Where can i buy jwh-018

Effect of legislation of synthetic cannabinoids

Already by the end of Jan. 2009, JWH-018 and CP-47,497-C8 were banned in Germany, due to reports of intoxication, abuse, and health problems associated with chronic use of Spice (Zimmermann et al., 2009). Nevertheless, already a few months later, it was demonstrated that JWH-018 had been replaced in Spice products by one of its “legal” structural analogs, JWH-073 (Lindigkeit et al., 2009).

This represented the start of an ongoing “cat-and-mouse game,” where the psychoactive additives in herbal smoking mixtures made illegal are rapidly removed and replaced with novel, similar synthetic cannabinoids (ie, “designer drugs”) that are ready in the pipeline, to maintain the legal standing of the products (ie, “legal highs”) (Helander, Bäckberg, Hultén, Al-Saffar, & Beck, 2014). Consequently, partly due to legislative actions undertaken in the European countries, the number of “new psychoactive substances” (NPS) noted by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has increased dramatically in the last years (EMCDDA, 2014). Of all NPS identified, synthetic cannabinoids make up an essential part (ie, 27–47% each year since 2009), totally counting to more than 100 during the period 2008–2013 (Fig. 87.3).

Since this Spice drug phenomenon first attracted a more widespread attention in the period 2008–2009, different “generations” of synthetic cannabinoids have been used in the herbal smoking products (Table 87.1). JWH-018, JWH-073, JWH-200, CP-47,497, and HU-210 are among the substances usually referred to as the “first generation” Spice substances (Fig. 87.2). Subsequent Spice products have contained a wide variety of synthetic cannabinoids with variable structural design and variable potency, that is, affinity for the CB1 and CB2 receptors (Wiley, Marusich, & Huffman, 2014). These include several other JWH variants, fluorinated substances such as AM-694 and AM-2201 (the latter being the fluorinated analog of JWH-018), two in a large series of substances examined by Alexandros Makriyannis (AM) at Northeastern University, USA (Moosmann et al., 2012), RCS-4 and RCS-8 (Kavanagh, Grigoryev, Melnik, & Simonov, 2012), and UR-144 and XLR-11 (ie, the fluorinated analog of UR-144) (Fig. 87.4). AKB48 (also known as APINACA), AB-FUBINACA, AB-CHMINACA, JWH-071, MN-18, and NM-2201 are among the more recently introduced synthetic cannabinoids (Fig. 87.4). In addition, even compounds binding allosterically to the CB1 receptor and thereby eliciting a conformational change that increases agonist affinity (eg, Org 27569) have also become used in Spice products (Price et al., 2005). A list of the synthetic cannabinoids or related substances with CB receptor activity that have been reported to the EMCDDA, by year, until Sep. 2014 are presented in Table 87.1 (EMCDDA-Europol, 2009–2014).

Table 87.1. New Synthetic Cannabinoids Appearing in Europe in 2008–2014

A list of all synthetic cannabinoid receptor agonists and related substances (eg, cannabinoid receptor allosteric modulators) reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) per year, from 2008 until Sep. 2014 (EMCDDA-Europol, 2009–2014).

Over the years, a multitude of Spice product and alternative herbal smoking blends with different brand names (eg, Spice Gold/Silver/Diamond, K2, K3, Bonzai, Kronic, Krypton) have been introduced on the recreational drugs market at a rising speed (Fig. 87.5). They have contained variable amounts and/or combinations of synthetic cannabinoids (Table 87.1), to hinder or avoid legal consequences. The Spice products are easily obtainable, initially in “head shops,” but since 2009 mainly over the internet from the many online retailers specialized in this and other types of NPS (Vardakou, Pistos, & Spiliopoulou, 2010; Spaderna, Addy, & D’Souza, 2013). They are also sold directly on the illicit drug market.

Drug–Drug Interactions

The hepatic cytochrome P450 (CYP) enzyme system is involved in SC metabolism. JWH-018 and AM-2201 (its fluorinated analogue) are metabolized in the liver by CYP2C9 and 1A2. Thus, there is the potential to cause AE when given concurrently with medications such as valproic acid, warfarin, phenytoin, and ciprofloxacin. CYP2C9 is also present in the intestines and is involved in the metabolism of orally ingested SCs whereas CYP1A2 is present in the lungs and involved in the metabolism of smoked SCs. CYP2D6 is thought to be involved in metabolism of these products in the cortex, hippocampus and cerebellum. Glucuronic acid conjugation facilitates elimination of these products in the urine and glucuronide metabolite formation involves UGT isoforms. Given the variability in SCs including products combined with other drugs, the possibility of within product interactions and interactions with prescribed medications exist and should be considered. However, additional studies are needed to better understand the clinical significance of these interactions [17R].

2.4 Regulatory status of synthetic cannabinoids

Synthetic cannabinoids have no accepted medical use in the US. The US Drug Enforcement Administration (DEA) classified five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homolog) under temporary Schedule I of the Controlled Substances Act (CSA) on March 2011 [22]. In July 2012, the U.S. Government passed the Synthetic Drug Abuse Prevention Act (SDAPA), which defined 15 synthetic cannabinoids (CP-47,497, CP-47,497 C8-homolog, JWH-018, JWH-073 JWH-019, JWH-200, JWH-250, JWH-081, JWH-122, JWH-398, AM2201, AM694, SR-19, SR-18, and JWH-203) (Fig. 1) as cannabimimetic agents and placed these compounds into controlled substances Schedule I [49]. Furthermore, FUB-AMB, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA, and MDMB-FUBINACA (Fig. 1) were emergency scheduled as Schedule I controlled substances by DEA in 2017 [50]. Additionally, five synthetic cannabinoids, including FUB-AKB48, were placed under temporary Schedule I of the CSA in April 2019 [51].

Other synthetic cannabinoids may be subject to prosecution under the Controlled Substance Analogue Enforcement Act, which covers any compounds that are not formally controlled substances, but structurally or pharmacologically similar to Schedule I or II controlled substances without any legitimate medical use [50].

Synthetic cannabinoids have also been scheduled in EU countries [52,53]. These compounds were not included in the original list of the scheduled psychoactive substances by the Convention on Psychotropic Substances of 1971, but the synthetic cannabinoids have been added to the list of the scheduled psychoactive substances by the Convention [54].

6.1 Changes in Long-Term Potentiation and Long-Term Depression

Impairment in synaptic plasticity appears to contribute to cannabinoid-induced NOR deficits in control animals. NOR impairment induced by the CB1R agonist JWH-018 reduces electrically evoked long-term potentiation (LTP) in the CA1 region of the hippocampus (Barbieri et al., 2016; Basavarajappa and Subbanna, 2014). Chronic WIN-induced object recognition impairment reduces LTP in the ventral subiculum-nucleus accumbens pathway (Abush and Akirav, 2012) and also reduces endocannabinoid-dependent long-term depression (LTD) and metabotropic glutamate receptor 2/3 (mGluR2/3)–dependent LTD in the medial prefrontal cortex (PFC) (Lovelace et al., 2015). In addition, CB1R agonist-induced NOR impairment is associated with impaired calcium-/calmodulin-dependent protein kinase type IV (CAMKIV) and cAMP response element-binding protein (CREB) phosphorylation. Reductions in these markers, in addition, to reduced LTP and LTD, suggest impaired synaptic mechanisms of learning and memory following CB1R agonist treatment. JWH-induced impairment in hippocampal LTP is reversed by application of the CB1R antagonist AM251 (Barbieri et al., 2016)—an effect not present in CB1R KO mice (Basavarajappa and Subbanna, 2014)—suggesting a CB1R-dependent mechanism underlying cannabinoid-induced changes in plasticity.

Emerging Drugs

Designer drugs, created to avoid drug laws, appear at a remarkable pace. ‘Spice’ refers to designer cannabinoids such as JWH-018, JWH-073, JWH-200 and (C8)-CP 47,497, initially found in ‘herbal smoking blends’; these are sold under many names, including K2, fake weed, Yucatan fire, skunk, moon rocks and others. Synthetic cannabinoid agonists, including RCS-4, RCS-8 and AB-001, are also available. Spice abusers report tachycardia, vomiting, agitation, confusion and hallucinations. Spice can raise blood pressure and cause myocardial ischaemia, and has occasionally been associated with heart attacks. Regular users may experience withdrawal and addiction symptoms. One concern is that there may be harmful heavy metal residues in spice mixtures.

‘Bath salts’ contain synthetic substituted cathinones related to amphetamines such as mephedrone, methylenedioxypyrovalerone (MDPV) and methylone – all highly addictive. Sometimes marketed as ‘plant food’, ‘jewellery cleaner’ or ‘phone screen cleaner’, they are sold online under a variety of names, such as K4 rage, cloud nine, ocean snow, ivory wave, sextacy ultra, white rush, white lightning, bloom, lunar wave, vanilla sky and scarface. Bath salts are typically taken orally, smoked, inhaled or injected – the worst outcomes being after snorting or injection. Users experience euphoria followed by paranoia, depression, agitation and intense craving for more, and some display psychotic and violent behaviour. Bath salts produce an intense high, extreme energy, tachycardia, excessive sweating and insomnia reported to last up to 8 hours, but with redosing the symptoms are prolonged, even for several days. Patients with the ‘excited delirium’ syndrome from taking bath salts may become dehydrated, with skeletal muscle breakdown, renal failure and even death. K2 can induce a limitless high the more a user smokes, and effects can be up to 10 times more intense than those of marijuana.

Salvia (Salvia divinorum) is an herb from Mexico and Central and South America that contains salvinorin A, a potent activator of brain kappa opioid receptors. Salvia users may chew leaves, drink extracted juices or use dried leaves smoked as a joint, consumed in water pipes, or vaporized and inhaled. People who abuse salvia generally have hallucinations or ‘psychotomimetic’ episodes (a transient psychosis).

Designer stimulants include geranamine, mephedrone, MDPV and desoxypipradrol. Designer sedatives include methylmethaqualone and premazepam.

Another novel development is the use of agents for cosmetic rather than recreational purposes, such as the non-approved alpha-melanocyte-stimulating hormone tanning drugs known as melanotan peptides. Designer analogues of sildenafil (Viagra) have been used as active compounds in ‘herbal’ aphrodisiac products.

Fatalities associated with synthetic cannabinoids use

Fatalities associated with synthetic cannabinoids abuse have been reported. Shanks et al. reported three cases where fatalities were associated with synthetic cannabinoid use. In case one, a 57-year old man died due to use of JWH-018. The cardiac blood showed 199 ng/mL of JWH-018 along with other prescription drugs. In the second case a 52-year old year man died who showed 19.6 ng/mL of JWH-018 and 68.3 ng/mL of JWH-073 in cardiac blood. In the third case a 29-year old man died who showed only the presence of JWH-018 (83.3 ng/mL) in the cardiac blood but no other drug [33]. Labay et al. recently reviewed cases where death was related to use of synthetic cannabinoids. The authors identified six deaths related to abuse of JWH-018 (postmortem blood levels: 0.11–0.65 ng/mL), six deaths related to abuse of JWH-122, six deaths related to abuse of JWH-210, one each associated with abuse of JWH-175 and JWH-250, respectively. In addition, two fatalities associated with abuse of XLR-11 and nine fatalities associated with abuse of AM-2201 (postmortem blood levels: 0.13–17.0 ng/mL) were also reported [34]. Patton et al. also reported death of a 23-year old man due to AM-2201 overdose. The metabolite of AM-2201 was detected in the postmortem blood [35].

Death due to use of synthetic cannabinoids (S)-methyl-2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (5F-AMB), a new synthetic cannabinoid first reported in Japan in early 2014, has also been reported. The concentration of 5F-AMB was only 0.3 ng/mL. However, the authors concluded that the death was accidental [36]. Shanks et al. described a death associated with use of a new synthetic cannabinoid ADB-4-fluorobenzyl-1H-indazole-3-carboxamide (FUBINACA). In this drug, 1-amino-3,3-deimethoxy-1-oxobutane-2yl (ABD) group is linked with FUBINACA base at the amide group. The concentration of this relatively new synthetic cannabinoid in the postmortem blood was 7.3 ng/mL. However, a small amount of THC (1.1 ng/mL) and its metabolite THC-COOH (4.7 ng/mL) was also detected in the postmortem blood using LC-MS/MS [37].

Legislation Status

Starting from 2009, different European countries subjected all products containing synthetic cannabinoids to the narcotics laws, preventing their sale in head shops and online stores (Fattore & Fratta, 2011; Seely et al., 2012). In 2011, JWH-018, JWH-073, JWH-200, CP-47,497, and (C8)-CP-47,497 were classified as Schedule I of the Controlled Substances Act, and 177 different synthetic cannabinoids were reported in 2014 to the United Nations Office on drugs and crime early warning advisory from 58 different countries and territories (UNODC, 2015). At present (2016), current legislations are adopting a more general approach by providing a broader definition of regulated compounds to target entire classes of substances derived from a certain chemical structure rather than specific molecules.

Animal data

In a rat discrimination study, where rats were initially trained to discriminate THC from vehicle, SCs such as CP-55,940 and WIN-55,212–2 were able to substitute for THC [201]. These effects could be attenuated by the effects of the CB1 antagonist SR-141,716A.

In a rhesus monkey model, animals were trained to discriminate THC, JWH-018, JWH-073 from vehicle in drug lever pressing studies [202]. The ED50 values were 0.044, 0.013, 0.058 mg/kg and duration of action was four, two and one hour for THC, JWH-018 and JWH-073, respectively. All three compounds could dose-dependently attenuate the rimonabant (CB1 receptor antagonist) discriminative stimulus in animals chronically treated with THC. The authors of this study concluded that the SCs (JWH-018 and JWH-073) had similar subjective effects to THC, and furthermore postulated that the shorter duration of action may lead to more frequent use and, in turn, increased dependence.

In another rhesus monkey study, animals were given either three or 14 days of pre-treatment with THC to study its effects on tolerance to three SCs (CP-55,940; JWH-073; JWH-018) [203]. Three days of pre-treatment with THC did not result in cross tolerance to any of these three SC compounds. Fourteen days pre-treatment with THC decreased sensitivity to THC, CP-55,940, JWH-018 and JWH-073 9.2-fold, 3.6-fold, 4.3-fold and 5.6-fold respectively. The differences in sensitivity to pre-treatment with THC may indicate differences in the potential for dependence associated with THC and SC and also between different SC.

11.5.1 Detection of Metabolites

In the previous paragraph, several methods describing the detection of SC in human hair have been presented. All studies have included only the parent drugs in the list of targeted analytes, but this does not exclude the possibility of external contamination, nor does it provide conclusive evidence of active drug consumption. As a matter of fact, and similarly to what has happened in the last two decades for THC, only the presence of metabolites and possibly the evaluation of concentration ratios between parent drugs and metabolites, can prove the active use of SC and exclude external contamination from sidestream smoke or handling material.

The first study to investigate the presence of metabolites in hair was presented by Kim et al. [63]. The authors established and validated an analytical method for simultaneous detection of JWH-018 and JWH-073, and their most abundant monohydroxylated and carboxylated metabolites. The incorporation of metabolites of SCs into hair was also investigated, together with the effect of pigmentation on the deposition of these compounds in hair, by means of an animal model. For the latter purpose, JWH-073 was chosen as representative for SCs. Finally, the developed method was applied to 18 hair samples from individuals suspected of use of SCs. Among the positive results, only the N-(5-hydroxypentyl) metabolite of JWH-018 (JWH-018 N-5-OH M) was found, suggesting its prevalence in hair. The concentrations varied widely, and so did the ratios between parent drug and metabolite. Even in those hair samples containing relatively high concentrations of JWH-018 (above 50 pg/mg), JWH-018 N-5-OH M was not detected. The highest concentrations of JWH-018 N-5-OH M was 85 pg/mg; in this case, the JWH-018 concentration was 151 pg/mg. Overall, in samples positive both to JWH-018 and JWH-018 N-5-OH M, parent drug-to-metabolite ratios were highly variable, ranging from 1.1 to 62.8. Noteworthy, JWH-018 N-5-OH is also the product of metabolism of AM-2201 [72]. Therefore, some high concentrations in hair could also be generated by the co-ingestion of other SC. Therefore, results about JWH-018 N-5-OH levels in hair might be inconclusive without a comprehensive screening of the most popular SC, including AM-2201.

Very recently, the same group published a new study in which they expended their previous method to AM-2201, JWH-122, MAM-2201, and their monohydroxylated metabolites in hair [65]. The method was also applied to investigate the distribution of five naphthoylindole-based SCs and their metabolites in authentic human hair samples from forensic cases and the deposition of AM-2201 and its metabolites in pigmented and nonpigmented rat hair. In real samples, JWH-018, JWH-018 N-5-OH M, JWH-018 N-COOH M, JWH-073, JWH-073 N-COOH M, AM-2201, AM-2201 N-4-OH M, AM-2201 N-6-OH indole M, JWH-122, JWH-122 N-5-OH M, and MAM-2201 were simultaneously or individually detected. The concentration range of parent drugs (e.g., AM-2201) was much wider than that of metabolites (e.g., JWH-018 N-5-OH M). Parent SCs and their monohydroxylated metabolites were identified in the hair samples of all nine cases, to confirm that the simultaneous determination of both parent drugs and metabolites in hair is helpful for the interpretation of results. Indeed, this allows to exclude the possibility of a passive contamination and provide information on the ingested parent SC [65].

The issue of possible external contamination has been recently raised [66,73]. These studies aimed to evaluate the extent of external contamination caused by handling of SC containing drug material under realistic conditions in a forensic laboratory. Hair of laboratory workers involved in the analysis of 670 herbal mixture samples (covering 31 brands and 12 different SCs) within a 2-week period was analyzed for SCs with a validated LC-MS/MS method. In addition, hair samples of laboratory staff not directly in contact with the drug material and close relatives of exposed subjects were analyzed to check for cross-contamination. All samples of persons who were in direct contact with drug material were tested positive for at least one of the SCs. Concentrations ranged from trace amounts up to a maximum of 170 pg/mg (JWH-210) and roughly reflected duration of exposure. Unexpectedly, subjects without direct contact to drug material also showed measurable hair concentrations. In one case, despite a JWH-210 concentration of less than 0.5 pg/mg in the hair sample of participant who was involved in the work, up to 11 pg/mg was detected in the hair sample of his girlfriend, who lived in the same household, but had no contact with the drug materials. One possible explanation from the authors for these results is the direct transfer through contaminated fingers; for example, from a head massage or by sleeping on pillows accidentally contaminated by the hands of the partner [66,73]. Overall, concentrations caused by contamination are in the typical range found in known users of these drugs, although the majority of them is below 50 pg/mg. Therefore, only the detection of metabolites in hair (or the simultaneous analysis of body fluids) can strongly suggest an actual consumption.

Recently, the first results from a comprehensive screening of metabolites on a large group of subjects were presented [74]. Initially, 15 samples which were previously found positive to SC were reprocessed [10]. The new results are presented in Table 11.7. In 10 cases (#1, 3–5, 7, 8, 12–15 in Table 11.7), low concentrations for the parent drug (below 50 pg/mg) were measured and no metabolites were found. For these cases, either sporadic exposure or external contamination could be suggested. In two cases (#6 and 10), where very high concentrations for JWH-122 were found, metabolites were present at very low concentration. For these two cases, it can be suggested that there was frequent exposure to SC, proven by the high levels, and active use, because of the presence of metabolites. Remarkably, JWH-122 metabolite can be also produced by the metabolism of MAM-2201 [75]. The remaining three cases (#2, 9, 11) were positive to different compounds at relatively high concentrations (above 50 pg/mg), but negative for metabolites. For these cases, frequent exposure to SC can be suggested, even though no metabolites were found.

Table 11.7. Results from Real Samples, Including Metabolites

n/a: not applicable

Afterward, 153 hair samples taken in 2012 and 2013 from young habitual THC consumers were tested. Results for hair and washing solution are shown in Table 11.8. Sample #4 was positive to several SC, of which two (JWH-073 and JWH-122) were present at high concentrations, but no metabolites were detected. The washing solutions were also negative. Therefore, frequent exposure can be suggested, but no conclusion can be definitely drawn about the active use. In the other four cases, very low concentrations (much below 50 pg/mg) were found and no metabolites were detected. For these cases, the washing solutions were also analyzed and all were found to be negative. Therefore, for these cases, sporadic exposure can be speculated and no conclusion can be drawn about possible external contamination.

Table 11.8. Results from Real Samples taken in 2012 and 2013, Including Metabolites

Lastly, 47 hair samples taken in 2014 from frequent THC consumers were processed (Table 11.9). Merely three positive samples were found, but only #3 (which was also positive to ketamine) is of interest. Some compounds of the JWH-series were detected at low concentrations, while the only high concentration was obtained for AM-2201, proving frequent exposure to this SC. The metabolites of AM-2201 were also present, confirming active use. Finally, the positive result for the washing solutions might likely indicate a recent exposure.

Table 11.9. Results from Real Samples taken in 2014, Including Metabolites

Synthetic Cannabinoids

These substances, synthetic cannabinoid receptor agonists, contain synthetic chemicals, often mixed with herbal mixtures, which mimic the main psychoactive compound of cannabis, Δ9-tetrahydrocannabinol (THC), binding to the same cannabinoid receptors (CB1 and CB2) in the brain and elsewhere in the body. However, often these substances are many more powerful than THC found in natural cannabis. For example, JWH-018 is approximately 4 times more potent than THC, and JWH-210 is 90 times more potent.

The synthetic cannabinoid JWH-018 was first detected in Spice products in 2008 and as of May 2013 84 synthetic cannabinoids have been notified to the EMCDDA (EMCDDA, 2013a,b). This is the largest group of chemicals monitored by the EU EWS. JWH-018 is a naphthoylindole, belonging to the aminoalkylindole family, having different chemical structure to THC but similar, more potent, effects. JWH compounds are named after John W. Huffman, the scientist who first synthesized these cannabinoids; AM compounds are named after Alexandros Makriyannis; HU are named after the Hebrew University Jerusalem where they were developed. More than one synthetic cannabinoid may be present in preparations sold.

The drugs are smoked, often with tobacco, with effects including mood elevation, relaxation, and perceptual disturbances. Other effects include chest pain, drowsiness, increase in pulse and blood pressure, dilated pupils, nausea and vomiting, and seizures. Anxiety, psychosis, hallucinations, paranoid delusions, insomnia and suicidal ideation, as well as cognitive impairment, confusion, disorientation, and effects on memory have been reported (Hermanns-Clausen et al., 2013; Seeley et al., 2012). Reemergence of psychotic symptoms may occur as well as new-onset psychosis and the protracted presence of psychotic symptoms beyond acute intoxication has been reported and is concerning (Hurst et al., 2011).