JWH-018

Last updated

JWH-018
JWH018.svg
JWH-018 ball-and-stick model.png
Clinical data
Routes of
administration
Drug class Cannabinoid
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life
Identifiers
  • (Naphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.163.574 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H23NO
Molar mass 341.454 g·mol−1
3D model (JSmol)
Solubility in water hydrophobic, n/a mg/mL (20 °C)
  • CCCCCN1C=C(C(C2=CC=CC3=CC=CC=C32)=O)C4=CC=CC=C41
  • InChI=1S/C24H23NO/c1-2-3-8-16-25-17-22(20-13-6-7-15-23(20)25)24(26)21-14-9-11-18-10-4-5-12-19(18)21/h4-7,9-15,17H,2-3,8,16H2,1H3 Yes check.svgY
  • Key:JDNLPKCAXICMBW-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO [3] or AM-678) [4] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effects in animals similar to those of tetrahydrocannabinol (THC), a cannabinoid naturally present in cannabis, leading to its use as synthetic cannabinoid products that, in some countries, are sold legally as "incense blends". [5] [6] [7] [8] [9]

Contents

As a full agonist at both the CB1 and CB2 cannabinoid receptors, this chemical compound is classified as an analgesic medication. [10] The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established in treatment of neuropathic pain, as well as cancer pain and arthritis. [10]

These compounds work by mimicking the body's naturally-produced endocannabinoid hormones such as 2-AG and anandamide (AEA), which are biologically active and can exacerbate or inhibit nerve signaling. [10] As the cause is poorly understood in chronic pain states, more research and development must be done before the therapeutic potential of this class of biologic compounds can be realized. [10]

History

John W. Huffman, an organic chemist at Clemson University, synthesized a variety of chemical compounds that affect the endocannabinoid system. JWH-018 is one of these compounds, with studies showing an affinity for the cannabinoid CB1 receptor five times greater than that of THC. [11]

On 15 December 2008, it was reported by German pharmaceutical companies that JWH-018 was found as one of the active components in at least three versions of the grey market drug Spice, which has been sold as an incense in a number of countries around the world since 2006. [12] [13] [14] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the manufacturers had shortened the alkyl chain by one carbon to circumvent the ban. [15]

Pharmacology

JWH-018 is a full agonist of both the CB1 and CB2 cannabinoid receptors, with a reported binding affinity of 9.00 ± 5.00  nM at CB1 and 2.94 ± 2.65 nM at CB2. [6] JWH-018 has an EC50 of 102 nM for human CB1 receptors, and 133 nM for human CB2 receptors. [16] JWH-018 produces bradycardia and hypothermia in rats at doses of 0.3–3 mg/kg, suggesting potent cannabinoid-like activity. [16]

Pharmacokinetics

Metabolism of JWH-018 was assessed using Wistar rats which had been administered an ethanolic extract containing JWH-018. Urine was collected for 24 hours, followed by extraction of JWH-018 metabolites using both liquid-liquid extraction and solid-phase extraction. GC-MS was utilized to separate and identify the extracted compounds. JWH-018 and its N-dealkylated metabolite were only detected in small amounts, with hydroxylated N-dealkylated metabolites comprising the primary signal. The observed mass shift indicates that it is likely that hydroxylation occurs in both the naphthalene and indole portions of the molecule. [17] Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide. [18] When inhaled, the median half-life of JWH-018 is 1.69 hours. [19]

Recreational use

At least one case of JWH-018 dependence has been reported by the media. [5] The user consumed JWH-018 daily for eight months. Withdrawal symptoms were more severe than those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound changes in CB1 receptor density following administration, causing desensitization to its effects more rapidly than related cannabinoids. [9]

On 15 October 2011, Anderson County coroner Greg Shore attributed the death of a South Carolina college basketball player to "drug toxicity and organ failure" caused by JWH-018. [20] A November 2011 email concerning the case was released in December 2011 under the Freedom of Information Act after multiple requests to see the information had been denied. [21]

Compared to THC, which is a partial agonist at CB1 receptors, JWH-018, and many synthetic cannabinoids, are full agonists. JWH-018 may cause intense anxiety, agitation, and in rare cases, has been assumed to have been the cause of seizures and convulsions. JWH-018 and analogs of it may present serious dangers to the user when used to excess. [22]

Various physical and psychological adverse effects have been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in well-treated patients with mental illness following JWH-018 inhalation. [23] Due to concerns about the potential of JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic disorders, such as a past or family history of psychosis, not use these substances. [24]

Detection in biological fluids

JWH-018 usage is readily detected in urine using "spice" screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites. [25] JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of six users of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate. [26] [27] [28] [29] [30] [31] [32] [33] [34]

JWH-018 powder as it was commonly sold online JWH-018.jpg
JWH-018 powder as it was commonly sold online
CountryDate of banNotes
Flag of Austria.svg  Austria 18 December 2008The Austrian Ministry of Health announced on 18 December 2008 that Spice would be controlled under Paragraph 78 of their drug law on the grounds that it contains an active substance that affects the functions of the body, and the legality of JWH-018 is under review.
Flag of Australia (converted).svg  Australia 9 September 2011JWH-018 is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). [35] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. [35]
Flag of Belarus.svg  Belarus 1 January 2010[ citation needed ]
Flag of Canada (Pantone).svg  Canada 21 February 2012[ needs update? ]Despite the Canadian federal government having officially legalized the recreational use of cannabis on October 17, 2018 (see Cannabis Act), substances such as JWH-018 and JWH-073 are both on the most recently amended Schedule II of the Controlled Drugs and Substances Act. [36]
Flag of the People's Republic of China.svg  China 1 January 2012China has made JWH-018 Illegal for sale. It is illegal to import or export JWH-018. [37]
Flag of Estonia.svg  Estonia 24 July 2009[ citation needed ]
Flag of Finland.svg  Finland 12 March 2012Illegal [38] [39] [40]
Flag of France.svg  France 24 February 2009 [41] [42]
Flag of Germany.svg  Germany 22 January 2009 [43]
Flag of Ireland.svg  Ireland 11 May 2010An immediate ban was announced on 11 May 2010 by Minister for Health Mary Harney. [44]
Flag of Italy.svg  Italy 2 July 2010 [45]
Flag of Japan.svg  Japan 3 August 2012 [46] [47]
Flag of Jordan.svg  Jordan 2 September 2014The Anti-narcotics department declared synthetic cannabinoids and their analogues illegal after an outbreak of JWH-018 containing product referred to as "Joker". [48]
Flag of Latvia.svg  Latvia 28 November 2009 [49]
Flag of New Zealand.svg  New Zealand 8 May 2014 [50]
Flag of Norway.svg  Norway 21 December 2011 [51]
Flag of Poland.svg  Poland 8 May 2009 [41]
Flag of Romania.svg  Romania 15 February 2010
Flag of Russia.svg  Russia 22 January 2010
Flag of South Korea.svg  South Korea 1 July 2009 [52]
Flag of Sweden.svg  Sweden 30 July 2009A bill to ban JWH-018 was accepted on 30 July 2009 and was in effect on 15 September 2009. [53]
Flag of Turkey.svg  Turkey 13 February 2011Turkish authorities were first informed about JWH-018 through the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). The seizure of 2C-B in blue pill form on 13 October 2010 and the seizure of 0.6 g JWH-018 on 16 April 2010 in Eskisehir was reported through the Early Warning System (EWS). Upon these reports the EWS committee initiated the regulation process by warning the Ministry of Health. [54] In response to the official letter #86106 issued by the Ministry of Health dated 22 December 2010, the Council of Ministers decided on 7 January 2011 to add 14 cannabinoids; namely JWH-018, CP 47,497, JWH-073, HU-210, JWH-200, JWH-250, JWH-398, JWH-081, JWH-073, JWH-015, JWH-122, JWH-203, JWH-210, JWH-019; phenethylamines 2C-B and 2C-P as well as Catha edulis to the list of substances subject to the Law on Control of Narcotic Drugs. The regulation is in effect since 13 February 2011. [55] Upon letter #12099 issued by the Ministry of Health dated 6 February 2012, 4 more cannabinoids (AM-2201, RCS-4, JWH-201 and JWH-302), Salvia divinorum and several other chemicals (complete list here [56] ) were added to the list of controlled substances on 17 February 2012 which is effective since 22 March 2012. [57]
Flag of Ukraine.svg  Ukraine 31 May 2010[ citation needed ]
Flag of the United Kingdom.svg  United Kingdom 23 December 2009 [58]
Flag of the United States.svg  United States 1 March 2011JWH-018 was temporarily scheduled on 1 March 2011 by 76 FR 11075. It was permanently scheduled on 9 July 2012 by Section 1152 of the Food and Drug Administration Safety and Innovation Act (FDASIA) [59]

Synthesis

Synthesis of JWH-018. JWH-018 synthesis.svg
Synthesis of JWH-018.

See also

Related Research Articles

<span class="mw-page-title-main">JWH-081</span> Chemical compound

JWH-081 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. With a Ki of 1.2nM it is fairly selective for the CB1 subtype, its affinity at this subtype is measured at approximately 10x the affinity at CB2(12.4nM). It was discovered by and named after John W. Huffman.

<span class="mw-page-title-main">JWH-073</span> Chemical compound

JWH-073, a synthetic cannabinoid, is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors. It is somewhat selective for the CB1 subtype, with affinity at this subtype approximately 5× the affinity at CB2. The abbreviation JWH stands for John W. Huffman, one of the inventors of the compound.

<span class="mw-page-title-main">JWH-015</span> Chemical compound

JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28 times more strongly to CB2 than to CB1. However, it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors, and therefore it is not as selective as newer drugs such as JWH-133. It has been shown to possess immunomodulatory effects, and CB2 agonists may be useful in the treatment of pain and inflammation. It was discovered and named after John W. Huffman.

<span class="mw-page-title-main">JWH-250</span> Chemical compound

JWH-250 or (1-pentyl-3-(2-methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a Ki of 11 nM at CB1 and 33 nM at CB2. Unlike many of the older JWH series compounds, this compound does not have a naphthalene ring, instead occupying this position with a 2'-methoxy-phenylacetyl group, making JWH-250 a representative member of a new class of cannabinoid ligands. Other 2'-substituted analogues such as the methyl, chloro and bromo compounds are also active and somewhat more potent.

<span class="mw-page-title-main">AM-694</span> Chemical compound

AM-694 (1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole) is a designer drug that acts as a potent and selective agonist for the cannabinoid receptor CB1. It is used in scientific research for mapping the distribution of CB1 receptors.

<span class="mw-page-title-main">JWH-398</span> Chemical compound

JWH-398 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It has mild selectivity for CB1 with a Ki of 2.3 nM and 2.8 nM at CB2. This synthetic chemical compound was identified by the EMCDDA as an ingredient in three separate "herbal incense" products purchased from online shops between February and June 2009. It was discovered by, and named after, John W. Huffman.

<span class="mw-page-title-main">JWH-203</span> Chemical compound

JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Ki of 8.0 nM at CB1 and 7.0 nM at CB2. It was originally discovered by, and named after, John W. Huffman, but has subsequently been sold without his permission as an ingredient of synthetic cannabis smoking blends. Similar to the related 2'-methoxy compound JWH-250, the 2'-bromo compound JWH-249, and the 2'-methyl compound JWH-251, JWH-203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and has the strongest in vitro binding affinity for the cannabinoid receptors of any compound in the phenylacetyl group.

<span class="mw-page-title-main">JWH-007</span> Chemical compound

JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was first reported in 1994 by a group including the noted cannabinoid chemist John W. Huffman. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), JWH-200 (WIN 55,225) and WIN 55,212-2 by the Sterling Winthrop group. Several other N-alkyl substituents were found to be active by Huffman's team including the n-butyl, n-hexyl, 2-heptyl, and cyclohexylethyl groups, but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead. Consequently, the 2-desmethyl derivative of JWH-007, JWH-018, has slightly higher binding affinity for CB1, with an optimum binding of 9.00 nM at CB1 and 2.94 nM at CB2, and JWH-007 displayed optimum binding of 9.50 nM at CB1 and 2.94 nM at CB2.

<span class="mw-page-title-main">JWH-019</span> Chemical compound

JWH-019 is an analgesic chemical from the naphthoylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is the N-hexyl homolog of the more common synthetic cannabinoid compound JWH-018. Unlike the butyl homolog JWH-073, which is several times weaker than JWH-018, the hexyl homolog is only slightly less potent, although extending the chain one carbon longer to the heptyl homolog JWH-020 results in dramatic loss of activity. These results show that the optimum side chain length for CB1 binding in the naphthoylindole series is the five-carbon pentyl chain, shorter than in the classical cannabinoids where a seven-carbon heptyl chain produces the most potent compounds. This difference is thought to reflect a slightly different binding conformation adopted by the naphthoylindole compounds as compared to the classical cannabinoids, and may be useful in characterizing the active site of the CB1 and CB2 receptors.

<span class="mw-page-title-main">JWH-164</span> Chemical compound

JWH-164 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It has approximately equal affinity for the CB1 and CB2 receptors, with a Ki of 6.6 nM at CB1 and 6.9 nM at CB2. JWH-164 is a positional isomer of the related compound JWH-081, but with a methoxy group at the 7-position of the naphthyl ring, rather than the 4-position as in JWH-081. Its potency is intermediate between that of JWH-081 and its ring unsubstituted derivative JWH-018, demonstrating that substitution of the naphthyl 7-position can also result in increased cannabinoid receptor binding affinity.

<span class="mw-page-title-main">JWH-302</span> Chemical compound

JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with moderate affinity at both the CB1 and CB2 receptors. It is a positional isomer of the more common drug JWH-250, though it is slightly less potent with a Ki of 17 nM at CB1, compared to 11 nM for JWH-250. Because of their identical molecular weight and similar fragmentation patterns, JWH-302 and JWH-250 can be very difficult to distinguish by GC-MS testing.

<span class="mw-page-title-main">AB-001</span> Chemical compound

AB-001 (1-pentyl-3-(1-adamantoyl)indole) is a designer drug that was found as an ingredient in synthetic cannabis smoking blends in Ireland in 2010 and Hungary and Germany in 2011. It is unclear who AB-001 was originally developed by, but it is structurally related to compounds such as AM-1248 and its corresponding 1-(tetrahydropyran-4-ylmethyl) analogue, which are known to be potent cannabinoid agonists with moderate to a high selectivity for CB2 over CB1. The first published synthesis and pharmacological evaluation of AB-001 revealed that it acts as a full agonist at CB1 (EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM). However, AB-001 was found to possess only weak cannabimimetic effects in rats at doses up to 30 mg/kg, making it less potent than the carboxamide analogue APICA, which possesses potent cannabimimetic activity at doses of 3 mg/kg.

<span class="mw-page-title-main">UR-144</span> Chemical compound

UR-144 (TMCP-018, KM-X1, MN-001, YX-17) is a drug invented by Abbott Laboratories, that acts as a selective full agonist of the peripheral cannabinoid receptor CB2, but with much lower affinity for the psychoactive CB1 receptor.

<span class="mw-page-title-main">JWH-047</span> Chemical compound

JWH-047 is a selective cannabinoid ligand that binds to both CB1 and CB2. It has a bindining affinity of Ki = 0.9 nM for the CB2 subtype, and more than 65 times selectivity over the CB1.

<span class="mw-page-title-main">MAM-2201</span> Chemical compound

MAM-2201 is a drug that presumably acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in the Netherlands and Germany in June 2011 as an ingredient in synthetic cannabis smoking blends. Like RCS-4 and AB-001, MAM-2201 thus appears to be a novel compound invented by "research chemical" suppliers specifically for grey-market recreational use. Structurally, MAM-2201 is a hybrid of two known cannabinoid compounds JWH-122 and AM-2201, both of which had previously been used as active ingredients in synthetic cannabis blends before being banned in many countries.

<span class="mw-page-title-main">APICA (synthetic cannabinoid drug)</span> Chemical compound

APICA is an indole based drug that acts as a potent agonist for the cannabinoid receptors.

<span class="mw-page-title-main">QUCHIC</span> Chemical compound

QUCHIC is a designer drug offered by online vendors as a cannabimimetic agent, and was first detected being sold in synthetic cannabis products in Japan in early 2013, and subsequently also in New Zealand. The structure of QUCHIC appears to use an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. QUCHIC, along with QUPIC, represents a structurally unique synthetic cannabinoid chemotype since it contains an ester linker at the indole 3-position rather than the precedented ketone of JWH-018 and its analogues, or the amide of SDB-001 and its analogues.

<span class="mw-page-title-main">SDB-005</span> Chemical compound

SDB-005 is an indazole-based synthetic cannabinoid that has been sold online as a designer drug. It is presumed to be an agonist of the CB1 and CB2 cannabinoid receptors. SDB-005 is the indazole core analog of PB-22 where the 8-hydroxyquinoline has also been replaced with a naphthalene group.

<span class="mw-page-title-main">MDMB-CHMICA</span> Chemical compound

'MDMB-CHMICAa' is an indole-based synthetic cannabinoid that is a potent agonist of the CB1 receptor and has been sold online as a designer drug. While MDMB-CHMICA was initially sold under the name "MMB-CHMINACA", the compound corresponding to this code name (i.e. the isopropyl instead of t-butyl analogue of MDMB-CHMINACA) has been identified on the designer drug market in 2015 as AMB-CHMINACA.

<span class="mw-page-title-main">ADB-BINACA</span> Chemical compound

ADB-BINACA (also known as ADMB-BZINACA using EMCDDA naming standards) is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products. It was originally developed by Pfizer as a potential analgesic, and is a potent agonist of the CB1 receptor with a binding affinity (Ki) of 0.33 nM and an EC50 of 14.7 nM.

References

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  25. ↑ Arntson A, Ofsa B, Lancaster D, Simon JR, McMullin M, Logan B (June 2013). "Validation of a novel immunoassay for the detection of synthetic cannabinoids and metabolites in urine specimens". Journal of Analytical Toxicology. 37 (5): 284–290. doi:10.1093/jat/bkt024. PMID   23625703.
  26. ↑ Möller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. 24 Sep 2010. [Epub ahead of print]
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