018 well. “We made the stuff in 1995,” he says. “I had an undergraduate student working under the supervision of a very capable postdoc, and this was just one of the things we made.” Their research was published in 1998 in the Journal of Pharmacology & Experimental Therapeutics (1998, 285, 995). In December 2008 Huffman got an e-mail revealing how a purely scientific research can be misused. E-mail from a German blogger warned Huffman about the presence of JWN-018 as an ingredient in a couple of herbal mixtures, sold through the Internet as a legal alternative to marijuana. Huffman considers the reason for JWH-018 popularity among all other compounds in the series to be the fact that “it is simple to produce and has powerful effects” Other compounds, present in all of these herbal products, are more effective than JWH-018, he says. For example, one of them is HU-210. It is a compound under the name of 1-dimethylgeptyl-11-hydroxy-∆-8-tetrahydrocannabinol, which was first synthesized by researchers from Hebrew University of Jerusalem. JWH-018 has a molecular formula C24H23NO, molecular weight 341.45 g/mol, log Kow = 6.90. It is odorless, has a powdery consistency of white colour. It is water-soluble 4.31X10-3 mg/L at 25 °C, 4.08X10-10 mm Hg at 25 °C. It has a melting point of 54-60 °С. The substance is considered to be relatively inert since it is replaced in position C-3 by a naphthenic motif and since aromatic indole system doesn’t contribute to significant activity. Analytical laboratory identification methods have been developed to study a sensitive and specific method of quantitative determination of JWH-018, JWH-073 and JWH-250 and qualitative identification of JWH-019 in whole blood. The linear range is 0.1-20 micrograms/l of all quantitative analytes.


Pharmacokinetics and Pharmacodynamics.
JWH-018 is metabolized by CYP450 enzymes. Using microsomal human liver enzymes and recombinant human protein, the main enzymes of the substance oxidation were determined to be CYP2C9 and CYP1A2. At the same time, CYP2C19, 2D6, 2E1 and 3A4 have relatively small contribution to metabolism. The main metabolites are JWH-018 N-(3-OH-pentyl), JWH-018 N-(4-OH-pentyl), JWH-018 N-(5-OH-pentyl), JWH-018 pentanoic acid, JWH-018 (5-OH-indole), JWH-018 (6-OH- indole), JWH-073 N-(3-OH-butyl), JWH-073 N-(4-OH-butyl), JWH-073 butanoic acid and JWH-073 (6-OH-indole). During incubation on HLM, the following metabolites are identified: JWH-018 N-(4-OH-pentyl) (21%), JWH-018 N-(5- OH-pentyl) (18%), JWH-018 (6-OH-indole) (36%) and JWH-018 (5-OH-indole) (19%) In case of JWH-018 N-(4- OH-pentyl) and JWH-018 N-(5-OH-pentyl), reactions obey the Michaelis Menten kinetics. Moreover, (3-(3-(1-naphthoyl)-1H-indol-1-yl) propanoic acid can be used as a biomarker. Almost all the metabolites are excreted in urine in form of glucuronides by UDP-glucuronosyltranseferase (mainly hepatic UGT1A1, UGT1A9 and UGT2B7). As a result of oxidative metabolism of JWH-018, some metabolites are formed, which preserve biological activity in terms of CBRs, including JWH-018 (u)-COOH, JWH-018 (u)-OH, JWH-018 (u-1)-OH(S), and JWH-018 (u-1)-OH(R). Genetic polymorphisms of these enzymes are associated with certain grade of toxicity and risk of side effects. Two variants are considered tob e the most common phenotypes, they are CYP2C9*2 (a cysteine substitutes for arginine at residue 144) and CYP2C9*3 (a leucine substitutes for isoleucine at residue 359). Both reduce enzymatic activity. It is possible that people carrying such variants of this cytochrome haplotypes are more susceptible to JWH-018 toxicity than people of other genotypes. Hence, genetic variability in oxidative metabolism, catabolized by CYP2C9, can be the reason for toxic effects, registered in JWH-018 users.


Monohydroxylated metabolites bind to CB2r at Ki from 23 nM (high affinity to М1) to 115 nM (intermediate affinity to М2). Rank order of affinity to СВ2r of these compounds goes as follows: JWH-018≥Δ9-THC≥M1≥M5>M3≥M7>M2≫M6. Monohydroxylated metabolites of JWH-018 act as partial and full agonists of CB2Rs through G-proteins activation in CHO-hCB2 membranes. Maximum efficiency of AC activity inhibition by JWH-018 metabolites is variable. So, compared to the full agonist of CB1r/CB2r CP-55,940 (67.3 ± 3.5%), all the metabolites of the substance, except for М1, М2 and М5, cause equivalent levels of AC activity inhibition. Value of Vmax for metabolite JWH-018 (u)-OH is two times higher for variant CYP2C9*2, than that of the enzyme WT (101.9 ± 3.24 and 52.58 ± 3.29 pmol/min/nmol respectively), whereas the Vmax value for the variant CYP2C9*3 is significantly lower - 6.02±0.31. The same tendency is observed for metabolites JWH-018 (u-1)-OH(S) and (R), so, the Vmax values for S-form are 14.61 pmol/min/nmol for CYP2C9*1, 26.62 for CYP2C9*2 and 2.75 for CYP2C9*3. Values of Km for metabolite JWH-018 (u)-OH for variant CYP2C9*1 are 2 times higher than that for the second variant (0.90 vs 0.21 nM). It is interesting to note that glucoronic acid omegahydroxyl metabolite preserves affinity to CB1-receptors, but acts as a neutral agonist. This conjugate can mainly be detected in urine. Tolerance and cross-tolerance are observed in people, chronically using THC. It can be caused by desensitization and downregulation of СВ1-receptors. As for the study of metabolites in human saliva, the concentration-time curves are characterized by maximum concentrations range of 2-2036 ng/ml, detected in the first sample after inhallation, followed by a very steep decline, turning into an exponential phase of elimination up to two hours after inhallation. In the process of elimination with a median half-life of 1.69 hours, the curve decreases to values LLOQ 0.025 ng/ml in six hours.

JWH-018 has relatively high binding affinity to cannabinoid receptors at values IC50 9.0 nM – to the first type, 2.94 – to the second type of cannabinoid receptors compared to that of THC, 40.7 and 36.4 nM (for 1st and 2nd receptor types, respectively). As for biological effects, during in vitro analysis of binding [35S] guanosine-5’-O-(3-thio)-triphosphate, the compound showed agonistic properties. JWH-018 causes inhibition of cAMP accumulation in cell lines, expressing CB1-receptors, stimulated by forskolin at ЕС50 14.7 and maximum inhibition at 79%. Its value in cells is EC50 of 5.31±0.4 nM. Based on these data and clinical observations, it can be assumed that JWH-018 shows typical effects of a CB-1 agonist, including sedation, cognitive dysfunction, tachycardia, postural hypotension, dry mouth, ataxia, immunosuppression and psychotropic effects. A pronounced difference from THC is the formation of active metabolites, which preserve the affinity to the receptor CB1 for a long time as rank order goes: JWH-018 > JWH-018 N-(4-OH-pentyl) > JWH-018 N-(5- OH-pentyl) > JWH-018 (5-OH-indole) = THC = JWH-018 (6-OH-indole) = JWH-018 N-(5-OH-pentyl) > JWH-073 N-(4-OH-butyl)>JWH-018 pentanoic acid. Moreover, the following metabolites have full agonistic binding to CB1: JWH-018, JWH-018 (5- OH-indole), JWH-018 (6-OH-indole) as well as for JWH-018 N-(5-OH-pentyl)-pplying [35S]GTPγS binding assays, and partial agonist activity for JWH-073 (6-OH- indole) and JWH-073 N-(4-OH-butyl). Glucuronidated metabolite JWH-018 - (5-OH-pentyl) preserves the affinity to СВ1-receptor (Ki: 922 nM), however, to this date, there are no objective experimental data proving whether this metabolite is capable of antagonizing pharmacological effects in vivo. Similar to preservance of affinity to CB1 receptor, metabolites JWH-018 also bind to СВ2 receptor with relative rank order of binding affinity -018 > JWH- 073 > THC > JWH-073-N-(3-OH-butyl) > JWH-018 N-(5-OH-pentyl) > JWH-018 (6- OH-indole) > JWH-018 N-(4-OH-pentyl) > JWH-073 N-(4-OH-butyl) > JWH-073 (6- OH indole) >> JWH-018 pentanoic acid and JWH-073 butanoic acid.


By binding analysis of [35S]GTPγS and analysis of adenylate cyclase to measure internal activity, JWH-018 is shown to have full agonistic activity on СВ2 receptors. Thus, in order to reach an equivalent level of adenylic activity, a smaller number of receptors must be involved. Since CB2 receptors are mainly expressed in different types of immune cells, intake of the substance can modulate immune function, which causes suppression of immunity. Studies on JWH-018 effects on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced inflammation and carcinogenesis have proven anti-inflammatory activity of JWH-018 compared to indometacin. Moreover, JWH-018 suppresses the development of tumors induced by the action of ТРА in the mouse skin carcinogenesis model. In studies of Atwood on JWH-018 influence on glutamatergic neurotransmission in cultured autaptic hippocampal neurons and activation of ERK1/2 mitogen activated protein kinase (MAPK), and also CB1-receptor internalization, it was revealed that JWH-018 inhibits excitatory postsynaptic potentials depending on concentration and CB1 receptor (at IC50=14.9 nM). It also increased the phosphorylation of MARK and caused rapid internalization of receptors, which indicates that typical effects of JWH-018 are associated with CB1-receptor activation.

In reports of Rominger short-term changes in dopamine D2/3 receptors (during acute toxicity due to JWH-018) are described. It indicates that JWH-018 use causes pronounced changes in dopaminergic system and, in case of the toxicity, it requires additional pharmacological intervention for treatment correction. In studies on mice after inhalation of smoke of 200mg herbal mixture, containing 3,6% JWH-018 the following symptoms were registered: hypothermia (it was significantly more pronounced, compared to that of the same THC dose) the animals also demonstrated hypomotor activity, antinociception, catalepsy, ptosis, hyperreflective reactions and Straub tail. According to the data of the experiments by Joshua S. Elmore, JWH-018 causes a decrease in СВ1 receptor density and desensitization, which indicates high potential of tolerance. There was also an increase in 5-HT1A receptors sensitivity and no significant changes in 5-HT2A receptors sensitivity. In the recent study on JWH-018 influence on intoxication due to medium dose of the substance (about 5,39 mg), the following side-effects have been revealed: abdominal pain, nausea, headache, fatigue, paranoia, as well as depersonalization, derealization, mild amnesia, increased dissociation. Each of the participants in the experiment felt moderate or mild effects, similar to that of THC, but with more pronounced consciousness alteration and undesirable effects. Peak concentration was 8.00 ng/mL (SD = 2.81, min-max: 1.07–22.45) and was reached 5 min after administration. Although statistical evaluations are needed in order to draw reliable conclusions about a direct comparison between JWH-018 and THC, these data suggest that the dissociative effects following JWH-018 are more apparent. Synthetic cannabinoids produce stronger and more frequent psychotic effects because they are potent and full CB1 agonists. THC, on the other hand, is a partial agonist. The currently studied SC, JWH-018, has an affinity for the CB1 receptor, which is five times greater than that of THC in natural cannabis. Therefore, it comes as no surprise that its psychotomimetic effects are stronger than those of natural cannabis. Psychotomimetic symptoms are especially concerning for people at risk for developing psychosis. As a result of the study by Uchiyama, JWH-018 increased the power of the EEG by almost 4 times, but reduced the activity of its parameters. At a dose of 10 mg/kg, rats died. In studies of Koller acute genotoxicity and estrogenic activity in low doses were not detected. However, antiestrogenic properties of JWH-018 were approximately 10 times stronger, than those of THC. JWH-018 shows cytotoxicity at the highest concentration (100 μM) on MCF-7 and TR146 cells. Tomiyama and Funada in their studies recorded cytotoxicity of JWH-018 on the primary neural cells of the forebrain, which depended on the concentration. Metabolite N-3-hydroxypentyl of the first phase of metabolism was toxic to human embryonic kidney (HEK283T) and human neuroblastoma (SH-SY5Y) cell lines, unlike JWH-018, which did not show such cytotoxicity. According to the published data, concentration of JWH-018 in postmortem blood was reported to be 5-150 ng/mL. In studies by Yigit Sezer it was proved that JWH-018 causes proven genotoxicity and neurotoxicity, mainly due to oxidative stress. In studies by Ren-shi Li there was significant increase in АЕА and 2-АG levels in hippocampus of mice, administrated 1 mg/kg of JWH-018, compared to control groups. This increase was inhibited by administration of АМ-261, СВ1-receptor antagonist. Increase in endocannabinoid levels was the result of hydrolase depression (FAAH and MAGL). In addition, the deterioration of cognitive functions was proven by the inhibition of synaptic transmission and other mechanisms regulating memory. JWH-018 disrupted BDNF expression, which is an important modulator of excitatory and inhibitory synaptic transmission, necessary for mediated cellular events, including differentiation and growth of neurons.


Clinical effects, doses and methods of use.
Desirable positive effects include: cognitive euphoria and empathy, similar to that of THC; in low doses - stimulating effect, medium and high doses – pronounced sedation and muscle weakness; mood improvement, conceptual thinking – in low doses; anesthetic effect manifests at medium dose and higher, there is a possibility of pleasant tactile sensations, but with the increase inthe dose, there is antinociception, which is manifested in a decrease in surface tactile sensitivity; increased appetite is less pronounced compared to that of THC; effects of "Changes in felt gravity"; the appearance of illusions of various nature, described by the change of colors, "play of colors", "changes in the geometry of static objects", acceleration or deceleration of dynamic objects, decreased visual acuity and brightness, the appearance of auditory hallucinations, distortion of images. Undesirable negative effects of JWH-018 include: motor skills' impairment, coordination and orientation in time and space depending on the dose; an increase in the convulsive threshold with the onset of convulsive syndrome, and the effect is dose-dependent; increased heart rate, increased blood pressure at low or medium doses, paradoxical decrease in blood pressure at high and extremely high doses up to a collapse and orthostatic hypotension with loss of consciousness and cardiac arrhythmias; pronounced hallucinations at extremely high doses with impaired consciousness up to deep stunning; anxiety and paranoia tend to develop even at low doses depending on the psychotype of a person, the density of the corresponding receptors, the presence of tolerance and other predominantly molecular factors; panic attacks even at low doses, however, at high doses panic attacks do not occur due to consciousness impairment and switching of cognitive patterns to other locations of the central nervous system; occurrence of transient depersonalization/derealization syndrome; pronounced hallucinations in high doses.


It is strongly not recommended for use by people with mental disorders. As for the addiction potential, mental dependence on this substance occurs only with long-term multiple use. There are data on the risk of withdrawal syndrome occurrence, which is characterized mainly by a disorder of the mood background, tremor of the extremities, anxiety, subdepressive state, spontaneous increase in heart rate and panic attacks. The above symptoms are leveled within 2-3 months of abstinence without the pharmacological therapy. As a rule, this substance is administered by smoking mixtures. Considering the fact that it is impossible to identify the dose of the substance in a number of plant materials without special laboratory test, it is recommended to start with minimum doses. The starting dose, which is associated with the onset of effects is 20-40 μg/kg, medium dose ranges from 40 to 80 μg/kg, high and extremely high dose range from 80 to 120 μg/kg, taking into consideration high risk of side effects (including lethal outcome), loss of control over the physical and mental state of the body, it is categorically not recommended to use high doses. When administered by inhalation, manifestation of effects occurs after 5-10 minutes and their duration is 1-3 hours. Depending on the dose, post-effects can remain up to 10 hours. When administered orally (e.g. by means of gelatin capsules), the time of onset of effects varies from 10 to 30 minutes, they can last for a long time (about 5 hours), depending on many factors and metabolism. The most dangerous combinations of drugs, which can cause severe sideeffects or irreversible physical/mental damage: 2C-Tx, 2C-x, 5-MeO-xxT, amphetamines, cocaine, aMT, DMT, DOx, LSD, mescaline, mushrooms, 25-x-NBOMe. According to the latest research, tolerance doesn't develop with single use of JWH-018. In case of long-term use (more than 3 months with a frequency of at least 2 times a week), mild tolerance is developed, so an increase in the dose by no more than 5-10% of the initial dose is required to get equivalent clinical effects.
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