JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the

naphthoylindole Naphthoylindoles are a class of synthetic cannabinoids. See also * Structural scheduling of synthetic cannabinoids References {{reflist ...

family that acts as a

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the a ...

at both the CB₁ and CB₂

cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recep ...

s, with some selectivity for CB₂. It produces effects in animals similar to those of

tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...

(THC), a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products that in some countries are sold legally as "

incense Incense is aromatic biotic material that releases fragrant smoke when burnt. The term is used for either the material or the aroma. Incense is used for aesthetic reasons, religious worship, aromatherapy, meditation, and ceremony. It may also b ...

blends". As a

at both the CB₁ and CB₂ cannabinoid receptors, this chemical compound is classified as an analgesic medication. 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. 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. 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.

History

John W. Huffman, an organic chemist at

Clemson University Clemson University () is a public land-grant research university in Clemson, South Carolina. Founded in 1889, Clemson is the second-largest university in the student population in South Carolina. For the fall 2019 semester, the university enr ...

, synthesized a variety of chemical compounds that affect the

endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed ...

. JWH-018 is one of these compounds, with studies showing an affinity for the cannabinoid (CB₁) receptor five times greater than that of THC.

Cannabinoid receptors Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...

are found in mammalian brain and spleen tissue; however, the structural details of the active sites are currently unknown. On December 15, 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 A grey market or dark market (sometimes confused with the similar term " parallel market") is the trade of a commodity through distribution channels that are not authorized by the original manufacturer or trade mark proprietor. Grey market pr ...

drug

Spice A spice is a seed, fruit, root, bark, or other plant substance primarily used for flavoring or coloring food. Spices are distinguished from herbs, which are the leaves, flowers, or stems of plants used for flavoring or as a garnish. Spice ...

, which has been sold as an incense in a number of countries around the world since 2002. 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.

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. JWH-018 has an EC₅₀ of 102 nM for human CB₁ receptors, and 133 nM for human CB₂ receptors. JWH-018 produces bradycardia and

hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...

in rats at doses of 0.3–3 mg/kg, suggesting potent cannabinoid-like activity.

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 Indole is an aromatic heterocyclic organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other c ...

portions of the molecule. 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 A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

Usage

At least one case of JWH-018 dependence has been reported by the media. The user consumed JWH-018 daily for eight months. Withdrawal symptoms were more severe than those experienced as a result of

cannabis dependence Cannabis use disorder (CUD), also known as cannabis addiction or marijuana addiction, is defined in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and ICD-10 as the continued use of cannabis despite cli ...

. 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. On October 15, 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. An 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.Mayo, Nikie, "City Releases Email in Lamar Jacks Case", independentmail.com, posted Dec 16, 2011, accessed 12/22/11, http://www.independentmail.com/news/2011/dec/16/city-releases-email-lamar-jack-case/ Compared to THC, which is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

at CB₁ receptors, JWH-018, and many synthetic cannabinoids, are full agonists. THC has been shown to inhibit

GABA receptor The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...

neurotransmission in the brain via several pathways. JWH-018 may cause intense anxiety, agitation, and, in rare cases (generally with non-regular JWH users), has been assumed to have been the cause of

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

and

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

by inhibiting GABA neurotransmission more effectively than THC. Cannabinoid receptor full agonists may present serious dangers to the user when used to excess. 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. 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 illnesses (like a past or family history of psychosis) not use these substances.

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. 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 biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

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.Free version
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Legal status

Synthesis

References

De Luca MA, Bimpisidis Z, Melis M, Marti M, Caboni P, Valentini V, Margiani G, Pintori N, Polis I, Marsicano G, Parsons LH, Di Chiara G. Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid. Neuropharmacology. 2015 Dec;99:705-14. doi: 10.1016/j.neuropharm.2015.08.041. Epub 2015 Oct 23. PMID 26327678.

External links

User of legal high
{{DEFAULTSORT:Jwh-018 Designer drugs Euphoriants JWH cannabinoids Naphthoylindoles CB1 receptor agonists CB2 receptor agonists