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[top]Introduction to JWH-018 (1-pentyl-3-(1-nahpthoyl)indole)

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 [2]

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 [3].


[top]Using JWH-018

In progress

[top]Routes of Administration

[top]Topical

[top]Internal

[top]Parenteral

[top]Tolerance

JWH-018 exhibits a traditional tachyphylactic response in repeated dosing, with a notable decrease in both effect and duration after 3 days of chronic dosing [4]. 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.


[top]Pharmacology and Pharmacokinetics of JWH-018

[top]Enzyme Inhibition by JWH-018

JWH-018 has been shown to inhibit the following enzymes:

- CYP1A2 (at 20.7% the potency of the reference compound, alpha-naphtoflavone) [5]
- CYP2C9 (at 7.1% the potency of the reference compound, sulphaphenazole) [5]
- CYP2C19 (at 357.1% the potency of the reference compound, tranylcypromine) [5]
- CYP3A4 (at 0.625% the potency of the reference compound, ketoconazole) [5]

[top]Cannabinoid Receptor (CB1/CB2) Binding of JWH-018


The 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].

[top]Molecular Pharmacology of JWH-018

Though 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 [6]. 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 [7].

[top]Metabolism of JWH-018

No accumulation of JWH-018 in peripheral tissues or albumin deposits was shown after 7 days of chronic dosing [4]. Bi-phasic distribution was shown for JWH-018 metabolism, suggesting that the drug undergoes both metabolism and elimination phases [8].

[top]Half-Life of JWH-018

The half-life of JWH-018 is approximately two hours (112.2min) [8].


[top]Dangers of JWH-018

[top]Cardiovascular

JWH-018 has been shown not to bind to hERG, the human gene encoding for cardiovascular potassium channels [9]. 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 [8][4]. The deaths were attributed to catatonia and respiratory depression, as no organ toxicity was detected.

[top]Cytotoxicity

JWH-018 has been shown not to cause direct cell-death [10].

[top]Carcinogenic/Mutagenic Properties

JWH-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 [11].

[top]Sensitivity

Male rats have been shown to possess greater sensitivity to JWH-018 than their female counterparts [8][4]. 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 [4].


[top]Producing JWH-018

John W. Huffman has been quoted as saying that, "It [JWH-018] is really easy to make"[3]. 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" [12].


[top]Forms of JWH-018

[top]Pure JWH-018

[top]Chemical characteristics

CAS#: 209414-07-3 [13]
Formula: C24H23NO [1][13][8]
Mol. Weight: 341.5 g/mol [1][13][8]
Solubility in water: Not soluble in water at 25ºc [13]
Soluble in nonpolar solvents: Soluble in DMF (dimethylformamide), DMSO (dimethyl sulfoxide), EtOH (ethanol)[13]
Ion classification: 1 (Highly Ionizable)[8].

[top]Appearance


White solid [8][14]
Note: The degradation of indole compounds such as JWH-018 results in a yellow-brown, gummy appearance due to melting point suppression [15]. 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% [16].

[top]Spice

Spice, Spice Silver, Spice Gold, Spice Diamond, Spice Tropical Synergy and Spice Arctic Synergy have all been confirmed in at least some analysis to contain JWH-018 [17], though not always as the only or primary active ingredient [17][18][19][20].

[top]Other JWH-018 containing herbal blends

[top]Confirmed

Buddha Melt [21]
Buddha Blend [22]

[top]Speculated

Smoke X, XX, & XXX [23]
Chillin XXX [24]
Spicey XXX [25]
ZoHai SX [26]
Eclipse [27]
ChillinMix [27]
Smoke Plus [27]
D-Raw [27]
Skunk ANBow [27]


[top]The legal status of JWH-018

[top]Argentina

JWH-018 has attracted negative government attention in Argentina, particularly following moves by Chile and Brazil to control JWH-018. Its legal status in Argentina remains ambiguous. [28]

[top]Austria

JWH-018 is illegal in Austria. [29]

[top]Brazil

As of 18th June 2010, JWH-018 is listed as a controlled psychotropic substance by ANVISA, the National Health Surveillance Agency of Brazil. [28].

[top]Canada

JWH-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 [30].

[top]Channel Islands

Sale of the smoking blend Spice has been banned from commercial shops in the Channel Islands [31]. JWH-018 itself is not scheduled or controlled.

[top]Chile

JWH-018 is illegal in Chile [28].

[top]Finland

JWH-018 is illegal in Finland as of 2012.

[top]France

JWH-018 is illegal in France as of February 24th, 2009 [32].

[top]Germany

JWH-018 is illegal in Germany as of January 22nd, 2009 [33].

[top]Luxembourg

JWH-018 is illegal in Luxembourg [28].

[top]Netherlands

JWH-018 is illegal in the Netherlands [source needed].

[top]Poland

JWH-018 is illegal in Poland as of May, 2009 [34].

[top]Romania

JWH-018 is illegal in Romania [28].

[top]Russia

Smoking 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[35].

[top]United Kingdom

JWH-018 is a class B controlled substance in the UK under an amendment to the Misuse of Drugs Act 1971, effective 23rd December 2009. A number of other synthetic cannabinoids were also controlled as these laws came into effect. [28][36]

[top]United States

JWH-018 is currently unscheduled at the Federal level. It is not a structural or positional isomer of any scheduled compound, including ∆-9-THC and HU-210 (both Schedule I substances). It may however contravene the Federal Analog Act under certain circumstances due to the functional similarity to Schedule I substances. [37][38]

On 24th November 2010 the Federal Drugs Enforcement Agency (DEA) published a notice of intent to use their emergency scheduling powers to add JWH-018, along with several other synthetic cannabinoids, to schedule I of the controlled substances list. This declaration triggers a minimum consultation period of 30 days. An official decision by the DEA is yet to be announced. [39][40]

Despite remaining unregulated at the federal level at this time, laws prohibiting the possession and sale of JWH-018 and other synthetic cannabinoids have been passed in several US states and municipalities. [41][42]




[top]The history of JWH-018

In progress





[top]More JWH-018 sections

JWH-018 Info- Read & discuss information regarding JWH-018

JWH-018 Experiences- Post & read experiences with JWH-018.

JWH-018 File archive entries- Upload & read research & articles about JWH-018.

JWH-018 Image gallery- Post & view pictures of JWH-018.

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[top]References

  1. ^ a b c d e f g Aung, M.M., Griffin, G., Huffman, J.W., et al. Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding. Drug and Alcohol Dependence 60 133-140 (2000).
  2. ^ Makriyannis, Alexandros, and Hongfeng Deng. Cannabimimetic indole derivatives. University of Connecticut, assignee. Patent 7241799. 2007.
  3. ^ a b Stafford, Ned. "Synthetic cannabis mimic found in herbal incense." Advancing the Chemical Sciences. 15 Jan. 2009. RSC. 10 June 2009 <http://www.rsc.org/chemistryworld/News/2009/January/15010901.asp>.
  4. ^ a b c d e Mouse99. JWH-018 Repeat Rat Toxicity. Raw data. Netherlands. 18 Dec. 2008.
  5. ^ a b c d Mouse99. JWH-018 CYP450 Inhibition. Raw data. Netherlands. 18 Dec. 2008.
  6. ^ J.L Wiley, D.R Compton, D Dai, J.W Huffman and B.R Martin, Structure-activity relationships of indole and pyrrole-derived cannabinoids, J. Pharmacol. Exp. Ther. 285 (1998), pp. 994–1004.
  7. ^ D.R Compton, K.C Rice, B.R De Costa, R.K Razdan, L.S Melvin, M.R Johnson and B.R Martin, Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities, J. Pharmacol. Exp. Ther. 265 (1993), pp. 218–226.
  8. ^ a b c d e f g h Mouse99. JWH-018 Rat Pharmacokinetics. Raw data. Netherlands. 18 Dec. 2008.
  9. ^ Mouse99. hERG: In vitro Test For The Potential of QT Interval Prolongation by JWH-018. Raw data. Netherlands. 18 Dec. 2008.
  10. ^ Mouse99. JWH-018 Cytotoxicity. Raw data. Netherlands. 18 Dec. 2008.
  11. ^ Mouse99. JWH-018 Genotoxicity. Raw data. Netherlands. 18 Dec. 2008.
  12. ^ Huffman et al. "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." Bioorganic and Medicinal Chemistry (2005): 89-112.
  13. ^ a b c d e Cayman Chemical Company. Material Satefy Data Sheet- JWH-018. Brochure. Ann Arbor, MI: Author, 2009.
  14. ^ Mouse99. JWH-018 Analysis. Raw data. Netherlands. 18 Dec. 2008.
  15. ^ http://www.drugs-forum.com/forum/sho...04&postcount=6
  16. ^ http://www.drugs-forum.com/forum/sho...374#post614374
  17. ^ a b THC Pharm Analysis. Raw data. Main, Frankfurt. 15 Dec. 2008.
  18. ^ EMCDDA Action on new drugs briefing paper: Understanding the Spice phenomenon. Publication. Lisbon, 2009.
  19. ^ Sie, Lesen. "Gefährlicher Kick mit "Spice"" Frankfurter Rundschau 2009. 10 June 2009 <http://www.fr-online.de/frankfurt_und_hessen/nachrichten/frankfurt/1646010_Gefaehrlicher-Kick-mit-Spice.html>.
  20. ^ http://www.drugs-forum.com/forum/showthread.php?t=73649
  21. ^ http://www.drugs-forum.com/forum/showthread.php?t=85201
  22. ^ http://www.drugs-forum.com/forum/showthread.php?t=86350
  23. ^ http://www.drugs-forum.com/forum/showthread.php?t=83048
  24. ^ http://www.drugs-forum.com/forum/showthread.php?t=44182
  25. ^ http://www.drugs-forum.com/forum/showthread.php?t=60209
  26. ^ http://www.drugs-forum.com/forum/showthread.php?t=50857
  27. ^ a b c d e http://www.drugs-forum.com/forum/showthread.php?t=25560
  28. ^ a b c d e f http://www.drugs-forum.com/forum/showthread.php?t=87079
  29. ^ http://www.bmgfj.gv.at/cms/site/pres...S1229603682504
  30. ^ Canada. Department of Justice. Controlled Drugs and Substances Act. 20 May 2009. Department of Justice Canada. 10 June 2009 <http://laws.justice.gc.ca/en/ShowFullDoc/cs/C-38.8//20090609/en>.
  31. ^ Heath, Richard. "Ban on Spice Sale." This is Jersey 7 Nov. 2008. Jersey Evening Post. 10 June 2009 <http://www.thisisjersey.com/2008/11/07/ban-on-spice-sale/>.
  32. ^ http://www.legifrance.gouv.fr/jopdf/...&pageFin=03495
  33. ^ http://www.bgblportal.de/BGBL/bgbl1f/bgbl109s0049.pdf
  34. ^ http://orka.sejm.gov.pl/Druki6ka.nsf/wgdruku/1547
  35. ^ http://www.rospotrebnadzor.ru/press_center/press/2510/
  36. ^ http://press.homeoffice.gov.uk/press...an-legal-highs
  37. ^ Auwarter V, Dresen S, Weinmann W, Muller M, Putz M, Ferreiros N. “Spice” and other herbal blends: Harmless incense or cannabinoid designer drugs? Journal of Mass Spectrometry 2009.
  38. ^ Analogs of JWH-018 illegal?
  39. ^ DEA Notice of Intent - Scheduling of synthetic cannabinoids
  40. ^ DEA moves to emergency control synthetic marijuana
  41. ^ US Legal Status of Synthetic Cannabinoids by State
  42. ^ JWH-x bans, direct link to State Bills


Created by Shampoo, 08-06-2009 at 21:41
Last edited by Alfa, 18-11-2012 at 17:04
Last comment by Phenoxide on 03-12-2010 at 17:16
8 Comments, 236,622 Views

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