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JWH-018

Discussion in 'Drug Articles' started by Shampoo, Jun 8, 2009.

  1. Shampoo

    Shampoo entity of sorts Staff Member

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    JWH-018 is a synthetic cannabinoid that binds CB1 and CB2 receptors, with a moderate selectivity for the CB2 receptor and produces effects consistent with naturally occuring cannabinoids with THC. Dr. John W. Huffman first synthesized it, and it has been found in herbal smoking blends like Spice.

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

    https://www.drugs-forum.com/forum/attachment.php?attachmentid=21218&d=1310117012[/IMG]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].

    Using JWH-018

    In progress

    Routes of Administration


    Topical

    Internal

    Parenteral


    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.

    Pharmacology and Pharmacokinetics of JWH-018


    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]

    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].

    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].

    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].

    Half-Life of JWH-018

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

    Dangers of JWH-018


    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.

    Cytotoxicity


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

    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].

    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].

    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].

    Forms of JWH-018


    Pure JWH-018


    Chemical characteristics


    Column 1 Column 2
    Systematic (IUPAC) name: naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone
    Synonyms: AM678, 1-pentyl-3-(1-naphthoyl)indole
    Molecular Formula: C[sub]24[/sub]H[sub]23[/sub]NO
    Molar mass: 341.45 g/mol [2]
    CAS Registry Number: 209414-07-3
    Melting Point: 51.9 °C [1]
    Boiling Point:
    Flash Point: no data
    Solubility:
    Additionnal data:
    Notes: aspect : off-white powder [1]


    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]

    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].

    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].

    Other JWH-018 containing herbal blends


    Confirmed


    Buddha Melt [21]
    Buddha Blend [22]

    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]


    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]

    Austria

    JWH-018 is illegal in Austria. [29]

    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].

    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].

    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.

    Chile

    JWH-018 is illegal in Chile [28].

    Finland

    JWH-018 is illegal in Finland as of 2012.

    France

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

    Germany

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

    Luxembourg

    JWH-018 is illegal in Luxembourg [28].

    Netherlands

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

    Poland

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

    Romania

    JWH-018 is illegal in Romania [28].

    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].

    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]

    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]

    [​IMG]

    The history of JWH-018

    In progress

    [insights]jwh-018[/insights]


    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.

    The latest JWH-018 threads

    [showthreads=10]336[/showthreads]

    [CAT]Cannabinoids[/CAT] [CAT]Research Chemicals[/CAT] [CAT]Relaxants[/CAT]
    [CAT]Naphthoylindoles[/CAT]

    References

    1. ^ a b c d eAung, 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 bStafford, 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 eMouse99. JWH-018 Repeat Rat Toxicity. Raw data. Netherlands. 18 Dec. 2008.
    5. ^ a b c dMouse99. 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 fMouse99. 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 bCayman 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. ^https://drugs-forum.com/forum/sho...04&postcount=6
    16. ^https://drugs-forum.com/forum/sho...374#post614374
    17. ^ a bTHC 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. ^https://drugs-forum.com/forum/showthread.php?t=73649
    21. ^https://drugs-forum.com/forum/showthread.php?t=85201
    22. ^https://drugs-forum.com/forum/showthread.php?t=86350
    23. ^https://drugs-forum.com/forum/showthread.php?t=83048
    24. ^https://drugs-forum.com/forum/showthread.php?t=44182
    25. ^https://drugs-forum.com/forum/showthread.php?t=60209
    26. ^https://drugs-forum.com/forum/showthread.php?t=50857
    27. ^ a b c d ehttps://drugs-forum.com/forum/showthread.php?t=25560
    28. ^ a b c d e fhttps://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. ^[DLMURL]http://www.rospotrebnadzor.ru/press_center/press/2510/[/URL]
    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

    [1] JWH-018 monograph
    [2] Calculated from Atomic Weights of the Elements, 2007
     
    Last edited by a moderator: Dec 2, 2010
  2. Bajeda

    Bajeda Super Moderator Platinum Member & Advisor Supporter

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    Regarding references:

    [6] Mouse99. JWH-018 Rat Pharmacokinetics. Raw data. Netherlands. 18 Dec. 2008.
    [7] Mouse99. JWH-018 Analysis. Raw data. Netherlands. 18 Dec. 2008.
    [8] Mouse99. JWH-018 Repeat Rat Toxicity. Raw data. Netherlands. 18 Dec. 2008.
    [9] Mouse99. JWH-018 Genotoxicity. Raw data. Netherlands. 18 Dec. 2008.
    [10] Mouse99. JWH-018 Cytotoxicity. Raw data. Netherlands. 18 Dec. 2008.
    [11] Mouse99. JWH-018 CYP450 Inhibition. Raw data. Netherlands. 18 Dec. 2008.
    [12] Mouse99. hERG: In vitro Test For The Potential of QT Interval Prolongation by JWH-018. Raw data. Netherlands. 18 Dec. 2008.


    Whats the 'Mouse99' bit at the start of each citation?
     
  3. Alfa

    Alfa Productive Insomniac Staff Member Administrator

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    That's the name of the member that uploaded the files to the archive. See the JWH-018 toxicology studies thread.
     
  4. runitsthepolice

    runitsthepolice Silver Member

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    The part about the legal status in the USA needs to be amended. In order for something to be considered an analog it has to be both a positional isomer and have similar pharmacological effects. If either condition is not satisfied it doesn't fall under the CSA. It is not a positional isomer so it's legal to possess in the USA. Also, it must be intended for human consumption, even if those two are satisfied.
     
  5. Phenoxide

    Phenoxide Super Moderator Staff Member

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    I've updated the information on legal status in the UK and Brazil based on what has been said in the forum. If anyone feels this information is incorrect please rectify it.
     
  6. Alfa

    Alfa Productive Insomniac Staff Member Administrator

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    Can someone update the legal status of JWH-018 in various countries and US states and include phenoxides legal map?
     
  7. Phenoxide

    Phenoxide Super Moderator Staff Member

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    The map has been added along with the recent developments in US federal law. I've also changed the legal status for Argentina as there seems to be some ambiguity there. The news article titled 'Argentina bans Spice' seemed to be more of a condemnation and warning rather than official legal change. Perhaps some spanish speaking members could throw some more light on this one?
     
  8. NeuroChi

    NeuroChi is not his mind Platinum Member & Advisor

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    Phenoxide, did you use a photo editing program and just a fill tool to generate this map?

    I'm wondering if we could someone use it as a standard for other such maps should other members be up for creating them. We would need a blank one I assume, the color's can be the same as the ones you've chosen.
     
  9. Phenoxide

    Phenoxide Super Moderator Staff Member

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    The map was made in Paint Shop Pro (Photoshop is too much for my small brain to handle). The base map was taken off the net and is not vectorized, so it doesn't color cleanly if the fill tool is used. I use a second layer to color the states in, outlining each with the brush tool then filling, which does not take very long to do. I also use additional layers for the state labels and Drugs-Forum watermark.

    If you want I can save the layers individually and send them to you. Then they can be stacked back together in your photo editing software of choice.