Tetrahydrocannabinol: Difference between revisions
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==Toxicity== acurately quoted the cited FDA paper. |
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{{Short description|Psychoactive component of cannabis}} |
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{{Redirect|THC}} |
{{Redirect|THC}} |
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{{For|the phytocannabinoid homologue of THC, that is much more potent than THC itself|Tetrahydrocannabiphorol{{!}}Tetrahydrocannabiphorol (THCP)}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{Drugbox |
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{{Infobox drug |
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| verifiedrevid = 418794368 |
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| Verifiedfields = changed |
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| IUPAC_name = (−)-(6a''R'',10a''R'')-6,6,9-trimethyl-<br />3-pentyl-6a,7,8,10a-tetrahydro-<br />6''H''-benzo[''c'']chromen-1-ol |
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| Watchedfields = changed |
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| image = Tetrahydrocannabinol.svg |
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| verifiedrevid = 420242758 |
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| width = 200px |
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| drug_name = Tetrahydrocannabinol |
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| imagename = |
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| INN = dronabinol |
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| image2 = Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls.png |
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| type = |
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| drug_name = Tetrahydrocannabinol (THC) |
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| image = THC.svg |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| width = |
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| alt = |
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| caption = |
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| image2 = Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls.png |
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| width2 = <!-- Clinical data --> |
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| tradename = Marinol, Syndros |
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| MedlinePlus = |
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| licence_EU = <!-- EMEA requires brand name --> |
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| licence_US = Dronabinol |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = C |
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| pregnancy_category = |
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| addiction_liability = Relatively low: 9% |
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| dependency_liability = [[Physical dependence|Physical]]: Low <br />[[Psychological dependence|Psychological]]: Low–moderate |
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| routes_of_administration = By mouth, topical, transdermal, sublingual, inhalation |
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| class = [[Cannabinoid]] |
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<!-- Legal status -->| legal_AU = Unscheduled: ACT, Schedule 8 (Controlled Drug) |
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| legal_BR = Dronabinol: [[Brazilian Controlled Drugs and Substances Act#Class A3|A3]]; THC <30mg/ml: [[Brazilian Controlled Drugs and Substances Act#Class A3|A3]]; others: [[Brazilian Controlled Drugs and Substances Act#Class F2|F2]] (prohibited). |
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| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-07-25}}</ref> |
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| legal_CA = Unscheduled |
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| legal_DE = Dronabinol: [[Anlage III]], Δ9-THC: [[Anlage II|II]], other isomers and their stereochemical variants: [[Anlage I|I]]. |
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| legal_DE_comment = (Does not apply to THC as part of cannabis, which is regulated separately, see [[Cannabis (drug)]]) |
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| legal_UK = Class B |
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| legal_US_comment = [[Controlled Substances Act#Schedule II|Schedule II]] as Syndros, and [[Controlled Substances Act#Schedule III|Schedule III]] as Marinol<ref>{{Cite web |url=https://www.fda.gov/ohrms/dockets/dockets/05n0479/05N-0479-emc0004-04.pdf |title=Marinol |website=[[Food and Drug Administration]] |access-date=2014-03-14 |archive-url=https://web.archive.org/web/20140513204010/https://www.fda.gov/ohrms/dockets/dockets/05n0479/05N-0479-emc0004-04.pdf |archive-date=2014-05-13 }}</ref> [[Controlled Substances Act#Schedule I|Schedule I]] delta-9 tetrahydrocannabinol in pure form. |
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| legal_UN = P I |
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| legal_UN_comment = /II |
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| legal_status = In general Rx-only |
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<!-- Pharmacokinetic data -->| bioavailability = 10–35% (inhalation), 6–20% (oral)<ref name="pmid12648025">{{cite journal | vauthors = Grotenhermen F | title = Pharmacokinetics and pharmacodynamics of cannabinoids | journal = Clinical Pharmacokinetics | volume = 42 | issue = 4 | pages = 327–60 | year = 2003 | pmid = 12648025 | doi = 10.2165/00003088-200342040-00003 | s2cid = 25623600 }}</ref> |
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| protein_bound = 97–99%<ref name="pmid12648025" /><ref name = Martindale>{{cite book|chapter=Cannabis |title=Martindale: The Complete Drug Reference: Single User |author=The Royal Pharmaceutical Society of Great Britain | veditors = Sweetman SC |publisher=Pharmaceutical Press |edition=35th |isbn=978-0-85369-703-9 |year=2006}}{{page needed|date=January 2014}}</ref><!--I'm not the original editor; but this appears to be a copy of https://books.google.com/books?id=5T8AGQAACAAJ--><ref>{{cite web |title=Tetrahydrocannabinol – Compound Summary |url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16078&loc=ec_rcs#x332 |work=National Center for Biotechnology Information |publisher=PubChem |access-date=12 January 2014 |quote=Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%. |archive-date=12 January 2014 |archive-url=https://web.archive.org/web/20140112050616/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16078&loc=ec_rcs#x332 |url-status=live }}</ref> |
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| metabolism = Mostly hepatic by CYP2C<ref name="pmid12648025" /> |
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| metabolites = |
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| onset = |
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| elimination_half-life = 1.6–59 h,<ref name="pmid12648025" /> 25–36 h (orally administered dronabinol) |
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| duration_of_action = |
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| excretion = 65–80% (feces), 20–35% (urine) as acid metabolites<ref name="pmid12648025" /> |
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<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 1972-08-3 |
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| ATC_prefix = A04 |
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| ATC_suffix = AD10 |
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| PubChem = 16078 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 66964 |
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| IUPHAR_ligand = 2424 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00470 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 15266 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 7J8897W37S |
| UNII = 7J8897W37S |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00306 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL |
| ChEMBL = 465 |
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| synonyms = (6a''R'',10a''R'')-delta-9-Tetrahydrocannabinol; (−)-''trans''-Δ<sup>9</sup>-Tetrahydrocannabinol; THC |
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| InChI = 1/C21H30O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h11-13,16-17,22H,5-10H2,1-4H3/t16-,17-/m1/s1 |
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| InChIKey = CYQFCXCEBYINGO-IAGOWNOFBK |
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<!-- Chemical data -->| IUPAC_name = (6a''R'',10a''R'')-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6''H''-benzo[''c'']chromen-1-ol |
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| C = 21 |
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| H = 30 |
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| O = 2 |
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| SMILES = CCCCCc1cc(c2c(c1)OC([C@H]3[C@H]2C=C(CC3)C)(C)C)O |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI |
| StdInChI = 1S/C21H30O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h11-13,16-17,22H,5-10H2,1-4H3/t16-,17-/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey |
| StdInChIKey = CYQFCXCEBYINGO-IAGOWNOFSA-N |
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| CAS_number = 1972-08-3 |
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<!-- Physical data -->| boiling_point = 155–157 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| boiling_notes = 0.05mmHg,<ref>{{cite journal| vauthors = Gaoni Y, Mechoulam R |title=Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish|journal=Journal of the American Chemical Society|date=April 1964|volume=86|issue=8|pages=1646–47|doi=10.1021/ja01062a046}}</ref> 157–160°C @ 0.05mmHg<ref>{{cite journal| vauthors = Adams R, Cain CK, McPhee WD, Wearn RB |title=Structure of Cannabidiol. XII. Isomerization to Tetrahydrocannabinols|journal=Journal of the American Chemical Society|date=August 1941|volume=63|issue=8|pages=2209–13|doi=10.1021/ja01853a052}}</ref> |
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| ChemSpiderID = 15266 |
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| solubility = 0.0028 |
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| CAS_supplemental = |
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| sol_units = mg/mL (23 °C)<ref name='Garrett1974' /> |
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| ATC_prefix = A04 |
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| specific_rotation = −152° (ethanol) |
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| ATC_suffix = AD10 |
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| ATC_supplemental = |
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| PubChem = 16078 |
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| DrugBank = DB00470 |
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| chemical_formula = |
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| C=21 | H=30 | O=2 |
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| molecular_weight = 314.45 |
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| smiles = CCCCCc1cc(c2c(c1)OC([C@H]3[C@H]2C=C(CC3)C)(C)C)O |
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| synonyms = Dronabinol |
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| density = |
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| melting_point = |
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| melting_high = |
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| melting_notes = |
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| boiling_point = 157 |
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| boiling_notes = <ref>{{Cite web |
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|url=http://www.omma1998.org/McPartland-Russo-JCANT%201(3-4)-2001.pdf |
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|title=Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? |
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|publisher=www.haworthpress.com |
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|accessdate=2011-01-25 |
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|last= |
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|first= }}</ref> |
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| solubility = 0.0028<ref> |
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{{Cite web |
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|url=http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=Search&actionHandle=getAll3DMViewFiles&nextPage=jsp%2Fcommon%2FChemFull.jsp%3FcalledFrom%3Dlite&chemid=001972083&formatType=_3D |
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|title=ChemIDplus Lite |
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|publisher=chem.sis.nlm.nih.gov |
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|accessdate=2008-08-08 |
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|last= |
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|first= |
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}} {{Dead link|date=August 2009}} {{Verify source|date=August 2009}} |
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</ref> (23 °C) |
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| specific_rotation = -152° (ethanol) |
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| sec_combustion = |
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| bioavailability = 10-35% (inhalation), 6-20% (oral)<ref name="pmid12648025">{{Cite journal|author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref> |
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| protein_bound = 95-99%<ref name="pmid12648025"/> |
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| metabolism = mostly hepatic by CYP2C<ref name="pmid12648025"/> |
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| elimination_half-life = 1.6-59 hours,<ref name="pmid12648025"/> 25-36 hours (orally administered Dronabinol) |
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| excretion = 65-80% (feces), 20-35% (urine) as acid metabolites<ref name="pmid12648025"/> |
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| licence_EU = <!-- EMEA requires brand name --> |
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| licence_US = <!-- FDA may use generic name --> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = C |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US = |
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| legal_status = [[Controlled Substances Act|Schedule I and III]] ([[United States|US]]) |
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| dependency_liability = |
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| routes_of_administration = |
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}} |
}} |
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'''Tetrahydrocannabinol''' ('''THC''') is a [[cannabinoid]] found in [[Cannabis (drug)|cannabis]].<ref>{{cite journal | vauthors = Pichersky E, Raguso RA | title = Why do plants produce so many terpenoid compounds? | journal = The New Phytologist | volume = 220 | issue = 3 | pages = 692–702 | date = November 2018 | pmid = 27604856 | doi = 10.1111/nph.14178 | hdl = 2027.42/146372 | hdl-access = free }}</ref> It is the principal [[psychoactive drug|psychoactive constituent]] of [[cannabis]] and one of at least 113 total [[cannabinoid]]s identified on the plant. Although the [[chemical formula]] for THC (C<sub>21</sub>H<sub>30</sub>O<sub>2</sub>) describes multiple [[isomer]]s,<ref>{{Cite web|title=THC Chemistry by Alexander Shulgin - January 21, 1995|url=http://www.druglibrary.org/olsen/dea/shulgin.html|access-date=2020-11-12|website=www.druglibrary.org|archive-date=2020-11-12|archive-url=https://web.archive.org/web/20201112203812/http://www.druglibrary.org/olsen/dea/shulgin.html|url-status=live}}</ref> the term ''THC'' usually refers to the delta-9-THC isomer with chemical name '''(−)-''trans''-Δ<sup>9</sup>-tetrahydrocannabinol'''. It is a colorless oil. |
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'''Tetrahydrocannabinol''' ({{pron-en|ˌtɛtrəˌhaɪdrɵkəˈnæbɨnɒl}} {{Respell|tet-rə|HY|drə-kə|NAB|i-nol}}) ('''THC'''), also known as '''delta-9-tetrahydrocannabinol''' (Δ<sup>9</sup>-THC), '''Δ<sup>1</sup>-THC''' (using an older [[International Union of Pure and Applied Chemistry nomenclature|chemical nomenclature]]), or '''dronabinol''', is the main [[psychoactive substance]] found in the [[cannabis]] plant. There is no evidence to suggest that THC is physically addictive. |
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==Medical uses== |
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It was first isolated by [[Yechiel Gaoni]] and [[Raphael Mechoulam]] from the [[Weizmann Institute of Science]] in [[Rehovot]], [[Israel]], in [[1964]].<ref name="doi10.1021/ja01062a046">{{Cite journal |
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{{Further|Dronabinol}} |
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| last = Gaoni | first = Yechiel |
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{{Distinguish|Droperidol}} |
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| coauthors = Raphael Mechoulam |
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| title = Isolation, structure and partial synthesis of an active constituent of hashish |
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| journal = Journal of the American Chemical Society |
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| volume = 86 |
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| issue = 8 |
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| pages = 1646–1647 |
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| year = 1964 |
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| url = http://pubs.acs.org/cgi-bin/searchRedirect.cgi/jacsat/1964/86/i08/pdf/ja01062a046.pdf |
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| doi = 10.1021/ja01062a046 |
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| accessdate = 2008-05-31 |format=PDF}} {{Dead link|date=September 2010|bot=H3llBot}}</ref><ref>[http://matters.ecnp.nl/number11/interview2.shtml Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel] February 2007</ref><ref>Geller, Tom. (2007)."[http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html Cannabinoids: A Secret History]", ''Chemical Heritage Newsmagazine'', '''25''' (2)</ref> In pure form, it is a glassy solid when cold, and becomes [[viscous]] and sticky if warmed. An [[aromatic]] [[terpenoid]], THC has a very low [[solubility]] in water, but good solubility in most organic [[solvent]]s. |
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[[Medical cannabis|Medical use of cannabis]] has a long history.<ref>{{cite journal| author=Atakan Z. |title=Cannabis, a complex plant: different compounds and different effects on individuals |journal=Therapeutic Advances in Psychopharmacology |year=2012|volume=2| issue=6 |pages=241–254|doi=10.1177/2045125312457586| pmid=23983983 | pmc=3736954 }}</ref> |
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Like most pharmacologically-active [[secondary metabolite]]s of plants, THC in [[cannabis]] is assumed to be involved in [[self-defense]], perhaps against [[herbivore]]s.<ref name=Pate1994>{{Cite journal |
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THC is an [[active pharmaceutical ingredient|active ingredient]] in [[nabiximols]], a specific extract of ''[[Cannabis]]'' that was approved as a [[botanical drug]] in the [[United Kingdom]] in 2010 as a mouth spray for people with [[multiple sclerosis]] to alleviate [[neuropathic pain]], [[spasticity]], [[overactive bladder]], and other symptoms.<ref>{{cite web|title=Sativex Oromucosal Spray – Summary of Product Characteristics|url=http://www.medicines.org.uk/emc/medicine/23262|publisher=UK Electronic Medicines Compendium|language=en|date=March 2015|access-date=2017-06-01|archive-date=2016-08-22|archive-url=https://web.archive.org/web/20160822231728/http://www.medicines.org.uk/emc/medicine/23262|url-status=dead}}</ref><ref>Multiple Sclerosis Trust. October 2014 [http://www.mstrust.org.uk/information/publications/factsheets/sativex.jsp Sativex (nabiximols) – factsheet] {{Webarchive|url=https://web.archive.org/web/20150920025939/http://www.mstrust.org.uk/information/publications/factsheets/sativex.jsp |date=2015-09-20 }}</ref> Nabiximols (as Sativex) is available as a [[prescription drug]] in Canada.<ref name="canada2018">{{cite web |title=Health products containing cannabis or for use with cannabis: Guidance for the Cannabis Act, the Food and Drugs Act, and related regulations |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-cannabis-act-food-and-drugs-act-related-regulations/document.html |publisher=Government of Canada |access-date=19 October 2018 |date=11 July 2018 |archive-date=19 October 2018 |archive-url=https://web.archive.org/web/20181019121912/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-cannabis-act-food-and-drugs-act-related-regulations/document.html |url-status=live }}</ref> In 2021, nabiximols was approved for medical use in [[Ukraine]].<ref>{{cite news |url=https://life.pravda.com.ua/health/2021/04/9/244505/ |vauthors= |work=УП.Життя (UP.Life) |date=9 April 2021 |language=Ukrainian |title=В Україні легалізували використання медичного канабісу, але не всього |trans-title=In Ukraine, some medical cannabis has been legalized, but not all |access-date=10 April 2021 |archive-date=9 April 2021 |archive-url=https://web.archive.org/web/20210409202156/https://life.pravda.com.ua/health/2021/04/9/244505/ |url-status=live }}</ref> |
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| last = Pate | first = D.W. |
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| year = 1994 |
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| title = Chemical ecology of Cannabis |
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| journal = J. Int. Hemp Assoc |
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| volume = 1 |
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| issue = 29 |
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| pages = 32–37 |
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| url = http://www.kew.org/kbd/detailedresult.do?id=91816 |
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}}</ref> THC also possesses high [[Ultraviolet|UV-B]] (280-315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.<ref name=Pate1983>{{Cite journal |
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| last = Pate | first = D.W. |
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| year = 1983 |
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| title = Possible role of ultraviolet radiation in evolution of Cannabis chemotypes |
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| journal = Economic Botany |
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| volume = 37 |
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| pages = 396–405 |
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| doi =10.1007/BF02904200 |
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}}</ref><ref name=Lydon1987a>{{Cite journal |
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| last = Lydon | first = J |
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| coauthors = A.H. Teramura |
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| year = 1987 |
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| journal = Phytochemistry |
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| volume = 26 |
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| pages = 1216 |
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| doi = 10.1016/S0031-9422(00)82388-2 |
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| title = Photochemical decomposition of cannabidiol in its resin base |
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}}</ref><ref name=Lydon1987b>{{Cite journal |
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| last = Lydon | first = J |
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| coauthors = A.H. Teramura, C.B. Coffman |
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| year = 1987 |
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| journal = Photochem. Photobiol. A |
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| volume = 46 |
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| pages = 201 |
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| doi = 10.1111/j.1751-1097.1987.tb04757.x |
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| title = UV-B radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes}}</ref> |
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==Side effects== |
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Dronabinol is the [[International Nonproprietary Name]] (INN) for a pure [[isomer]] of THC, (-)-trans-Δ<sup>9</sup>-tetrahydrocannabinol, that is, the main isomer in cannabis.<ref>http://www.incb.org/pdf/e/list/green.pdf</ref> It is sold as '''Marinol''' (a registered trademark of [[Solvay (company)|Solvay Pharmaceuticals]]). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. |
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[[Side effect]]s of THC include [[red eye (medicine)|red eye]]s, [[Xerostomia|dry mouth]], [[sedation|drowsiness]], [[short-term memory]] [[memory impairment|impairment]], difficulty concentrating, [[ataxia]], [[appetite stimulant|increased appetite]], [[anxiety]], [[paranoia]], [[psychosis]] (i.e., [[Hallucination|hallucinations]], [[Delusion|delusions]]), [[Amotivational syndrome|decreased motivation]], and [[Time perception#Tachypsychia|time dilation]], among others.<ref name=":0">{{cite book | vauthors = Ng T, Keshock MC | chapter = Tetrahydrocannabinol (THC) |date=2024 | title = StatPearls | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK563174/ |access-date=2024-08-20 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=33085321 }}</ref><ref>{{Cite web |title=Short-Term Effects of Cannabis Consumption {{!}} Washington State Liquor and Cannabis Board |url=https://lcb.wa.gov/education2ch/short-term_effects_of_cannabis_consumption |access-date=2024-08-20 |website=lcb.wa.gov}}</ref> |
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Chronic usage of THC may result in [[cannabinoid hyperemesis syndrome]] (CHS), a condition characterized by cyclic nausea, vomiting, and abdominal pain that may persist for months to years after discontinuation.<ref name=":0" /> |
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==Pharmacology== |
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The [[pharmacology|pharmacological]] actions of THC result from its binding to the [[cannabinoid receptor]] [[Cannabinoid receptor type 1|CB<sub>1</sub>]], located mainly in the [[central nervous system]], and the [[Cannabinoid receptor type 2|CB<sub>2</sub>]] receptor, mainly present in cells of the [[immune system]]. It acts as a partial [[agonist]] on both receptors, i.e., it activates them but not to their full extent. The psychoactive effects of THC are mediated by its activation of the [[Cannabinoid receptor type 1|CB<sub>1</sub>]] receptor, which is the most abundant [[G protein-coupled receptor]] in the [[brain]]. |
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==Overdose== |
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The presence of these specialized receptors in the [[brain]] implied to researchers that [[endogenous]] [[cannabinoids]] are manufactured by the body, so the search began for a substance normally manufactured in the brain that binds to these receptors, the so-called natural [[ligand]] or [[agonist]], leading to the eventual discovery of [[anandamide]], 2-arachidonoyl glyceride ([[2-AG]]), and other related compounds known as [[endocannabinoid]]s. This is similar to the story of the discovery of endogenous [[opiates]] ([[endorphins]], [[enkephalins]], and [[dynorphin]]), after the realization that [[morphine]] and other opiates bind to specific receptors in the brain. In addition, it has been shown that cannabinoids, through an unknown mechanism, activate endogenous opioid pathways involving the μ<sub>1</sub> [[opioid receptor]], precipitating a [[dopamine]] release in the [[nucleus accumbens]]. The effects of the drug can be suppressed by the CB1 [[cannabinoid receptor]] antagonist [[rimonabant]] (SR141716A) as well as [[opioid receptor]] antagonists (opioid blockers) [[naloxone]] and [[naloxonazine]].<ref name="Lupica 2004">{{Cite journal |author=Lupica CR, Riegel AC, Hoffman AF |title=Marijuana and cannabinoid regulation of brain reward circuits |journal=Br. J. Pharmacol. |volume=143 |issue=2 |pages=227–34 |year=2004 |month=September |pmid=15313883 |pmc=1575338 |doi=10.1038/sj.bjp.0705931}}</ref> |
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The [[median lethal dose]] of THC in humans is not fully known as there is conflicting evidence. A 1972 study gave up to 90 mg/kg of THC to dogs and monkeys without any lethal effects. Some rats died within 72 hours after a dose of up to 36 mg/kg.<ref>{{cite journal | vauthors = Thompson GR, Rosenkrantz H, Schaeppi UH, Braude MC | title = Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys | journal = Toxicology and Applied Pharmacology | volume = 25 | issue = 3 | pages = 363–72 | date = July 1973 | pmid = 4199474 | doi = 10.1016/0041-008X(73)90310-4 | bibcode = 1973ToxAP..25..363T | quote = In dogs and monkeys, single oral doses of Δ9-THC and Δ8-THC between 3000 and 9000/mg/kg were nonlethal.}}</ref> A 2014 case study based on the toxicology reports and relative testimony in two separate cases gave the median lethal dose in humans at 30 mg/kg (2.1 grams THC for a person who weighs 70 kg; 154 lb; 11 stone), observing [[cardiovascular]] death in the one otherwise healthy subject of the two cases studied.<ref>{{cite journal | vauthors = Hartung B, Kauferstein S, Ritz-Timme S, Daldrup T | title = Sudden unexpected death under acute influence of cannabis | journal = Forensic Science International | volume = 237 | pages = e11–e13 | date = April 2014 | pmid = 24598271 | doi = 10.1016/j.forsciint.2014.02.001 }}</ref> A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.<ref>{{cite journal |vauthors=Nahas GC |title=UNODC - Bulletin on Narcotics - 1972 Issue 2 - 002 |journal=United Nations: Office on Drugs and Crime |date=1 January 1972 |pages=11–27 |url=https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1972-01-01_2_page003.html |language=en |access-date=2022-12-11 |archive-date=2022-12-11 |archive-url=https://web.archive.org/web/20221211181839/https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1972-01-01_2_page003.html |url-status=live }}</ref> |
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==Interactions== |
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The mechanism of endocannabinoid synaptic transmission is thought to occur as follows: First, transmission of the excitatory neurotransmitter [[glutamate]] causes an influx of [[calcium]] ions into the [[post-synaptic]] neuron. Through a mechanism not yet fully understood, the presence of post-synaptic calcium induces the production of endocannabinoids in the post-synaptic neuron. These endocannabinoids (such as anandamide), then, are released into the synaptic cleft, where binding occurs at cannabinoid receptors present on pre-synaptic neurons, where they modulate neurotransmission. Thus, this form of neurotransmission is termed [[retrograde signaling|retrograde transmission]], as the signal is carried in the opposite direction of orthodox propagation, which previously was thought to be exclusively one way. |
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Formal [[drug interaction|drug–drug interaction]] studies with THC have not been conducted and are limited.<ref name="MarinolLabel2023" /><ref name="pmid30001569" /> The [[elimination half-life]] of the [[barbiturate]] [[pentobarbital]] has been found to increase by 4{{nbsp}}hours when concomitantly administered with oral THC.<ref name="MarinolLabel2023" /> |
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==Pharmacology== |
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THC has mild to moderate [[analgesic]] effects, and [[cannabis]] can be used to treat pain. The mechanism for analgesic effects caused directly by THC or other cannabinoid agonists is not fully understood. Other effects include relaxation; [[euphoria]]; altered space-time perception; alteration of visual, auditory, and olfactory senses; loss of anxiety;<ref name="norml.org">http://norml.org/index.cfm?Group_ID=3472</ref> anxiety in neurotic individuals or individuals unfamilar with effects;<ref name="norml.org"/> disorientation;<ref name="norml.org"/> fatigue; and [[Effects of cannabis#Appetite|appetite stimulation]] (colloquially known as "the munchies"). The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis.{{Citation needed|date=February 2011}} CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone [[ghrelin]] increase prior to consuming a meal. After chyme is passed into the [[duodenum]], signaling [[hormone]]s such as [[cholecystokinin]] and [[leptin]] are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release. It also has [[anti-emetic]] properties, and also may reduce aggression in certain subjects. |
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{{See also|Effects of cannabis|Long-term effects of cannabis|Cannabis in pregnancy}} |
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===Mechanism of action=== |
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THC has an active [[metabolite]], [[11-Hydroxy-THC]], which may also play a role in the analgesic and recreational effects of [[cannabis]]. |
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{{For|a review of the mechanisms behind endocannabinoid synaptic transmission|Endocannabinoid system}} |
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The actions of Delta-9-THC result from its [[partial agonist]] activity at the [[cannabinoid receptor]] [[Cannabinoid receptor type 1|CB<sub>1</sub>]] (K<sub>i</sub> = 40.7 nM<ref name="Bow & Rimoldi 2016">{{cite journal | vauthors = Bow EW, Rimoldi JM | title = The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation | journal = Perspectives in Medicinal Chemistry | volume = 8 | pages = 17–39 | date = 28 June 2016 | pmid = 27398024 | pmc = 4927043 | doi = 10.4137/PMC.S32171 }}</ref>), located mainly in the [[central nervous system]], and the [[Cannabinoid receptor type 2|CB<sub>2</sub>]] receptor (K<sub>i</sub> = 36 nM<ref name="Bow & Rimoldi 2016"/>), mainly expressed in cells of the [[immune system]].<ref name="pmid16570099">{{cite journal | vauthors = Pertwee RG | title = The pharmacology of cannabinoid receptors and their ligands: an overview | journal = International Journal of Obesity | volume = 30 | issue = Suppl 1 | pages = S13–S18 | date = April 2006 | pmid = 16570099 | doi = 10.1038/sj.ijo.0803272 | doi-access = free }}</ref> The psychoactive effects of THC are primarily mediated by the activation of (mostly G-coupled) cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule [[cyclic adenosine monophosphate|cAMP]] through inhibition of [[adenylate cyclase]].<ref name="pmid11316486">{{cite journal | vauthors = Elphick MR, Egertová M | title = The neurobiology and evolution of cannabinoid signalling | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1407 | pages = 381–408 | date = March 2001 | pmid = 11316486 | pmc = 1088434 | doi = 10.1098/rstb.2000.0787 }}</ref> The presence of these specialized cannabinoid receptors in the [[brain]] led researchers to the discovery of [[endocannabinoids]], such as [[anandamide]] and 2-arachidonoyl glyceride ([[2-AG]]).{{Citation needed|date=December 2020}} |
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The α<sub>7</sub> nicotinic receptor antagonist [[methyllycaconitine]] can block self-administration of THC in rats comparable to the effects of [[varenicline]] on nicotine administration.<ref>"Plant extract may block cannabis addiction" http://www.newscientist.com/article/dn11904-plant-extract-may-block-cannabis-addiction-.html</ref><ref>{{Cite journal |author=Solinas M, Scherma M, Fattore L, ''et al.'' |title=Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse |journal=J. Neurosci. |volume=27 |issue=21 |pages=5615–20 |year=2007 |month=May |pmid=17522306 |doi=10.1523/JNEUROSCI.0027-07.2007}}</ref> |
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THC is a [[lipophilic]] molecule<ref>{{cite journal | vauthors = Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA | title = Hydroxylation and further oxidation of delta9-tetrahydrocannabinol by alkane-degrading bacteria | journal = Applied and Environmental Microbiology | volume = 75 | issue = 22 | pages = 7135–41 | date = November 2009 | pmid = 19767471 | pmc = 2786519 | doi = 10.1128/AEM.01277-09 | quote = Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-[[octanol-water partition coefficient]] (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reverse-phase high-performance liquid chromatography estimation. | bibcode = 2009ApEnM..75.7135R }}</ref> and may bind non-specifically to a variety of entities in the brain and body, such as [[adipose tissue]] (fat).<ref>{{cite journal | vauthors = Ashton CH | title = Pharmacology and effects of cannabis: a brief review | journal = The British Journal of Psychiatry | volume = 178 | issue = 2 | pages = 101–06 | date = February 2001 | pmid = 11157422 | doi = 10.1192/bjp.178.2.101 | quote = Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas. | doi-access = free }}</ref><ref>{{cite journal | vauthors = Huestis MA | title = Human cannabinoid pharmacokinetics | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1770–804 | date = August 2007 | pmid = 17712819 | pmc = 2689518 | doi = 10.1002/cbdv.200790152 | quote = THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver. }}</ref> THC, as well as other cannabinoids that contain a phenol group, possess mild [[antioxidant]] activity sufficient to protect neurons against [[oxidative stress]], such as that produced by [[glutamate]]-induced [[excitotoxicity]].<ref name="pmid16570099" /> |
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Two studies indicate that THC also has an anticholinesterase action <ref>"Possible anticholinesterase-like effects of trans(-) 8 and - 9 tetrahydrocannabinol as observed in the general motor activity of mice.http://www.ncbi.nlm.nih.gov/pubmed/4638205</ref><ref>"A molecular link between the active component of marijuana and Alzheimer's disease pathology."http://www.ncbi.nlm.nih.gov/pubmed/17140265?dopt=AbstractPlus</ref> which may implicate it as a potential treatment for [[Alzheimer's]] and [[Myasthenia Gravis]]. |
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THC targets receptors in a manner far less selective than endocannabinoid molecules released during [[retrograde signaling]], as the drug has a relatively low cannabinoid receptor affinity. THC is also limited in its efficacy compared to other cannabinoids due to its partial agonistic activity, as THC appears to result in greater [[downregulation]] of cannabinoid receptors than [[endocannabinoid]]s. Furthermore, in populations of low cannabinoid receptor density, THC may even act to antagonize endogenous agonists that possess greater receptor efficacy. However while THC's pharmacodynamic tolerance may limit the maximal effects of certain drugs, evidence suggests that this tolerance mitigates undesirable effects, thus enhancing the drug's therapeutic window.<ref name="pmid17828291">{{cite journal | vauthors = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | date = January 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}</ref> |
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==Toxicity== |
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[[Image:Thc.pdb.gif|thumb|3D rendering of the THC molecule]] |
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[[Image:Kolkata-Kut.jpg|thumb|A ''Cannabis sativa'' flower coated with [[trichomes]], which contain more THC than any other part of the plant]] |
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{{See also|Health issues and effects of cannabis}} |
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Recently, it has been shown that THC is also a partial [[autotaxin]] inhibitor, with an apparent IC50 of 407 ± 67 nM for the ATX-gamma isoform.<ref>{{cite journal | vauthors = Eymery MC, McCarthy AA, Hausmann J | title = Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling | journal = Life Science Alliance | volume = 6 | issue = 2 | pages = e202201595 | date = February 2023 | pmid = 36623871 | pmc = 9834664 | doi = 10.26508/lsa.202201595 }}</ref> THC was also co-crystallized with autotaxin, deciphering the binding interface of the complex. These results might explain some of the effects of THC on inflammation and neurological diseases, since autotaxin is responsible of LPA generation, a key lipid mediator involved in numerous diseases and physiological processes. However, clinical trials need to be performed in order to assess the importance of ATX inhibition by THC during medicinal cannabis consumption. |
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There has never been a documented human fatality from overdosing on tetrahydrocannabinol or cannabis in its natural form.<ref name="Walker and Huang">{{Cite journal |author=Walker JM, Huang SM |title=Cannabinoid analgesia |journal=Pharmacol. Ther. |volume=95 |issue=2 |pages=127–35 |year=2002 |month=August |pmid=12182960 |quote=...to date, there are no deaths known to have resulted from overdose of cannabis. (p. 128) |doi=10.1016/S0163-7258(02)00252-8}}</ref> However, the THC pill [[Marinol]] was cited by the FDA as being responsible for 4 of the 11,687 deaths from 17 different FDA approved drugs between January 1, 1997 to June 30, 2005. <ref>{{cite web |url=http://www.oregon.gov/Pharmacy/Imports/Marijuana/Public/DeathsFromMarijuanaV17FDAdrugs.pdf |title=Deaths from Marijuana v. 17 FDA-Approved Drugs |date=2005-06-30 |format=pdf |accessdate=2011-02-03 }}</ref> Information about THC's [[toxicity]] is derived from animal studies. The toxicity depends on the route of administration and the laboratory animal. Absorption is limited by [[serum lipids]], which can become saturated with THC, mitigating toxicity.<ref name="ErowidMSDS">[http://www.erowid.org/plants/cannabis/thc_data_sheet.shtml Erowid Cannabis Vault : THC Material Safety Data Sheet<!-- Bot generated title -->]</ref> According to the [[Merck Index]], 12th edition, THC has an {{LD50}} (dose killing half of the research subjects) value of 1270 [[Milligram|mg]]/[[Kilogram|kg]] (male rats) and 730 mg/kg (female rats) administered orally dissolved in [[sesame oil]].<ref name="Erowid">{{Cite web |url=http://www.erowid.org/plants/cannabis/cannabis_chemistry.shtml |title=Cannabis Chemistry |author=Erowid |accessdate=2006-03-20}}</ref> The LD<sub>50</sub> value for rats by inhalation of THC is 42 mg/kg of body weight.<ref name="Erowid" /> One estimate of THC's LD<sub>50</sub> for humans indicates that about {{convert|1500|lb|kg}} of cannabis would have to be smoked within 14 minutes.<ref>{{Cite journal |author=Annas GJ |title=Reefer madness--the federal response to California's medical-marijuana law |journal=N. Engl. J. Med. |volume=337 |issue=6 |pages=435–9 |year=1997 |month=August |pmid=9241134 |doi=10.1056/NEJM199708073370621}}</ref> This estimate is supported by studies which indicate that the effective dose of THC is at least 1000 times lower than the estimated lethal dose (a "[[therapeutic ratio]]" of 1000:1). This is much higher than [[alcoholic beverage|alcohol]] (therapeutic ratio 10:1), [[cocaine]] (15:1), or [[heroin]] (6:1).<ref name=Gable2004>{{Cite journal |
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| last = Gable | first = R.S. |
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| year = 2004 |
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| title = Comparison of acute lethal toxicity of commonly abused psychoactive substances |
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| journal = Addiction |
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| volume = 99 |
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| issue = 6 |
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| pages = 686–696 |
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| doi = 10.1111/j.1360-0443.2004.00744.x |
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| url = http://web.cgu.edu/faculty/gabler/toxicity%20Addiction%20offprint.pdf |
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|format=PDF |
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| pmid = 15139867}}</ref> |
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===Pharmacokinetics=== |
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{| class="wikitable" |
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====Absorption==== |
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|- |
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With oral administration of a single dose, THC is almost completely [[absorption (pharmacokinetics)|absorbed]] by the [[gastrointestinal tract]].<ref name="MarinolLabel2023">https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/018651s033lbl.pdf {{Bare URL PDF|date=August 2024}}</ref> However, due to [[first-pass metabolism]] in the [[liver]] and the high [[lipid solubility]] of THC, only about 5 to 20% reaches circulation.<ref name="pmid12648025" /><ref name="MarinolLabel2023" /> Following oral administration, concentrations of THC and its major [[active metabolite]] [[11-hydroxy-THC]] (11-OH-THC) [[Tmax (pharmacology)|peak]] after 0.5 to 4{{nbsp}}hours, with median time to peak of 1.0 to 2.5{{nbsp}}hours at different doses.<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> In some cases, peak levels may not occur for as long as 6{{nbsp}}hours.<ref name="pmid12648025" /> Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration.<ref name="MarinolLabel2023" /> There is a slight increase in [[dose proportionality]] in terms of [[Cmax (pharmacology)|peak]] and [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] levels of THC with increasing oral doses over a range of 2.5 to 10{{nbsp}}mg.<ref name="MarinolLabel2023" /> A high-fat meal delays time to peak concentrations of oral THC by 4{{nbsp}}hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.<ref name="MarinolLabel2023" /> A high-fat meal additionally increases absorption of THC via the [[lymphatic system]] and allows it to bypass first-pass metabolism.<ref name="pmid35523678">{{cite journal | vauthors = Tagen M, Klumpers LE | title = Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC | journal = Br J Pharmacol | volume = 179 | issue = 15 | pages = 3915–3933 | date = August 2022 | pmid = 35523678 | doi = 10.1111/bph.15865 | url = | doi-access = free }}</ref> Consequently, a high-fat meal increases levels of 11-hydroxy-THC by only 25% and most of the increase in [[bioavailability]] is due to increased levels of THC.<ref name="pmid35523678" /> |
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! Animal |
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! Administration |
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! LD<sub>50</sub> [mg/kg] |
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|- |
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| rat |
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| oral |
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| 666 <ref name="ErowidMSDS" /> |
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|- |
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| rat (male) |
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| oral |
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| 1270 <ref name="Erowid" /> |
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|- |
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| rat (female) |
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| oral |
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| 730 <ref name="Erowid" /> |
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|- |
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| rat |
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| inhalation |
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| 42 <ref name="Erowid" /> |
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|- |
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| rat |
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| intraperitoneal |
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| 373 <ref name="ErowidMSDS" /> |
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|- |
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| rat |
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| intravenous |
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| 29 <ref name="ErowidMSDS" /> |
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|- |
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| mouse |
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| intravenous |
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| 42 <ref name="ErowidMSDS" /> |
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|- |
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| mouse |
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| oral |
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| 482 <ref name="ErowidMSDS" /> |
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|- |
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| mouse |
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| intraperitoneal |
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| 168 <ref name="ErowidMSDS" /> |
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|- |
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| monkey ([[LDLo]]) |
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| intravenous |
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| 128 <ref name="ErowidMSDS" /> |
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|- |
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| dog |
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| oral |
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| 525 <ref name="ErowidMSDS" /> |
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|- |
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|} |
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The bioavailability of THC when [[smoking]] or [[inhalational administration|inhaling]] is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%).<ref name="pmid30001569">{{cite journal | vauthors = Lucas CJ, Galettis P, Schneider J | title = The pharmacokinetics and the pharmacodynamics of cannabinoids | journal = Br J Clin Pharmacol | volume = 84 | issue = 11 | pages = 2477–2482 | date = November 2018 | pmid = 30001569 | pmc = 6177698 | doi = 10.1111/bcp.13710 | url = }}</ref><ref name="pmid31152723">{{cite journal | vauthors = Foster BC, Abramovici H, Harris CS | title = Cannabis and Cannabinoids: Kinetics and Interactions | journal = Am J Med | volume = 132 | issue = 11 | pages = 1266–1270 | date = November 2019 | pmid = 31152723 | doi = 10.1016/j.amjmed.2019.05.017 | s2cid = 173188471 | url = }}</ref><ref name="pmid12648025" /> The large range and marked [[interindividual variability|variability between individuals]] is due to variation in factors including product matrix, ignition temperature, and inhalational dynamics (e.g., number, duration, and intervals of inhalations, breath hold time, depth and volume of inhalations, size of inhaled particles, deposition site in the lungs).<ref name="pmid30001569" /><ref name="pmid31152723" /> THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10{{nbsp}}minutes.<ref name="pmid12648025" /><ref name="pmid31152723" /> Smoking or inhaling THC results in greater blood levels of THC and its metabolites and a much faster [[onset of action]] than oral administration of THC.<ref name="pmid30001569" /><ref name="pmid31152723" /> Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" /> The bioavailability of THC with inhalation is increased in heavy users.<ref name="pmid12648025" /> |
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==Research== |
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The discovery of THC was first described in "Isolation, structure and partial synthesis of an active constituent of hashish", published in the [[Journal of the American Chemical Society]] in 1964.<ref name="doi10.1021/ja01062a046" /> Research was also published in the [[academic journal]] ''[[Science (journal)|Science]]'', with "Marihuana chemistry" by [[Raphael Mechoulam]] in June 1970,<ref>{{Cite journal |
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| last = Mechoulam | first = Raphael |
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| title = Marijuana Chemistry |
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| journal = Science |
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| volume = 168 |
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| issue = 3936 |
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| pages = 1159–1165 |
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| date = 5 June 1970 |
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| url = http://www.sciencemag.org/cgi/content/citation/168/3936/1159 |
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| doi = 10.1126/science.168.3936.1159 |
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| accessdate = 2008-05-31 |
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| pmid = 4910003}}</ref> followed by "Chemical basis of hashish activity" in August 1970.<ref>{{Cite journal |
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| last = Mechoulam | first = Raphael |
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| coauthors = Arnon Shani, Habib Edery, and Yona Grunfeld |
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| title = Chemical Basis of Hashish Activity |
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| journal = Science |
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| volume = 169 |
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| issue = 3945 |
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| pages = 611–612 |
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| date = 7 August 1970 |
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| url = http://www.sciencemag.org/cgi/content/abstract/169/3945/611 |
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| doi = 10.1126/science.169.3945.611 |
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| accessdate = 2008-05-31 |
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| pmid = 4987683}}</ref> In the latter, the team of researchers from [[Hebrew University of Jerusalem|Hebrew University]] Pharmacy School and [[Tel Aviv University]] Medical School experimented on monkeys to isolate the active compounds in [[hashish]]. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hashish. |
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[[Transdermal administration]] of THC is limited by its extreme [[hydrophobicity|water insolubility]].<ref name="pmid30001569" /> Efficient skin transport can only be obtained with permeation enhancement.<ref name="pmid30001569" /> Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" /> |
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===Studies in humans=== |
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A number of studies show that THC provides medical benefits for [[cancer]] and [[AIDS]] patients by increasing appetite and decreasing nausea. It has also been shown to assist some [[glaucoma]] patients by reducing pressure within the eye, and is used in the form of cannabis by a number of [[multiple sclerosis]] patients, who use it to alleviate [[neuropathic pain]] and [[spasticity]]. The [[National Multiple Sclerosis Society]] is currently supporting further research into these uses.<ref name="MS society">{{Cite web |url=http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/complementary--alternative-medicine/marijuana/index.aspx |title=Marijuana (Cannabis) |publisher=National Multiple Sclerosis Society |accessdate=2009-09-05}}</ref><br> |
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In August 2009 a [[Clinical study#Phase IV|phase IV clinical trial]] by the [[Hadassah Medical Center]] in Jerusalem, Israel was started to investigate the effects of THC on [[post-traumatic stress disorder]]s.<ref name="urlAdd on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) - Full Text View - ClinicalTrials.gov">{{Cite web |url=http://clinicaltrials.gov/ct2/show/NCT00965809 |title=Add on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) - Full Text View - ClinicalTrials.gov |format= |work= |accessdate=}}</ref> THC and other cannabinoid agonists have been shown to be beneficial both in [[Open-label trial|open label studies]], as well as in laboratory experiments with animals to ameliorate post-traumatic stress disorders.<br> |
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Preliminary research on synthetic THC has been conducted on patients with [[Tourette syndrome]], with results suggesting that it may help in reducing nervous tics and urges by a significant degree. Research on twelve patients showed that Marinol reduced tics with no significant adverse effects. A six-week controlled study on 24 patients showed that the patients taking [[dronabinol]] had a significant reduction in tic severity without serious adverse effects. More significant reduction in tic severity was reported with longer treatment. No detrimental effects on cognitive functioning and a trend towards improvement in cognitive functioning were reported during and after treatment. [[Dronabinol|Dronabinol's]] usefulness as a treatment for TS cannot be determined until/unless longer controlled studies on larger samples are undertaken.<ref>{{Cite journal | author = Müller-Vahl,K.R. Schneider,U. Koblenz,A. Jöbges,M. Kolbe,H. Daldrup,T. Emrich,H.M. | title =Treatment of Tourette's Syndrome with Δ9-Tetrahydrocannabinol (THC): A Randomized Crossover Trial | journal =Pharmacopsychiatry | volume =35 | issue =2 | pages =57–61 | pmid =11951146 | doi =10.1055/s-2002-25028 | year =2002}}</ref><ref>{{Cite journal| doi =10.4088/JCP.v64n0417 | author =Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, Emrich HM. | title =Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial | journal= J Clin Psychiatry | month = April | year = 2003 | volume =64 | issue =4 | pages =459–65 | pmid =12716250}}</ref><ref>{{Cite journal| author = Muller-Vahl KR, Prevedel H, Theloe K, Kolbe H, Emrich HM, Schneider U. | title =Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (delta 9-THC): no influence on neuropsychological performance | journal = Neuropsychopharmacology | month = February | year = 2003 | volume =28 | issue =2 | pages =384–388 | pmid =12589392 | doi =10.1038/sj.npp.1300047 }}</ref> |
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====Distribution==== |
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===Studies in animals and in vitro=== |
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The [[volume of distribution]] of THC is large and is approximately 10{{nbsp}}L/kg (range 4–14{{nbsp}}L/kg), which is due to its high lipid solubility.<ref name="MarinolLabel2023" /><ref name="pmid30001569" /><ref name="pmid31152723" /> The [[plasma protein binding]] of THC and its [[metabolite]]s is approximately 95 to 99%, with THC bound mainly to [[lipoprotein]]s and to a lesser extent [[human serum albumin|albumin]].<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> THC is rapidly distributed into well-vascularized organs such as [[lung]], [[heart]], [[brain]], and [[liver]], and is subsequently equilibrated into less vascularized tissue.<ref name="pmid30001569" /><ref name="pmid31152723" /> It is extensively distributed into and sequestered by [[adipose tissue|fat tissue]] due to its high lipid solubility, from which it is slowly released.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="pmid31152723" /> THC is able to cross the [[placenta]] and is excreted in human [[breast milk]].<ref name="pmid30001569" /><ref name="pmid12648025" /> |
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New scientific evidence is showing that THC can prevent [[Alzheimer's Disease]] in an [[animal model]] by preventing the inflammation caused by [[microglia]] cells which are activated by binding of [[amyloid]] protein.<ref name="pmid15728830">{{Cite journal |
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|author=Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán M, de Ceballos ML |
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|title=Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation |
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|journal=J. Neurosci. |
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|volume=25 |
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|issue=8 |
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|pages=1904–13 |
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|year=2005 |
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|pmid=15728830 |
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|doi=10.1523/JNEUROSCI.4540-04.2005 |
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}}</ref><br> |
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In ''[[in-vitro]]'' experiments, THC at extremely high concentrations, which could not be reached with commonly-consumed doses, caused inhibition of plaque formation (which are associated with [[Alzheimer's disease]]) better than currently-approved drugs.<ref>{{Cite journal |author=Eubanks LM, Rogers CJ, Beuscher AE, ''et al.'' |title=A molecular link between the active component of marijuana and Alzheimer's disease pathology |journal=Mol. Pharm. |volume=3 |issue=6 |pages=773–7 |year=2006 |pmid=17140265 |doi=10.1021/mp060066m |pmc=2562334}}</ref> |
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====Metabolism==== |
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THC may also be an effective anti-cancer treatment, with studies showing tumor size reduction in mice conducted in 1975<ref>Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA. [http://www.drugpolicycentral.com/bot/pg/cancer/THC_cancer_sep_1975.htm "Anticancer activity of cannabinoids."] Journal of the National Cancer Institute. September 1975;'''55'''(3):597-602. Accessed 2007-10-27.</ref> and 2007,<ref>{{Cite journal |author=Preet A, Ganju RK, Groopman JE |title=Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo |journal=Oncogene |volume=27 |issue=3 |pages=339–46 |year=2008 |month=January |pmid=17621270 |doi=10.1038/sj.onc.1210641}}</ref> as well as in a pilot study in humans with [[glioblastoma multiforme]] (a type of brain cancer).<ref>{{Cite journal|author=Guzmán M, Duarte MJ, Blázquez C, ''et al.'' |title=A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme |journal=Br. J. Cancer |volume=95 |issue=2 |pages=197–203 |year=2006 |month=July |pmid=16804518 |pmc=2360617 |doi=10.1038/sj.bjc.6603236}}</ref> |
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The [[metabolism]] of THC occurs mainly in the [[liver]] by [[cytochrome P450]] [[enzyme]]s [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]].<ref>{{cite journal | vauthors = Qian Y, Gurley BJ, Markowitz JS | title = The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications | journal = Journal of Clinical Psychopharmacology | volume = 39 | issue = 5 | pages = 462–71 | year = 2019 | pmid = 31433338 | doi = 10.1097/JCP.0000000000001089 | s2cid = 201118659 }}</ref><ref>{{cite journal | vauthors = Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I | title = Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes | journal = Life Sciences | volume = 80 | issue = 15 | pages = 1415–19 | date = March 2007 | pmid = 17303175 | doi = 10.1016/j.lfs.2006.12.032 }}</ref> CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC.<ref name="MarinolLabel2023" /> [[Pharmacogenomic]] research has found that oral THC exposure is 2- to 3-fold greater in people with [[Gene polymorphism|genetic variant]]s associated with reduced CYP2C9 function.<ref name="MarinolLabel2023" /> When taken orally, THC undergoes extensive [[first-pass metabolism]] in the liver, primarily via [[hydroxylation]].<ref name="MarinolLabel2023" /> The principal active metabolite of THC is [[11-hydroxy-THC]] (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="MarinolLabel2023" /> This metabolite is further [[oxidation|oxidized]] to [[11-nor-9-carboxy-THC]] (THC-COOH). In animals, more than 100 metabolites of THC could be identified, but 11-OH-THC and THC-COOH are the predominant metabolites.<ref name="pmid35523678" /><ref name="pmid27341312">{{cite journal | vauthors = Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A | title = Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis | journal = Drug Testing and Analysis | volume = 9 | issue = 4 | pages = 626–33 | date = April 2017 | pmid = 27341312 | doi = 10.1002/dta.1998 | s2cid = 27488987 | url = https://figshare.com/articles/journal_contribution/5028359 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025824/https://figshare.com/articles/journal_contribution/Simultaneous_quantification_of_major_cannabinoids_and_metabolites_in_human_urine_and_plasma_by_HPLC-MS_MS_and_enzymealkaline_hydrolysis/5028359 | url-status = live }}</ref> |
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====Elimination==== |
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A two-year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused [[testicular atrophy]] and uterine and ovarian [[hypoplasia]], as well as hyperactivity and convulsions immediately after administration, of which the onset and frequency were dose related.<ref>{{Cite journal |author=Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR |title=Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice |journal=Fundamental and applied toxicology : official journal of the Society of Toxicology |volume=30 |issue=1 |pages=109–17 |year=1996 |pmid=8812248 |doi=10.1006/faat.1996.0048}}</ref> |
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More than 55% of THC is [[excretion|excreted]] in the [[feces]] and approximately 20% in the [[urine]]. The main metabolite in urine is the ester of [[glucuronic acid]] and 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.<ref name="pmid16596792">{{cite journal | vauthors = Huestis MA | title = Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ<sup>9</sup>-Tetrahydrocannabinol, Cannabidiol and Cannabinol | journal = Handbook of Experimental Pharmacology | volume = 168 | issue = 168 | pages = 657–90 | year = 2005 | pmid = 16596792 | doi = 10.1007/3-540-26573-2_23 | isbn = 978-3-540-22565-2}}</ref> |
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Estimates of the [[elimination half-life]] of THC are variable.<ref name="pmid30001569" /> THC was reported to have a fast initial half-life of 6{{nbsp}}minutes and a long [[terminal half-life]] of 22{{nbsp}}hours in a [[Pharmacokinetics#Population pharmacokinetics|population pharmacokinetic]] study.<ref name="pmid30001569" /><ref name="pmid31152723" /> Conversely, the [[Food and Drug Administration]] label for dronabinol reports an initial half-life of 4{{nbsp}}hours and a terminal half-life of 25 to 36{{nbsp}}hours.<ref name="MarinolLabel2023" /> Many studies report an elimination half-life of THC in the range of 20 to 30{{nbsp}}hours.<ref name="pmid12648025" /> 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36{{nbsp}}hours relative to 25 to 36{{nbsp}}hours in one study.<ref name="pmid12648025" /> The elimination half-life of THC is longer in heavy users.<ref name="pmid30001569" /> This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.<ref name="pmid30001569" /> |
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Research in rats indicates that THC prevents [[hydroperoxide]]-induced [[oxidative damage]] as well as or better than other [[antioxidant]]s in a chemical ([[Fenton reaction]]) system and [[neuron]]al cultures.<ref name="pmid9653176">{{Cite journal |author=Hampson AJ, Grimaldi M, Axelrod J, Wink D |title=Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=14 |pages=8268–73 |year=1998 |month=July |pmid=9653176 |pmc=20965 |doi= 10.1073/pnas.95.14.8268 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9653176}}</ref> In [[mice]] low doses of Δ<sup>9</sup>-THC reduces the progression of [[atherosclerosis]].<ref name="pmid15815632">{{Cite journal |
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|author=Steffens S, Veillard NR, Arnaud C, ''et al.'' |
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|title=Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice |
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|journal=Nature |
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|volume=434 |
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|issue=7034 |
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|pages=782–6 |
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|year=2005 |
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|pmid=15815632 |
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|doi=10.1038/nature03389 |
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}}</ref> |
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==Chemistry== |
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Research has also shown that past claims of brain damage from cannabis use fail to hold up to the scientific method.<ref>{{Cite web |
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===Solubility=== |
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|title=Heavy Marijuana Use Doesn't Damage Brain |
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As with many [[aromatic]] [[terpenoid]]s, THC has a very low [[solubility]] in water, but good solubility in lipids and most organic [[solvent]]s, specifically [[hydrocarbon]]s and [[Alcohol (chemistry)|alcohol]]s.<ref name='Garrett1974'>{{cite journal | vauthors = Garrett ER, Hunt CA | title = Physiochemical properties, solubility, and protein binding of delta9-tetrahydrocannabinol | journal = Journal of Pharmaceutical Sciences | volume = 63 | issue = 7 | pages = 1056–64 | date = July 1974 | pmid = 4853640 | doi = 10.1002/jps.2600630705 }}</ref> |
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|url=http://www.webmd.com/mental-health/news/20030701/heavy-marijuana-use-doesnt-damage-brain |
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|publisher=[[WebMD]] Medical News |
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|author=Sid Kirchheimer |
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|date=July 1, 2003 |
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}}</ref> Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate [[neurogenesis]],<ref name=Jiang2005>{{Cite journal |
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| author = Jiang, W.; Zhang, Y.; Xiao, L.; Van Cleemput, J.; Ji, S.P.; Bai, G.; Zhang, X. |
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| year = 2005 |
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| title = Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic-and … |
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| journal = Journal of Clinical Investigation |
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| volume = 115 |
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| issue = 11 |
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| pages = 3104 |
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| url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1253627 |
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| publisher = American Society for Clinical Investigation |
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| doi = 10.1172/JCI25509 |
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| pmid = 16224541 |
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| pmc = 1253627 |
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}}</ref> as well as neuroprotection,<ref name=Sarne2005>{{Cite journal |
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| author = Sarne, Y.; Mechoulam, R. |
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| year = 2005 |
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| title = Cannabinoids: Between Neuroprotection and Neurotoxicity |
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| journal = Current Drug Targets-Cns and Neurological Disorders- |
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| volume = 4 |
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| issue = 6 |
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| pages = 677 |
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| doi = 10.2174/156800705774933005 |
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| url = http://www.ingentaconnect.com/content/ben/cdtcnsnd/2005/00000004/00000006/art00008 |
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| pmid = 16375685 |
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}}</ref> and can even help prevent natural neural degradation from neurodegenerative diseases such as MS, Parkinson's, and Alzheimer's. This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support.<ref name=Correa2005>{{Cite journal |
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| author = Correa, F.; Mestre, L.; Molina-holgado, E.; Arevalo-martin, A.; Docagne, F.; Romero, E.; Molina-holgado, F.; Borrell, J.; Guaza, C. |
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| year = 2005 |
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| title = The Role of Cannabinoid System on Immune Modulation: Therapeutic Implications on CNS Inflammation |
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| journal = Mini Rev Med Chem |
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| volume = 5 |
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| issue = 7 |
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| pages = 671–5 |
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| doi = 10.2174/1389557054368790 |
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| url = http://www.ingentaconnect.com/content/ben/mrmc/2005/00000005/00000007/art00008 |
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| pmid = 16026313 |
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}}</ref><ref name=Fernández-ruiz2007>{{Cite journal |
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| author = Fernández-ruiz, J.; Romero, J.; Velasco, G.; Tolón, R.M.; Ramos, J.A.; Guzmán, M. |
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| year = 2007 |
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| title = Cannabinoid CB2 receptor: A new target for controlling neural cell survival? |
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| journal = Trends in Pharmacological Sciences |
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| volume = 28 |
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| issue = 1 |
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| pages = 39–45 |
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| doi = 10.1016/j.tips.2006.11.001 |
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| url = http://linkinghub.elsevier.com/retrieve/pii/S0165614706002677 |
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| pmid = 17141334 |
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}}</ref> THC is both a CB1 and CB2 agonist.<ref>http://www.tocris.com/pdfs/cannabinoid_receptor_review/page_003.html</ref> |
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===Total synthesis=== |
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===Research indicating negative side-effects=== |
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{{See also|Conversion of CBD to THC}} |
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Conceivable long-term ill effects of THC on humans are disputed, yet its status as an illegal drug in most countries makes research difficult. |
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A [[total synthesis]] of the compound was reported in 1965; that procedure called for the intramolecular alkyl lithium attack on a starting [[Carbonyl group|carbonyl]] to form the fused rings, and a [[tosyl chloride]] mediated formation of the ether.<ref>{{cite journal | vauthors = Mechoulam R, Gaoni Y | title = A Total Synthesis of Dl-Delta-1-Tetrahydrocannabinol, the Active Constituent of Hashish | journal = Journal of the American Chemical Society | volume = 87 | issue = 14 | pages = 3273–75 | date = July 1965 | pmid = 14324315 | doi = 10.1021/ja01092a065 }}</ref>{{third-party inline|date=March 2017}} |
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Some studies claim a variety of negative effects associated with constant, long-term use, including short-term memory loss.<ref name="pmid19825904">{{Cite journal |author=Bartholomew J, Holroyd S, Heffernan TM |title=Does cannabis use affect prospective memory in young adults? |journal=J. Psychopharmacol. (Oxford) |volume= 24 |issue= 2 |pages= 241–6 |year=2009 |month=October |pmid=19825904 |doi=10.1177/0269881109106909 |url=}}</ref><ref name="pmid18635709">{{Cite journal |author=Indlekofer F, Piechatzek M, Daamen M, ''et al.'' |title=Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol |journal=J. Psychopharmacol. (Oxford) |volume=23 |issue=5 |pages=495–509 |year=2009 |month=July |pmid=18635709 |doi=10.1177/0269881108091076 |url=}}</ref> Other studies have refuted this by evidence of MRIs of long-term users, showing little or no difference to MRIs of the non-using control group. Using [[positron emission tomography]] (PET), one study reports altered memory-related brain function in chronic daily marijuana users.<ref name="Block2002">{{Cite journal |author=Block RI, O'Leary DS, Hichwa RD, ''et al.'' |title=Effects of frequent marijuana use on memory-related regional cerebral blood flow |journal=Pharmacol. Biochem. Behav. |volume=72 |issue=1-2 |pages=237–50 |year=2002 |month=May |pmid=11900794 |doi=10.1016/S0091-3057(01)00771-7}}</ref> |
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===Biological function=== |
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Some studies have suggested that cannabis users have a greater risk of developing [[psychosis]] than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.<ref>{{Cite journal |author=Moore TH, Zammit S, Lingford-Hughes A, ''et al.'' |title=Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review |journal=Lancet |volume=370 |issue=9584 |pages=319–28 |year=2007 |month=July |pmid=17662880 |doi=10.1016/S0140-6736(07)61162-3}}</ref> Other studies have made similar associations, especially in individuals predisposed to psychosis prior to cannabis use.<ref>{{Cite journal|author=Henquet C, Krabbendam L, Spauwen J, ''et al.'' |title=Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people |journal=BMJ |volume=330 |issue=7481 |pages=11 |year=2005 |month=January |pmid=15574485 |pmc=539839 |doi=10.1136/bmj.38267.664086.63}}</ref> A 2005 paper from the [[Dunedin Multidisciplinary Health and Development Study|Dunedin study]] suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.<ref>{{Cite journal |author=Caspi A, Moffitt TE, Cannon M, ''et al.'' |title=Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction |journal=Biol. Psychiatry |volume=57 |issue=10 |pages=1117–27 |year=2005 |month=May |pmid=15866551 |doi=10.1016/j.biopsych.2005.01.026}}</ref> However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.<ref name="pmid17978319">{{cite journal | author = Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ | title = Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use | journal = Br J Psychiatry | volume = 191 | issue = | pages = 402–7 | year = 2007 | month = November | pmid = 17978319 | doi = 10.1192/bjp.bp.107.036129 | laysummary = http://www.medwire-news.md/47/71003/Psychiatry/Cannabis_and_smoking_gene_links_to_schizophrenia_%E2%80%98unfounded%E2%80%99.html | laysource = MedWireNews }}</ref> A literature review on the subject concluded that "Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis."<ref name=Arseneault2004>{{Cite journal |
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As a [[phytochemical]], THC is assumed to be involved in the plant's evolutionary [[adaptation]] against [[predation|insect predation]], [[ultraviolet light]], and [[stress (biology)|environmental stress]].<ref name=Pate1994>{{cite journal |vauthors=Pate DW |year=1994 |title=Chemical ecology of Cannabis |journal=Journal of the International Hemp Association |volume=2 |issue=29 |pages=32–37 |url=http://www.internationalhempassociation.org/jiha/iha01201.html |access-date=2017-12-09 |archive-date=2018-12-21 |archive-url=https://web.archive.org/web/20181221001352/http://www.internationalhempassociation.org/jiha/iha01201.html |url-status=live }}</ref><ref name=Pate1983>{{cite journal|doi=10.1007/BF02904200 |title=Possible role of ultraviolet radiation in evolution of Cannabis chemotypes |year=1983 | vauthors = Pate DW |journal=Economic Botany |volume=37 |issue=4 |pages=396–405|bibcode=1983EcBot..37..396P |s2cid=35727682 }}</ref><ref name=Lydon1987b>{{cite journal | vauthors = Lydon J, Teramura AH, Coffman CB | title = UV-B radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes | journal = Photochemistry and Photobiology | volume = 46 | issue = 2 | pages = 201–06 | date = August 1987 | pmid = 3628508 | doi = 10.1111/j.1751-1097.1987.tb04757.x | url = https://zenodo.org/record/1230776 | s2cid = 7938905 | access-date = 2019-07-04 | archive-date = 2020-06-27 | archive-url = https://web.archive.org/web/20200627065313/https://zenodo.org/record/1230776 | url-status = live }}</ref> |
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| author = Arseneault, Louise; Cannon, Mary; Witton, John; Murray, Robin M. |
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| year = 2004 |
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| title = Causal association between cannabis and psychosis: examination of the evidence |
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| journal = The British Journal of Psychiatry |
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| volume = 184 |
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| issue = 2 |
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| pages = 110–117 |
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| doi = 10.1192/bjp.184.2.110 |
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| url = http://bjp.rcpsych.org/cgi/content/full/184/2/110 |
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| pmid = 14754822 |
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}}</ref> Contrastingly, a French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.<ref name="Laqueille">{{Cite journal |author=Laqueille, X. |date=September 2009 |title=Is cannabis a vulnerability factor in schizophrenic disorders |journal=Arch Pediatr. |volume=16 |issue=9 |pages=1302–5 |pmid= 19640690 |publisher=Elsevier |language=French |doi=10.1016/j.arcped.2009.03.016}}</ref> |
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A 2008 German review reported that cannabis was supposedly a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.<ref>{{Cite journal |author=Kawohl W, Rössler W. |year=2008 |title=Cannabis and Schizophrenia: new findings in an old debate |journal=Neuropsychiatr |volume=22 |issue=4 |pages=223–9 |pmid= 19080993 |language=German}}</ref> Interestingly, however, though cannabis use has increased dramatically in several countries over the past few decades, the rates of psychosis and schizophrenia have not generally increased, casting some doubt over whether the drug can cause cases that would not otherwise have occurred.<ref>{{Cite journal |author=Degenhardt L, Hall W, Lynskey M |title=Comorbidity between cannabis use and psychosis: Modelling some possible relationships. | version = Technical Report No. 121. |publisher=Sydney: National Drug and Alcohol Research Centre. |year=2001 |url=http://ndarc.med.unsw.edu.au/NDARCWeb.nsf/resources/TR_18/$file/TR.121.PDF |format=[[PDF]] |accessdate=2006-08-19 }}</ref> |
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===Biosynthesis=== |
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Research from 2007 reported a correlation between cannabis use and ''increased'' cognitive function in schizophrenic patients.<ref>{{Cite journal |author=Coulston CM, Perdices M, Tennant CC |title=The neuropsychological correlates of cannabis use in schizophrenia: lifetime abuse/dependence, frequency of use, and recency of use |journal=Schizophr. Res. |volume=96 |issue=1-3 |pages=169–84 |year=2007 |month=November |pmid=17826035 |doi=10.1016/j.schres.2007.08.006}}</ref> |
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In the ''[[Cannabis]]'' plant, THC occurs mainly as [[tetrahydrocannabinolic acid]] (THCA, 2-COOH-THC). [[Geranyl pyrophosphate]] and [[olivetolic acid]] react, catalysed by an [[enzyme]] to produce [[cannabigerolic acid]],<ref name="pmid9607329">{{cite journal | vauthors = Fellermeier M, Zenk MH | title = Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol | journal = FEBS Letters | volume = 427 | issue = 2 | pages = 283–85 | date = May 1998 | pmid = 9607329 | doi = 10.1016/S0014-5793(98)00450-5 | doi-access = free | bibcode = 1998FEBSL.427..283F }}</ref> which is cyclized by the enzyme [[THC acid synthase]] to give THCA. Over time, or when heated, THCA is [[decarboxylation|decarboxylated]], producing THC. The pathway for THCA [[biosynthesis]] is similar to that which produces the bitter acid [[humulone]] in [[hops]].<ref>{{cite journal | vauthors = Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, Gang DR, Weiblen GD, Dixon RA | title = Identification of candidate genes affecting Delta9-tetrahydrocannabinol biosynthesis in Cannabis sativa | journal = Journal of Experimental Botany | volume = 60 | issue = 13 | pages = 3715–26 | year = 2009 | pmid = 19581347 | pmc = 2736886 | doi = 10.1093/jxb/erp210 }}</ref><ref>{{cite journal | vauthors = Baker PB, Taylor BJ, Gough TA | title = The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products | journal = The Journal of Pharmacy and Pharmacology | volume = 33 | issue = 6 | pages = 369–72 | date = June 1981 | pmid = 6115009 | doi = 10.1111/j.2042-7158.1981.tb13806.x | s2cid = 30412893 }}</ref> It can also be produced in genetically modified [[yeast]].<ref name="pmid30814733">{{cite journal | vauthors = Luo X, Reiter MA, d'Espaux L, Wong J, Denby CM, Lechner A, Zhang Y, Grzybowski AT, Harth S, Lin W, Lee H, Yu C, Shin J, Deng K, Benites VT, Wang G, Baidoo EE, Chen Y, Dev I, Petzold CJ, Keasling JD | title = Complete biosynthesis of cannabinoids and their unnatural analogues in yeast | journal = Nature | volume = 567 | issue = 7746 | pages = 123–26 | date = March 2019 | pmid = 30814733 | doi = 10.1038/s41586-019-0978-9 | bibcode = 2019Natur.567..123L | s2cid = 71147445 | url = https://backend.orbit.dtu.dk/ws/files/240436196/qt3fn1m6p5_noSplash_be06dd7b6fdfa004bec17ec4fed2cabd.pdf | access-date = 2021-12-30 | archive-date = 2022-01-14 | archive-url = https://web.archive.org/web/20220114042915/https://backend.orbit.dtu.dk/ws/files/240436196/qt3fn1m6p5_noSplash_be06dd7b6fdfa004bec17ec4fed2cabd.pdf | url-status = live }}</ref> |
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:[[File:THC biosynthesis labeled.svg|thumb|left|600px|Biosynthesis of THC]]{{clear left}} |
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==History== |
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A 2008 [[National Institutes of Health]] study of 18 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 78 to 350 marijuana cigarettes per week, or 30 g to 270 g (1 to 9.5 ounces)) and 24 controls found elevated levels of [[Apolipoprotein C3|apolipoprotein C-III]] (apoC-III) in the chronic smokers.<ref>{{Cite journal |author=Jayanthi S, Buie S, Moore S, ''et al.'' |title=Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses |journal=Mol. Psychiatry |volume= 15 |issue= 1 |pages= 101–12 |year=2008 |month=May |pmid=18475272 |doi=10.1038/mp.2008.50 |pmc=2797551}}</ref><ref>{{Cite news |url=http://www.reuters.com/article/healthNews/idUSN1231013620080513 |title=Marijuana may up heart attack, stroke risk: study |last=Dunham |first=Will |date=May 13, 2008 |publisher=Reuters |accessdate=2009-09-05}}</ref> An increase in apoC-III levels induces the development of [[hypertriglyceridemia]]. |
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{{Further|Removal of cannabis from Schedule I of the Controlled Substances Act}} |
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[[Cannabidiol]] was isolated and identified from ''Cannabis sativa'' in 1940 by [[Roger Adams]] who was also the first to document the synthesis of THC (both Delta-9-THC and [[Delta-8-THC]]) from the acid-based cyclization of CBD in 1942.<ref>{{Cite journal |pmid=19312292 |date=1942 | vauthors = Adams R |title=Marihuana: Harvey Lecture, February 19, 1942 |journal=Bulletin of the New York Academy of Medicine |volume=18 |issue=11 |pages=705–730 |pmc=1933888 }}</ref><ref>{{Cite journal | vauthors = Adams R, Loewe S, Smith CM, McPhee WD |date=March 1942 |title=Tetrahydrocannabinol Homologs and Analogs with Marihuana Activity. XIII 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01255a061 |journal=Journal of the American Chemical Society |language=en |volume=64 |issue=3 |pages=694–697 |doi=10.1021/ja01255a061 |issn=0002-7863}}</ref><ref>{{cite patent | country = US | number = 2419937 | url=https://patents.google.com/patent/US2419937A/en | title=Marihuana active compounds | inventor = Roger A | assign = Individual | gdate = 6 May 1947 }}</ref><ref>{{cite journal | doi=10.1021/ja01858a058 | volume=62 | title=Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. | year=1940 | journal=Journal of the American Chemical Society | pages=196–200 | vauthors = Adams R, Hunt M, Clark JH }}</ref> THC was first isolated from Cannabis by [[Raphael Mechoulam]] in 1964.<ref name="pmid4910003">{{cite journal | vauthors = Mechoulam R | title = Marihuana chemistry | journal = Science | volume = 158 | issue = 3936 | pages = 1159–66 | date = June 1970 | pmid = 4910003 | doi = 10.1126/science.168.3936.1159 | bibcode = 1970Sci...168.1159M }}</ref><ref name="doi10.1021/ja01062a046">{{cite journal|title=Isolation, structure and partial synthesis of an active constituent of hashish |vauthors=Gaoni Y, Mechoulam R | journal = Journal of the American Chemical Society |year=1964 |volume=86 |issue=8 |pages=1646–47 |doi=10.1021/ja01062a046}}</ref><ref>{{cite web |url=http://matters.ecnp.nl/number11/interview2.shtml |title=Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel |date=February 2007 |archive-url=https://web.archive.org/web/20110430032241/http://matters.ecnp.nl/number11/interview2.shtml |archive-date=2011-04-30 }}</ref><ref>{{cite journal| vauthors = Geller T |year=2007 |url=http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html |archive-url=https://web.archive.org/web/20080619013348/http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html |archive-date=19 June 2008 |title=Cannabinoids: A Secret History |journal=Chemical Heritage Newsmagazine |volume=25 |issue=2}}</ref> |
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A 2008 study by the [[University of Melbourne]] of 15 heavy marijuana users (consuming at least 5 marijuana cigarettes daily for on average 20 years) and 16 controls found an average size difference for the smokers in the [[hippocampus]] (12 percent smaller) and the [[amygdala]] (7 percent smaller).<ref>{{Cite journal |author=Yücel M |coauthors=''et al.'' |year=2008 |title=Regional brain abnormalities associated with long-term heavy cannabis use |journal=Arch Gen Psychiatry |volume=65 |issue=6 |pages=694–701 |pmid=18519827 |doi=10.1001/archpsyc.65.6.694}}</ref> It has been suggested that such effects can be reversed with long term abstinence.<ref name=Chang2006>{{Cite journal |
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| author = Chang, L.; Yakupov, R.; Cloak, C.; Ernst, T. |
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| year = 2006 |
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| title = Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation. |
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| journal = Brain |
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| pmid = 16585053 |
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| volume = 129 |
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| issue = 5 |
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| pages = 1096 |
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| doi = 10.1093/brain/awl064 |
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| url = http://brain.oxfordjournals.org/cgi/content/full/129/5/1096 |
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}}</ref> However, the study indicates that they are unsure that the problems were caused by marijuana alone. Furthermore, this correlation might suggest self-medication by individuals with these brain features. |
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==Society and culture== |
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A 2008 study at [[Karolinska Institute]] suggested that young rats treated with [[THC]] received an increased motivation for drug use, heroin in the study, under conditions of stress.<ref>{{Cite book |last=Ellgren, Maria |title=Neurobiological effects of early life cannabis exposure in relation to the gateway hypothesis |date=9 February 2007|isbn=978-91-7357-064-0 |url=http://diss.kib.ki.se/2007/978-91-7357-064-0/ |language=English and Swedish |location=Stockholm}}</ref><ref>{{Cite journal |author=Ellgren M, Spano SM, Hurd YL |year=2007 |title=Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats |journal=Neuropsychopharmacology |volume=32 |issue=3 |pages=607–15 |pmid=16823391 |doi=10.1038/sj.npp.1301127}}</ref> |
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===Comparisons with medical cannabis=== |
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{{Further|Medical cannabis}} |
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{{Cannabis sidebar}} |
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Female cannabis plants contain at least 113 cannabinoids,<ref>{{cite journal | vauthors = Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A | title = Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes | journal = Journal of Natural Products | volume = 79 | issue = 2 | pages = 324–31 | date = February 2016 | pmid = 26836472 | doi = 10.1021/acs.jnatprod.5b00949 | url = https://figshare.com/articles/journal_contribution/5028338 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025827/https://figshare.com/articles/journal_contribution/Evolution_of_the_Cannabinoid_and_Terpene_Content_during_the_Growth_of_Cannabis_sativa_Plants_from_Different_Chemotypes/5028338 | url-status = live }}</ref> including [[cannabidiol]] (CBD), thought to be the major [[anticonvulsant]] that helps people with [[multiple sclerosis]],<ref name="pmid6269680">{{cite journal | vauthors = Pickens JT | title = Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content | journal = British Journal of Pharmacology | volume = 72 | issue = 4 | pages = 649–56 | date = April 1981 | pmid = 6269680 | pmc = 2071638 | doi = 10.1111/j.1476-5381.1981.tb09145.x }}</ref> and [[cannabichromene]] (CBC), an [[anti-inflammatory]] which may contribute to the [[Analgesic|pain-killing]] effect of cannabis.<ref name="morales">{{cite book | vauthors = Morales P, Hurst DP, Reggio PH | title = Phytocannabinoids | chapter = Molecular Targets of the Phytocannabinoids: A Complex Picture | series = Progress in the Chemistry of Organic Natural Products | volume = 103 | pages = 103–31 | date = 2017 | pmid = 28120232 | pmc = 5345356 | doi = 10.1007/978-3-319-45541-9_4 | isbn = 978-3-319-45539-6 }}</ref> |
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A 2009 study found that there was a high prevalence of cannabis in the toxicologic analysis of homicide (22%) and suicide victims (11%) in Australia.<ref>{{Cite journal |author=Darke S, Duflou J, Torok M |year=2009 |title=Drugs and violent death: comparative toxicology of homicide and non-substance toxicity suicide victims. |journal=Addiction |volume=104 |issue=6 |pages=1000–5 |pmid=19466923 |doi=10.1111/j.1360-0443.2009.02565.x}}</ref> In a similar study from Sweden it was also found that suicide victims had a significant higher use of cannabis, but the authors found that "this was explained by markers of psychological and behavioural problems."<ref name="pmid19949196">{{Cite journal|author=Price C, Hemmingsson T, Lewis G, Zammit S, Allebeck P |title=Cannabis and suicide: longitudinal study |journal=Br J Psychiatry |volume=195 |issue=6 |pages=492–7 |year=2009 |month=December |pmid=19949196 |doi=10.1192/bjp.bp.109.065227 |url=}}</ref> |
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== |
===Drug testing=== |
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{{Main|Cannabis drug testing}} |
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[[Image:THC biosynthesis.png|thumb|Biosynthesis of THC]] |
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In the [[cannabis]] plant, THC occurs mainly as tetrahydrocannabinol [[carboxylic acid]] (THC-COOH). [[Geranyl pyrophosphate]] and [[olivetol]]ic acid react, catalysed by an [[enzyme]] to produce [[cannabigerol|cannabigerolic acid]],<ref name="pmid9607329">{{Cite journal|author=Fellermeier M, Zenk MH |title=Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol |journal=FEBS Lett. |volume=427 |issue=2 |pages=283–5 |year=1998 |month=May |pmid=9607329 |doi= 10.1016/S0014-5793(98)00450-5|url=}}</ref> which is cyclized by the enzyme THC acid [[synthase]] to give THC-COOH. Over time, or when heated, THC-COOH is [[decarboxylation|decarboxylated]] producing THC. The pathway for THC-COOH biosynthesis is similar to that which produces the bitter acid [[humulone]] in [[hops]].<ref>{{cite doi|10.1093/jxb/erp210}}</ref> |
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THC and its 11-OH-THC and THC-COOH metabolites can be detected and quantified in blood, urine, hair, oral fluid or sweat using a combination of [[immunoassay]] and [[chromatographic]] techniques as part of a drug use testing program or in a forensic investigation.<ref>{{cite journal | vauthors = Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA | title = Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC | journal = Clinical Chemistry | volume = 55 | issue = 12 | pages = 2180–89 | date = December 2009 | pmid = 19833841 | pmc = 3196989 | doi = 10.1373/clinchem.2008.122119 }}</ref><ref>{{cite journal | vauthors = Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R | title = Concentrations of delta9-tetrahydrocannabinol and 11-nor-9-carboxytetrahydrocannabinol in blood and urine after passive exposure to Cannabis smoke in a coffee shop | journal = Journal of Analytical Toxicology | volume = 34 | issue = 4 | pages = 196–203 | date = May 2010 | pmid = 20465865 | doi = 10.1093/jat/34.4.196 | doi-access = free }}</ref><ref>{{cite book| vauthors = Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=1644–48}}</ref> There is ongoing research to create devices capable of detecting THC in breath.<ref name="cnn">{{cite news | vauthors = Wallace A |title=Testing drivers for cannabis is hard. Here's why |url=https://www.cnn.com/2020/01/02/business/cannabis-breathalyzers-are-coming-to-market/index.html |access-date=26 February 2020 |work=CNN Business |date=January 2, 2020 |archive-date=26 February 2020 |archive-url=https://web.archive.org/web/20200226030155/https://www.cnn.com/2020/01/02/business/cannabis-breathalyzers-are-coming-to-market/index.html |url-status=live }}</ref><ref>{{cite journal | vauthors = Mirzaei H, O'Brien A, Tasnim N, Ravishankara A, Tahmooressi H, Hoorfar M | title = Topical review on monitoring tetrahydrocannabinol in breath | journal = Journal of Breath Research | volume = 14 | issue = 3 | pages = 034002 | date = May 2020 | pmid = 31842004 | doi = 10.1088/1752-7163/ab6229 | bibcode = 2020JBR....14c4002M | s2cid = 209388839 }}</ref> |
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==Metabolism== |
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THC is metabolized mainly to [[11-Hydroxy-THC|11-OH-THC]] (11-hydroxy-THC) by the human body. This [[metabolite]] is still psychoactive and is further oxidized to [[11-Nor-9-carboxy-THC]] (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by [[cytochrome P450]] enzymes [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]]. More than 55% of THC is excreted in the [[feces]] and ~20% in the [[urine]]. The main metabolite in urine is the ester of [[glucuronic acid]] and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.<ref name="pmid16596792">{{Cite journal |
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|author=Huestis MA |
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|title=Pharmacokinetics and metabolism of the plant cannabinoids, Δ<sup>9</sup>-tetrahydrocannabinol, cannabidiol and cannabinol |
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|journal=Handb Exp Pharmacol |
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|volume=168 |
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|issue=168 |
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|pages=657–90 |
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|year=2005 |
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|pmid=16596792 |
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|doi=10.1007/3-540-26573-2_23 |
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}}</ref> |
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===Regulation=== |
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===Detection in body fluids=== |
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THC, along with its double bond isomers and their [[Stereoisomerism|stereoisomers]],<ref>{{cite journal | vauthors = Mazzoccanti G, Ismail OH, D'Acquarica I, Villani C, Manzo C, Wilcox M, Cavazzini A, Gasparrini F | title = Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra high performance supercritical fluid chromatography | journal = Chemical Communications | volume = 53 | issue = 91 | pages = 12262–65 | date = November 2017 | pmid = 29072720 | doi = 10.1039/C7CC06999E | hdl-access = free | hdl = 11573/1016698 }}</ref> is one of only three cannabinoids scheduled by the UN [[Convention on Psychotropic Substances]] (the other two are [[dimethylheptylpyran]] and [[parahexyl]]). It was listed under Schedule I in 1971, but reclassified to Schedule II in 1991 following a recommendation from the [[World Health Organization|WHO]]. Based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III.<ref>{{cite web|url=https://www.tni.org/en/publication/the-un-drug-control-conventions#box3|title=The UN Drug Control Conventions|date=8 October 2015|access-date=3 December 2015|archive-date=3 February 2018|archive-url=https://web.archive.org/web/20180203181126/https://www.tni.org/en/publication/the-un-drug-control-conventions#box3|url-status=live}}</ref> Cannabis as a plant is scheduled by the [[Single Convention on Narcotic Drugs]] (Schedule I and IV). It is specifically still listed under Schedule I by US federal law<ref>{{cite web |date=1 December 2017 |title=Drug Schedules; Schedule 1 |url=https://www.dea.gov/drug-information/drug-scheduling |archive-date=7 May 2021 |access-date=14 January 2018 |website=United States Drug Enforcement Administration |publisher=US Drug Enforcement Administration, Department of Justice |archive-url=https://web.archive.org/web/20210507061910/https://www.dea.gov/drug-information/drug-scheduling |url-status=live }}</ref> under the [[Controlled Substances Act]] for having "no accepted medical use" and "lack of accepted safety". However, [[dronabinol]], a pharmaceutical form of THC, has been approved by the [[Food and Drug Administration|FDA]] as an appetite stimulant for people with [[AIDS]] and an [[antiemetic]] for people receiving [[chemotherapy]] under the trade names Marinol and Syndros.<ref name="fda">{{cite web|title=Marinol (Dronabinol)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf|publisher=US Food and Drug Administration|access-date=14 January 2018|date=September 2004|archive-date=10 February 2017|archive-url=https://web.archive.org/web/20170210093236/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf|url-status=live}}</ref> |
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THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of [[immunoassay]] and [[chromatographic]] techniques as part of a drug use testing program or in a forensic investigation of a traffic or other criminal offense or suspicious death. The concentrations obtained from such analyses can often be helpful in distinguishing active from passive use or prescription from illicit use, the route of administration (oral versus smoking), elapsed time since use and extent or duration of use.<ref>Schwilke EW, Schwope DM, Karschner EL, et al. Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC. Clin Chem. 55: 2180-2189, 2009.</ref><ref>Röhrich J, Schimmel I, Zörntlein S, et al. Concentrations of delta9-tetrahydrocannabinol and 11-nor-9-carboxytetrahydrocannabinol in blood and urine after passive exposure to Cannabis smoke in a coffee shop. J Anal. Toxicol. 34: 196-203, 2010.</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp 1513-1518.</ref> |
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In 2003, the [[World Health Organization]] Expert Committee on Drug Dependence recommended transferring THC to [[Amphetamine-type stimulants|Schedule IV]] of the convention, citing its medical uses and low abuse and addiction potential.<ref>{{cite web|url=https://www.who.int/substance_abuse/right_committee/en/index.html |archive-url=https://web.archive.org/web/20050107200642/http://www.who.int/substance_abuse/right_committee/en/index.html |archive-date=January 7, 2005 |title=WHO Expert Committee on Drug Dependence |publisher=World Health Organization |access-date=12 January 2014}}</ref> In 2019, the Committee recommended transferring Δ<sup>9</sup>-THC to Schedule I of the [[Single Convention on Narcotic Drugs|Single Convention on Narcotic Drugs of 1961]], but its recommendations were rejected by the [[United Nations Commission on Narcotic Drugs]].<ref>{{Cite journal | vauthors = Riboulet-Zemouli K, Krawitz MA, Ghehiouèche F |date=2021 |title=History, Science, and Politics of International Cannabis Scheduling, 2015–2021 |url=https://papers.ssrn.com/abstract=3932639 |journal=[[FAAAT think & do tank|FAAAT editions]] |language=en |location=Rochester, NY |ssrn=3932639 |via=SSRN}}</ref> |
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==Dronabinol== |
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Synthesized THC is known as ''dronabinol''. It is available as a prescription drug (under Marinol<ref>http://www.usdoj.gov/dea/ongoing/marinol.html</ref>) in several countries including the [[United States]] and [[Germany]]. In the United States, Marinol is a [[Controlled Substances Act#Schedule III drugs|Schedule III]] drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a [[Removal of cannabis from Schedule I of the Controlled Substances Act#2002 Coalition for Rescheduling Cannabis petition|2002 petition]] has been accepted by the [[Drug Enforcement Administration|DEA]]. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the [[U.S. Food and Drug Administration]] (FDA) in the treatment of [[anorexia (symptom)|anorexia]] in [[AIDS]] patients, as well as for refractory [[nausea]] and [[vomiting]] of patients undergoing [[chemotherapy]], which has raised much controversy as to why natural THC is still a [[Controlled Substances Act#Schedule I controlled substances|schedule I]] drug.<ref>http://arthritis.about.com/cs/medmarijuana/a/marijuanadebate.htm</ref> |
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====In the United States==== |
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An analog of dronabinol, [[nabilone]], is available commercially in Canada under the trade name Cesamet, manufactured by Valeant. Cesamet has also received FDA approval and began marketing in the U.S. in 2006; it is a [[Controlled Substances Act#Schedule II drugs|Schedule II]] drug. |
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As of 2023, 38 states, four territories, and the [[Washington, D.C.|District of Columbia]] in the United States allow [[Medical cannabis in the United States|medical use of cannabis]] (in which THC is the primary psychoactive component), with the exception of Georgia, Idaho, Indiana, Iowa, Kansas, Nebraska, North Carolina, South Carolina, Tennessee, Texas, Wisconsin, and Wyoming.<ref name="ncsl-states">{{cite web|title=State Medical Cannabis Laws|url=http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx|publisher=National Conference of State Legislatures|date=3 February 2022|access-date=10 December 2022|archive-date=11 December 2018|archive-url=https://web.archive.org/web/20181211125951/http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx|url-status=live}}</ref> As of 2022, the U.S. federal government maintains cannabis as a schedule I controlled substance, while dronabinol is classified as Schedule III in capsule form (Marinol) and Schedule II in liquid oral form (Syndros).<ref name="dea-22">{{cite web |title=Drug scheduling: Marijuana (Cannabis) |url=https://www.dea.gov/drug-information/drug-scheduling |publisher=US Department of Justice, Drug Enforcement Administration |access-date=10 December 2022 |date=2022 |archive-date=10 December 2022 |archive-url=https://web.archive.org/web/20221210002749/https://www.dea.gov/drug-information/drug-scheduling |url-status=live }}</ref><ref>{{cite web |title=Controlled Substances |url=https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf |website=usdoj.gov |access-date=December 11, 2022 |archive-date=April 21, 2021 |archive-url=https://web.archive.org/web/20210421180644/https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf |url-status=live }}</ref> |
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====In Canada==== |
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In April 2005, [[Canada|Canadian]] authorities approved the marketing of [[Sativex]], a mouth spray for [[multiple sclerosis]] patients, who can use it to alleviate [[neuropathic pain]] and [[spasticity]]. Sativex contains tetrahydrocannabinol together with [[cannabidiol]]. It is marketed in [[Canada]] by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world (in modern times). In addition, [[Sativex]] received European regulatory approval in 2010. |
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As of October 2018 when recreational use of cannabis was [[Cannabis in Canada|legalized in Canada]], some 220 [[dietary supplement]]s and 19 [[Holistic veterinary medicine|veterinary health products]] containing not more than 10 parts per million of THC [[extract]] were approved with general [[health claim]]s for treating minor conditions.<ref name=canada2018/> |
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==Research== |
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===Comparisons to medical marijuana=== |
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The status of THC as an illegal drug in most countries imposes restrictions on research material supply and funding, such as in the [[Legal history of cannabis in the United States|United States]] where the [[National Institute on Drug Abuse]] and [[Drug Enforcement Administration]] continue to control the sole federally-legal source of cannabis for researchers. Despite an August 2016 announcement that licenses would be provided to growers for supplies of medical marijuana, no such licenses were ever issued, despite dozens of applications.<ref name="MAPS">{{cite web |url=http://www.maps.org/research/mmj/ |title=Medical Marijuana |publisher=Multidisciplinary Association for Psychedelic Studies |access-date=12 January 2014 |archive-date=14 April 2012 |archive-url=https://web.archive.org/web/20120414114518/http://www.maps.org/research/mmj/ |url-status=live }}</ref> Although cannabis is legalized for medical uses in more than half of the states of the United States, no products have been approved for federal commerce by the Food and Drug Administration, a status that limits cultivation, manufacture, distribution, clinical research, and therapeutic applications.<ref>{{cite journal | vauthors = Mead A | title = The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law | journal = Epilepsy & Behavior | volume = 70 | issue = Pt B | pages = 288–91 | date = May 2017 | pmid = 28169144 | doi = 10.1016/j.yebeh.2016.11.021 | url = http://www.epilepsybehavior.com/article/S1525-5050(16)30585-6/fulltext | doi-access = free | access-date = 2018-01-26 | archive-date = 2022-10-21 | archive-url = https://web.archive.org/web/20221021191845/https://www.epilepsybehavior.com/article/S1525-5050(16)30585-6/fulltext | url-status = live }}</ref> |
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{{Main|Medical marijuana}} |
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Dronabinol is known to produce mild side effects similar to cannabis.{{Citation needed|date=April 2010}} Many scientists{{Who|date=April 2010}} believe that dronabinol lacks the beneficial properties of cannabis{{Clarify|date=October 2010}}, which contains more than 60 cannabinoids, including [[cannabidiol]] (CBD), thought to be the major [[anticonvulsant]] that helps [[multiple sclerosis]] patients;<ref name="pmid6269680">{{Cite journal |
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|author=Pickens JT |
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|title=Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content |
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|journal=Br. J. Pharmacol. |
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|volume=72 |
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|issue=4 |
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|pages=649–56 |
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|year=1981 |
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|pmid=6269680 |
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|doi= |
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|pmc=2071638 |
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}}</ref> and [[cannabichromene]] (CBC), an [[anti-inflammatory]] which may contribute to the [[Analgesic|pain-killing]] effect of cannabis.<ref name=Burns2006>{{Cite journal |
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| last1 = Burns | first1 = Tammy L. |
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| last2 = Ineck | first2 = Joseph R. |
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| year = 2006 |
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| title = Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain |
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| journal = The Annals of Pharmacotherapy |
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| volume = 40 |
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| issue = 2 |
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| pages = 251–260 |
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| doi = 10.1345/aph.1G217 |
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| url = http://www.theannals.com/cgi/content/abstract/40/2/251 |
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| pmid = 16449552 |
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}}</ref> Others have countered that the effects of all of cannabis's cannabinoids have not been completely studied and are not fully understood.{{Citation needed|date=November 2008}} |
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In April 2014, the [[American Academy of Neurology]] found evidence supporting the effectiveness of the cannabis extracts in treating certain symptoms of [[multiple sclerosis]] and pain, but there was insufficient evidence to determine effectiveness for treating several other neurological diseases.<ref name="AAN">{{cite journal | vauthors = Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D | title = Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 82 | issue = 17 | pages = 1556–63 | date = April 2014 | pmid = 24778283 | pmc = 4011465 | doi = 10.1212/WNL.0000000000000363 }}</ref> A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting [[adverse event]]s, such as dizziness.<ref name="whiting">{{cite journal | vauthors = Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J | title = Cannabinoids for Medical Use: A Systematic Review and Meta-analysis | journal = JAMA | volume = 313 | issue = 24 | pages = 2456–73 | year = 2015 | pmid = 26103030 | doi = 10.1001/jama.2015.6358 | doi-access = free | hdl = 10757/558499 | hdl-access = free }}</ref> |
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It takes over one hour for Marinol to reach full systemic effect,<ref>http://www.druglibrary.org/schaffer/hemp/medical/marinol1.htm</ref> compared to minutes for [[Cannabis smoking|smoked]] or [[Vaporizer|vaporized]] cannabis.<ref name="mckim">{{Cite book | author=McKim, William A | title=Drugs and Behavior: An Introduction to Behavioral Pharmacology (5th Edition) |publisher=Prentice Hall |year=2002 |pages=400 |isbn=0-13-048118-1 }}</ref> Some patients accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages. Many patients have said that Marinol produces a more acute psychedelic effect than cannabis, and it has been speculated that this disparity can be explained by the moderating effect of the many non-THC cannabinoids present in cannabis. [[Mark Kleiman]], director of the Drug Policy Analysis Program at UCLA's School of Public Affairs said of Marinol, "It wasn't any fun and made the user feel bad, so it could be approved without any fear that it would penetrate the recreational market, and then used as a club with which to beat back the advocates of whole cannabis as a medicine."<ref name="Respectable Reefer">{{Cite news |last=Greenberg |first=Gary |title=Respectable Reefer |publisher=Mother Jones |date=2005-11-01 |url=http://motherjones.com/politics/2005/11/respectable-reefer?page=3 |accessdate = 8 April 2010}}</ref> United States federal law currently registers dronabinol as a [[Schedule III controlled substance]], but all other cannabinoids remain [[Controlled Substances Act#Schedule I controlled substances|Schedule I]], excepting synthetics like [[nabilone]]. |
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===Multiple sclerosis symptoms=== |
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==Regulatory history== |
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* ''[[Spasticity]]''. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving people's subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.<ref name="AAN"/><ref name=whiting/> |
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Since at least 1986, the trend has been for THC in general, and especially the Marinol preparation, to be downgraded to less and less stringently-controlled schedules of controlled substances, in the U.S. and throughout the rest of the world. |
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* ''Centrally mediated pain and painful spasms''. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.<ref name="AAN"/> |
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* ''Bladder dysfunction''. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis<ref name="AAN"/> |
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===Neurodegenerative disorders=== |
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On July 13, 1986, the [[Drug Enforcement Administration]] (DEA) issued a Final Rule and Statement of Policy authorizing the "Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule I to Schedule II" (DEA 51 FR 17476-78). This permitted medical use of Marinol, albeit with the severe restrictions associated with Schedule II status. For instance, refills of Marinol prescriptions were not permitted. At its 1045th meeting, on April 29, 1991, the [[Commission on Narcotic Drugs]], in accordance with article 2, paragraphs 5 and 6, of the [[Convention on Psychotropic Substances]], decided that Δ<sup>9</sup>-tetrahydrocannabinol (also referred to as Δ<sup>9</sup>-THC) and its stereochemical variants should be transferred from Schedule I to Schedule II of that Convention. This released Marinol from the restrictions imposed by Article 7 of the Convention [http://www.ukcia.org/pollaw/lawlibrary/conventiononpsychotropicsubstances1971.html]. |
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* ''Huntington disease''. No reliable conclusion could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference<ref name="AAN"/> |
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* ''Parkinson's disease''. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.<ref name="AAN"/> |
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* ''Alzheimer's disease''. A 2009 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.<ref>{{cite journal | vauthors = Krishnan S, Cairns R, Howard R | title = Cannabinoids for the treatment of dementia | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD007204 | date = April 2009 | volume = 2009 | pmid = 19370677 | pmc = 7197039 | doi = 10.1002/14651858.CD007204.pub2 | veditors = Krishnan S }}</ref> |
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===Other neurological disorders=== |
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An article published in the April–June 1998 issue of the [[Journal of Psychoactive Drugs]] found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.<ref name="pmid9692381">{{Cite journal |author=Calhoun SR, Galloway GP, Smith DE |title=Abuse potential of dronabinol (Marinol) |journal=Journal of psychoactive drugs |volume=30 |issue=2 |pages=187–96 |year=1998 |pmid=9692381 |doi= |url=}}</ref> |
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* ''[[Tourette syndrome]]''. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.<ref name="AAN"/> |
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* ''[[Spasmodic torticollis|Cervical dystonia]]''. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.<ref name="AAN"/> |
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===Potential for toxicity=== |
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In 1999, Marinol was rescheduled from Schedule II to III of the [[Controlled Substances Act]], reflecting a finding that THC had a potential for abuse less than that of [[cocaine]], and [[heroin]]. This rescheduling comprised part of the argument for a 2002 petition for [[removal of cannabis from Schedule I of the Controlled Substances Act]], in which petitioner [[Jon Gettman]] noted, "Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol".<ref>[http://www.drugscience.org/pt/b.htm]</ref>{{Citation broken|date=September 2009}} |
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Preliminary research indicates that prolonged exposure to high doses of THC may interfere with chromosomal stability, which may be hereditary as a factor affecting cell instability and cancer risk. The carcinogenicity of THC in the studied populations of so-called "heavy users" remains dubious due to various confounding variables, most significantly concurrent tobacco use.<ref>{{cite journal | vauthors = Reece AS, Hulse GK | title = Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity | journal = Mutation Research | volume = 789 | pages = 15–25 | date = July 2016 | pmid = 27208973 | doi = 10.1016/j.mrfmmm.2016.05.002 | bibcode = 2016MRFMM.789...15R }}</ref> |
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At its 33rd meeting, the [[World Health Organization]] Expert Committee on Drug Dependence recommended transferring THC to [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule IV]] of the Convention, citing its medical uses and low abuse potential. |
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==See also== |
==See also== |
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{{Portal|Cannabis|Chemistry}} |
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{{Div col|colwidth=30}} |
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* [[Psychoactive drug]] |
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* [[Cannabinoids]] |
* [[Cannabinoids]] |
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** [[11-Hydroxy-THC]], [[metabolite]] of THC |
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** [[Anandamide]], [[2-Arachidonoylglycerol]], endogenous cannabinoid agonists |
** [[Anandamide]], [[2-Arachidonoylglycerol]], endogenous cannabinoid agonists |
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** [[Cannabidiol]] (CBD) |
** [[Cannabidiol]] (CBD) |
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** [[Cannabinol]] (CBN), a |
** [[Cannabinol]] (CBN), a metabolite of THC |
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** [[Cis-THC]], an isomer of THC |
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** [[HU-210]], [[WIN 55,212-2]], [[JWH-133]], synthetic cannabinoid agonists |
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** [[Delta-7-Tetrahydrocannabinol]], a synthetic isomer of THC |
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** [[Delta-8-Tetrahydrocannabinol]], a double bond isomer of THC |
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** [[Delta-10-Tetrahydrocannabinol]], a positional isomer of THC |
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** [[THC-O-acetate]], the [[acetate]] [[ester]] of THC. |
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** [[THC hemisuccinate]], the hemisuccinate ester of THC that's water soluble and has rectal bioavailability to reach CNS |
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** [[Dimethylheptylpyran]] |
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** [[Dronabinol]], the name of THC-based pharmaceutical ([[International nonproprietary name|INN]]) |
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** [[HU-210]], [[WIN 55,212-2]], [[JWH-133]], synthetic cannabinoid agonists ([[Synthetic cannabinoids|neocannabinoids]]) |
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** [[Nabilone]], a novel synthetic cannabinoid analog ([[Synthetic cannabinoids|neocannabinoid]]) |
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** [[Parahexyl]] |
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** [[Tetrahydrocannabinolic acid]] (THCA), the biosynthetic precursor for THC |
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** [[Tetrahydrocannabiphorol]], the heptyl homologue |
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* [[Hashish]] |
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* [[List of investigational analgesics]] |
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* [[Medical cannabis]] |
* [[Medical cannabis]] |
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** [[Dronabinol]] |
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** [[Epidiolex]] (prescription form of purified cannabidiol derived from hemp used for treating some rare neurological diseases) |
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** [[Sativex]] |
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* [[Effects of cannabis]] |
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* [[War on Drugs]] |
* [[War on Drugs]] |
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* [[Vaping-associated pulmonary injury]] |
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* [[Cannabis rescheduling in the United States]] |
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* [[Cannabinoid hyperemesis syndrome]] (CHS) |
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* [[Health issues and the effects of cannabis]] |
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{{Div col end}} |
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==References== |
==References== |
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{{Reflist |
{{Reflist}} |
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==Further reading== |
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{{Refbegin}} |
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* {{Cite journal |author=Calhoun SR, Galloway GP, Smith DE |title=Abuse potential of dronabinol (Marinol) |journal=J Psychoactive Drugs |volume=30 |issue=2 |pages=187–96 |year=1998 |pmid=9692381}} |
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* [http://www.marijuananews.com/marijuananews/cowan/dea_moves_marinol_to_schedule_th.htm DEA Moves Marinol To Schedule Three, But Leaves Marijuana in Schedule One. The Magic of Sesame Oil], [[Richard Cowan (cannabis activist)|Richard Cowan]], MarijuanaNews.Com. |
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* [http://www.drugscience.org/pt/b.htm Petition to Reschedule Cannabis (Marijuana) per 21 CFR §1308.44(b)], Filed October 9, 2002 with the DEA by the [[Coalition for Rescheduling Cannabis]]. |
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{{Refend}} |
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==External links== |
==External links== |
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* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Tetrahydrocannabinol U.S. National Library of Medicine: Drug Information Portal |
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Tetrahydrocannabinol U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol] |
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