John W. Huffman JWH-018,JWH-018 Manufacture,jwh-018 procurement:synthetic cannabinoid agonist ,Synthetic Cannabis

John W Huffman,JWH-018

John W Huffman ,JWH-018:JWH-018,synthetic cannabinoid agonist Synthetic Cannabis found to be 4-5 times stronger then pot addendum : Online procurement JWH-0181-Pentyl-3-(1-naphthoyl)indole Introduction:Synthetic Cannabis found to be 4-5 times stronger then pot JWH-018 is a synthetic cannabinoid agonist without the classical cannabinoid chemical structure. JWH-018 (1-pentyl-3-(1-naphthoyl)indole) is a synthetic aminoalkylindole Cannabinoid agonist which acts at both the CB1 and CB2 receptors, with a moderate selectivity for the CB2 receptor [1]. It is covered by US patent #7241799 [35]Synthesized primarily for radioligand binding studies, JWH-018 (named after it's creator, John W. Huffman) has shown in vivo and in vitro activity [1] similar to that of the classic exogenous agonist of Cannabinoid receptors, ∆-9-THC, though it is considerably (4-5x) more potent It is used in scientific research as a tool to study the cannabinoid system. It was recently purported to be found in the herbal mixture "Spice", sold in European countries mainly via internet shops. Although JWH-018 is likely to have the same effects in humans as Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of marijuana, it is not controlled in the U.S.Licit Uses: JWH-018 is used in basic scientific research to identify cannabinoid receptors in the brain and study Δ9-THC's mechanisms of action.Chemistry:1-Pentyl-3-(1-naphthoyl)indole or JWH-018 has been identified as a substance that has some pharmacological similarities to tetrahydrocannabinols contained in Cannabis sativa L. (marijuana). However, it is not related in chemical structure to tetrahydrocannabinols (THC), or other cannabinoids contained within the cannabis plant. Nor is it structurally related to other substances controlled under the CSA.The chemical structure of JWH-018 (left) and Δ 9-THC (right), a compound found in marijuana and representative of the THC structural class, are shown below. Based on the structural analysis, JWH-018 is not categorized as a THC substance, and is not similar in chemical structure to other substances controlled under the CSA. Pharmacology: Behavioral pharmacology studies show that JWH-018 has Δ9-THC-like activity in animals. In mice, it decreases overall activity, produces analgesia, decreases body temperature and produces catalepsy. Together, these four effects are used by scientists to predict Δ9-THC-like psychoactivity in humans. JWH-018's activity in all four tests suggests that it is likely to have THC-like psychoactive effects in humans.In vitro studies show that JWH-018 binds to the brain cannabinoid receptor CB1 with higher affinity than Δ9-THC, suggesting that it would have the same effects as Δ9-THC in vivo.A search in the literature resulted in no published studies of the effects of JWH-018 in humans.JWH-018 has been shown to inhibit the following enzymes:- CYP1A2 (at 20.7% the potency of the reference compound, alpha-naphtoflavone) [11]- CYP2C9 (at 7.1% the potency of the reference compound, sulphaphenazole) [11]- CYP2C19 (at 357.1% the potency of the reference compound, tranylcypromine) [11]- CYP3A4 (at 0.625% the potency of the reference compound, ketoconazole) [11]Cannabinoid Receptor (CB1/CB2) Binding of JWH-018The Ki (binding affinity) values for primary cannabinoid (CB1/CB2) receptors are 9.00±5.00 and 2.94±2.65 nM, respectively, showing a general selectivity for the CB2 receptor over the CB1 receptor. The Ki ratio for the receptors is thus CB1:CB2, 3.06 [1].Molecular Pharmacology of JWH-018Though based on the structure of WIN 55,212-2, the JWH analogues lack a methyl group at C-2. Various N-Alkyl side chains define the various JWH analogues, which range from N-Propyl (JWH-072) to N-Hexyl (JWH-019) and of course N-Pentyl (JWH-018). The N-Pentyl substitute on the compound reduced CB2 selectivity as compared to N-Butyl substitute (JWH-073, which has a CB1:CB2 affinity ratio of 0.23) [1].In terms of the structure-activity-relationship (SAR) between CB receptors and their ligands, some primary components are necessary for a best-fit-alignment scenario: the cyclohexene and naphthalene ring, the phenolic hydroxyl and carbonyl group, the carbon side chain at C-3 and the morpholinoethyl group. In the case of JWH-018, the morpholinoethyl group has been replaced with the N-Pentyl side chain, which exhibits similar steric and electrostatic properties as the morpholinoethyl group [1]. N-Alkyl chains of increasing length have been shown to increase binding affinity to CB2 receptors, and are maximized by the 4 and 6 carbon chains of JWH-018, JWH-007, JWH-048, JWH-081 and JWH-098 [3]. Compounds with shorter carbon chain lengths exhibited weak binding affinities and no in vivo activity (JWH-070, JWH-077, and JWH-043), as has also been shown with other CB agonists [4].Metabolism of JWH-018No accumulation of JWH-018 in peripheral tissues or albumin deposits was shown after 7 days of chronic dosing [8]. Bi-phasic distribution was shown for JWH-018 metabolism, suggesting that the drug undergoes both metabolism and elimination phases [6].Half-Life of JWH-018The half-life of JWH-018 is approximately two hours (112.2min) [6].ToleranceJWH-018 exhibits a traditional tachyphylactic response in repeated dosing, with a notable decrease in both effect and duration after 3 days of chronic dosing [8]. This tolerance is likely the result of CB1/2 receptor downregulation, similar to the tolerance developed from ∆-9-THC or Cannabis administration as discussed here under the Tolerance heading and in much greater detail in a dedicated thread here: Cannabis and Cannabinoid Tolerance. The health risks of JWH-018CardiovascularJWH-018 has been shown not to bind to hERG, the human gene encoding for cardiovascular potassium channels [12]. It is thus unlikely to cause an increased QT interval, which could have deleterious and possibly deadly effects on the cardiovascular system.At the highest tested laboratory dose (10mg/kg) some respiratory depression was shown, which resulted in some animal deaths [6][8]. The deaths were attributed to catatonia and respiratory depression, as no organ toxicity was detected.CytotoxicityJWH-018 has been shown not to cause direct cell-death [10].Carcinogenic/Mutagenic PropertiesJWH-018 has been shown not to interfere with DNA in vivo. The combustion products of the material are still unknown and have not been tested for potential mutagenic or carcinogenic properties, but P.O. administration has been shown to not result in genotoxicity [9].SensitivityMale rats have been shown to possess greater sensitivity to JWH-018 than their female counterparts [6][8]. This may potentially translate to an increased sensitivity in male humans as compared to females, though abnormalities in CB1/CB2 receptor distribution in male and female rats have been demonstrated in previous studies [8]. Producing JWH-018J John W. Huffman has been quoted as saying that, "It [JWH-018] is really easy to make"[5]. A synthesis of the related compounds can be found in paper entitled "Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists" [36]. Forms of JWH-018Pure JWH-018Chemical characteristicsCAS#: 209414-07-3 [2]Formula: C24H23NO [1][2][6]Mol. Weight: 341.5 g/mol [1][2][6]Solubility in water: Not soluble in water at 25ºc [2]Soluble in nonpolar solvents: Soluble in DMF (dimethylformamide), DMSO (dimethyl sulfoxide), EtOH (ethanol)[2]Ion classification: 1 (Highly Ionizable)[6].AppearanceWhite solid [6][7]Note: The degradation of indole compounds such as JWH-018 results in a yellow-brown, gummy appearance due to melting point suppression [33]. Samples of JWH-018 circulating as a gummy, rust-brown solid are highly oxidized samples of the compound, though appear to have degraded less than 5% Spice, Spice Silver, Spice Gold, Spice Diamond, Spice Tropical Synergy and Spice Arctic Synergy have all been confirmed in at least some analyses to contain JWH-018 [22], though not always as the only or primary active ingredient [22][23][24][25].Other JWH-018 containing herbal blendsConfirmedBuddha Melt [26]Buddha Blend [27]SpeculatedSmoke X, XX, & XXX [28]Chillin XXX [29]Spicey XXX [30]ZoHai SX [31]Eclipse [32]ChillinMix [32]Smoke Plus [32]D-Raw [32]Skunk ANBow [32] The legal status of JWH-018 ArgenteniaJWH-018 is illegal in Argentenia [20].AustriaJWH-018 is illegal in Austria [15].BrazilJWH-018 is illegal in Brazil [20].CanadaJWH-018 falls under item 1 of Schedule 2 of the Controlled Drugs and Substances Act which lists similar synthetic preparations of ∆-9-THC and other Cannabinoids [13].Channel IslandsSale of the smoking blend Spice has been banned from commercial shops in the Channel Islands [21]. JWH-018 itself is not scheduled or controlled.ChileJWH-018 is illegal in Chile [20]. FranceJWH-018 is illegal in France as of February 24th, 2009 [18].GermanyJWH-018 is illegal in Germany as of January 22nd, 2009 [17]. LuxembourgJWH-018 is illegal in Luxembourg [20].NetherlandsJWH-018 is illegal in the Netherlands [source needed].PolandJWH-018 is illegal in Poland as of May, 2009 [16].RomaniaJWH-018 is illegal in Romania [20].RussiaSmoking mixtures, including AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Pep Spice, Yucatan Fire and others are considered controlled substances, however JWH-018 and other synthetic Cannabinoid agonists have not been directly declared as scheduled or illegal[14].United KingdomJWH-018 Scheduling in the United Kingdom is imminent [20] The ACMD have released wording of analogue style laws which will cover a variety of cannabinoids including JWH-018. This is expected to be written into law in early 2010 subject to parliamentary approval [37].United StatesJWH-018 is not considered a structural/positional isomer of any scheduled compound, including ∆-9-THC and HU-210 (both Schedule I substances). It may however fall under the analogue act due to its similar activity to these compounds [19]. The history of JWH-018 A chemical substance first synthesized in 1995 in a university lab in the US for purely experimental. The chemist who designed (and lent his initials to) JWH-18, John W Huffman, an organic chemist at Clemson University in South Carolina, told Chemistry World that his goal had been to make a simple compound to study structure-receptor relationships. The compound interacts with both cannabis receptors. The first batch was actually made by an undergraduate student working under a post-doc. 'It is really easy to make,' Huffman said.JWH-018 has not been licensed anywhere in the world for medical applications and little is known about the effect on humans, as not even pre-clinical studies have been to determine potential toxicity,he is inclined to believe it is not toxic, and that he would be more concerned about any lingering impurities from the production process. Illicit Distribution: Seizures of herbal mixtures called "Spice" were reported in Ohio and Florida. "Spice" is purported to contain JWH-018 and other substances that are similar in pharmacological activity to Δ9-THC. Control Status: JWH-018 is not currently controlled under the USA CSA. Online Procurement purported 99percent pure jwh-018JWH-018,synthetic cannabinoid agonist Synthetic Cannabis found to be 4-5 times stronger then pot addendum : Online procurement JWH-0181-Pentyl-3-(1-naphthoyl)indole Introduction:Synthetic Cannabis found to be 4-5 times stronger then pot</strong> JWH-018 is a synthetic cannabinoid agonist without the classical cannabinoid chemical structure. JWH-018 (1-pentyl-3-(1-naphthoyl)indole) is a synthetic aminoalkylindole Cannabinoid agonist which acts at both the CB1 and CB2 receptors, with a moderate selectivity for the CB2 receptor [1]. It is covered by US patent #7241799 [35]Synthesized primarily for radioligand binding studies, JWH-018 (named after it's creator, John W. Huffman) has shown in vivo and in vitro activity [1] similar to that of the classic exogenous agonist of Cannabinoid receptors, ∆-9-THC, though it is considerably (4-5x) more potent It is used in scientific research as a tool to study the cannabinoid system. It was recently purported to be found in the herbal mixture "Spice", sold in European countries mainly via internet shops. Although JWH-018 is likely to have the same effects in humans as Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of marijuana, it is not controlled in the U.S.Licit Uses: JWH-018 is used in basic scientific research to identify cannabinoid receptors in the brain and study Δ9-THC's mechanisms of action.Chemistry:1-Pentyl-3-(1-naphthoyl)indole or JWH-018 has been identified as a substance that has some pharmacological similarities to tetrahydrocannabinols contained in Cannabis sativa L. (marijuana). However, it is not related in chemical structure to tetrahydrocannabinols (THC), or other cannabinoids contained within the cannabis plant. Nor is it structurally related to other substances controlled under the CSA.The chemical structure of JWH-018 (left) and Δ 9-THC (right), a compound found in marijuana and representative of the THC structural class, are shown below. Based on the structural analysis, JWH-018 is not categorized as a THC substance, and is not similar in chemical structure to other substances controlled under the CSA. Pharmacology: Behavioral pharmacology studies show that JWH-018 has Δ9-THC-like activity in animals. In mice, it decreases overall activity, produces analgesia, decreases body temperature and produces catalepsy. Together, these four effects are used by scientists to predict Δ9-THC-like psychoactivity in humans. JWH-018's activity in all four tests suggests that it is likely to have THC-like psychoactive effects in humans.In vitro studies show that JWH-018 binds to the brain cannabinoid receptor CB1 with higher affinity than Δ9-THC, suggesting that it would have the same effects as Δ9-THC in vivo.A search in the literature resulted in no published studies of the effects of JWH-018 in humans.JWH-018 has been shown to inhibit the following enzymes:- CYP1A2 (at 20.7% the potency of the reference compound, alpha-naphtoflavone) [11]- CYP2C9 (at 7.1% the potency of the reference compound, sulphaphenazole) [11]- CYP2C19 (at 357.1% the potency of the reference compound, tranylcypromine) [11]- CYP3A4 (at 0.625% the potency of the reference compound, ketoconazole) [11]Cannabinoid Receptor (CB1/CB2) Binding of JWH-018The Ki (binding affinity) values for primary cannabinoid (CB1/CB2) receptors are 9.00±5.00 and 2.94±2.65 nM, respectively, showing a general selectivity for the CB2 receptor over the CB1 receptor. The Ki ratio for the receptors is thus CB1:CB2, 3.06 [1].Molecular Pharmacology of JWH-018Though based on the structure of WIN 55,212-2, the JWH analogues lack a methyl group at C-2. Various N-Alkyl side chains define the various JWH analogues, which range from N-Propyl (JWH-072) to N-Hexyl (JWH-019) and of course N-Pentyl (JWH-018). The N-Pentyl substitute on the compound reduced CB2 selectivity as compared to N-Butyl substitute (JWH-073, which has a CB1:CB2 affinity ratio of 0.23) [1].In terms of the structure-activity-relationship (SAR) between CB receptors and their ligands, some primary components are necessary for a best-fit-alignment scenario: the cyclohexene and naphthalene ring, the phenolic hydroxyl and carbonyl group, the carbon side chain at C-3 and the morpholinoethyl group. In the case of JWH-018, the morpholinoethyl group has been replaced with the N-Pentyl side chain, which exhibits similar steric and electrostatic properties as the morpholinoethyl group [1]. N-Alkyl chains of increasing length have been shown to increase binding affinity to CB2 receptors, and are maximized by the 4 and 6 carbon chains of JWH-018, JWH-007, JWH-048, JWH-081 and JWH-098 [3]. Compounds with shorter carbon chain lengths exhibited weak binding affinities and no in vivo activity (JWH-070, JWH-077, and JWH-043), as has also been shown with other CB agonists [4].Metabolism of JWH-018No accumulation of JWH-018 in peripheral tissues or albumin deposits was shown after 7 days of chronic dosing [8]. Bi-phasic distribution was shown for JWH-018 metabolism, suggesting that the drug undergoes both metabolism and elimination phases [6].Half-Life of JWH-018The half-life of JWH-018 is approximately two hours (112.2min) [6].ToleranceJWH-018 exhibits a traditional tachyphylactic response in repeated dosing, with a notable decrease in both effect and duration after 3 days of chronic dosing [8]. This tolerance is likely the result of CB1/2 receptor downregulation, similar to the tolerance developed from ∆-9-THC or Cannabis administration as discussed here under the Tolerance heading and in much greater detail in a dedicated thread here: Cannabis and Cannabinoid Tolerance. The health risks of JWH-018CardiovascularJWH-018 has been shown not to bind to hERG, the human gene encoding for cardiovascular potassium channels [12]. It is thus unlikely to cause an increased QT interval, which could have deleterious and possibly deadly effects on the cardiovascular system.At the highest tested laboratory dose (10mg/kg) some respiratory depression was shown, which resulted in some animal deaths [6][8]. The deaths were attributed to catatonia and respiratory depression, as no organ toxicity was detected.CytotoxicityJWH-018 has been shown not to cause direct cell-death [10].Carcinogenic/Mutagenic PropertiesJWH-018 has been shown not to interfere with DNA in vivo. The combustion products of the material are still unknown and have not been tested for potential mutagenic or carcinogenic properties, but P.O. administration has been shown to not result in genotoxicity [9].SensitivityMale rats have been shown to possess greater sensitivity to JWH-018 than their female counterparts [6][8]. This may potentially translate to an increased sensitivity in male humans as compared to females, though abnormalities in CB1/CB2 receptor distribution in male and female rats have been demonstrated in previous studies [8]. Producing JWH-018J John W. Huffman has been quoted as saying that, "It [JWH-018] is really easy to make"[5]. A synthesis of the related compounds can be found in paper entitled "Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists" [36]. Forms of JWH-018Pure JWH-018Chemical characteristicsCAS#: 209414-07-3 [2]Formula: C24H23NO [1][2][6]Mol. Weight: 341.5 g/mol [1][2][6]Solubility in water: Not soluble in water at 25ºc [2]Soluble in nonpolar solvents: Soluble in DMF (dimethylformamide), DMSO (dimethyl sulfoxide), EtOH (ethanol)[2]Ion classification: 1 (Highly Ionizable)[6].AppearanceWhite solid [6][7]Note: The degradation of indole compounds such as JWH-018 results in a yellow-brown, gummy appearance due to melting point suppression [33]. Samples of JWH-018 circulating as a gummy, rust-brown solid are highly oxidized samples of the compound, though appear to have degraded less than 5% Spice, Spice Silver, Spice Gold, Spice Diamond, Spice Tropical Synergy and Spice Arctic Synergy have all been confirmed in at least some analyses to contain JWH-018 [22], though not always as the only or primary active ingredient [22][23][24][25].Other JWH-018 containing herbal blendsConfirmedBuddha Melt [26]Buddha Blend [27]SpeculatedSmoke X, XX, & XXX [28]Chillin XXX [29]Spicey XXX [30]ZoHai SX [31]Eclipse [32]ChillinMix [32]Smoke Plus [32]D-Raw [32]Skunk ANBow [32] The legal status of JWH-018 ArgenteniaJWH-018 is illegal in Argentenia [20].AustriaJWH-018 is illegal in Austria [15].BrazilJWH-018 is illegal in Brazil [20].CanadaJWH-018 falls under item 1 of Schedule 2 of the Controlled Drugs and Substances Act which lists similar synthetic preparations of ∆-9-THC and other Cannabinoids [13].Channel IslandsSale of the smoking blend Spice has been banned from commercial shops in the Channel Islands [21]. JWH-018 itself is not scheduled or controlled.ChileJWH-018 is illegal in Chile [20]. FranceJWH-018 is illegal in France as of February 24th, 2009 [18].GermanyJWH-018 is illegal in Germany as of January 22nd, 2009 [17]. LuxembourgJWH-018 is illegal in Luxembourg [20].NetherlandsJWH-018 is illegal in the Netherlands [source needed].PolandJWH-018 is illegal in Poland as of May, 2009 [16].RomaniaJWH-018 is illegal in Romania [20].RussiaSmoking mixtures, including AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Pep Spice, Yucatan Fire and others are considered controlled substances, however JWH-018 and other synthetic Cannabinoid agonists have not been directly declared as scheduled or illegal[14].United KingdomJWH-018 Scheduling in the United Kingdom is imminent [20] The ACMD have released wording of analogue style laws which will cover a variety of cannabinoids including JWH-018. This is expected to be written into law in early 2010 subject to parliamentary approval [37].United StatesJWH-018 is not considered a structural/positional isomer of any scheduled compound, including ∆-9-THC and HU-210 (both Schedule I substances). It may however fall under the analogue act due to its similar activity to these compounds [19]. The history of JWH-018 A chemical substance first synthesized in 1995 in a university lab in the US for purely experimental. The chemist who designed (and lent his initials to) JWH-18, John W Huffman, an organic chemist at Clemson University in South Carolina, told Chemistry World that his goal had been to make a simple compound to study structure-receptor relationships. The compound interacts with both cannabis receptors. The first batch was actually made by an undergraduate student working under a post-doc. 'It is really easy to make,' Huffman said.JWH-018 has not been licensed anywhere in the world for medical applications and little is known about the effect on humans, as not even pre-clinical studies have been to determine potential toxicity,he is inclined to believe it is not toxic, and that he would be more concerned about any lingering impurities from the production process. Illicit Distribution: Seizures of herbal mixtures called "Spice" were reported in Ohio and Florida. "Spice" is purported to contain JWH-018 and other substances that are similar in pharmacological activity to Δ9-THC. Control Status: JWH-018 is not currently controlled under the USA CSA. Online Procurement purported 99percent pure jwh-018