Tetrahydrocannabinol

Last updated

Tetrahydrocannabinol
INN: dronabinol
THC.svg
Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls.png
Clinical data
Trade names Marinol, Syndros
Other names(6aR,10aR)-delta-9-Tetrahydrocannabinol; (−)-trans-Δ9-Tetrahydrocannabinol; THC
License data
Dependence
liability 		Physical: Low
Psychological: Low–moderate
Addiction
liability 		Relatively low: 9%
Routes of
administration 		By mouth, transdermal, sublingual, inhalation
Drug class Cannabinoid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability
  • Oral: 6–20% [3]
  • Inhalation: 10–35%
Protein binding 97–99% [3] [4] [5]
Metabolism Mostly hepatic by CYP2C [3]
Elimination half-life 1.6–59 h, [3] 25–36 h (orally administered dronabinol)
Excretion
  • 65–80% (feces)
  • 20–35% (urine) as acid metabolites [3]
Identifiers
  • (6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.153.676 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H30O2
Molar mass 314.469 g·mol−1
3D model (JSmol)
Specific rotation −152° (ethanol)
Boiling point 155–157 °C (311–315 °F) 0.05mmHg, [6] 157–160°C @ 0.05mmHg [7]
Solubility in water 0.0028 mg/mL (23 °C) [8]
  • CCCCCc1cc(c2c(c1)OC([C@H]3[C@H]2C=C(CC3)C)(C)C)O
  • InChI=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 Yes check.svgY
  • Key:CYQFCXCEBYINGO-IAGOWNOFSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. [9] It is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, [10] the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.

Contents

Medical uses

THC, referred to as dronabinol in the pharmaceutical context, is approved in the United States as a capsule or solution to relieve chemotherapy-induced nausea and vomiting and HIV/AIDS-induced anorexia. [11]

THC is an 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. [12] [13] Nabiximols (as Sativex) is available as a prescription drug in Canada. [14] In 2021, nabiximols was approved for medical use in Ukraine. [15]

Side effects

Side effects of THC include red eyes, dry mouth, drowsiness, short-term memory impairment, difficulty concentrating, ataxia, increased appetite, anxiety, paranoia, psychosis (i.e., hallucinations, delusions), decreased motivation, and time dilation, among others. [16] [17]

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. [16]

Overdose

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. [18] 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. [19] A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg. [20]

Interactions

Formal drug–drug interaction studies with THC have not been conducted and are limited. [21] [22] The elimination half-life of the barbiturate pentobarbital has been found to increase by 4 hours when concomitantly administered with oral THC. [21]

Pharmacology

Mechanism of action

The actions of Δ9-THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 40.7 nM [23] ), located mainly in the central nervous system, and the CB2 receptor (Ki = 36 nM [23] ), mainly expressed in cells of the immune system. [24] 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 cAMP through inhibition of adenylate cyclase. [25] 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 ]

THC is a lipophilic molecule [26] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat). [27] [28] 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. [24]

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 endocannabinoids. 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. [29]

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. [30] 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.

Pharmacokinetics

Absorption

With oral administration of a single dose, THC is almost completely absorbed by the gastrointestinal tract. [21] However, due to first-pass metabolism in the liver and the high lipid solubility of THC, only about 5 to 20% reaches circulation. [3] [21] Following oral administration, concentrations of THC and its major active metabolite 11-hydroxy-THC (11-OH-THC) peak after 0.5 to 4 hours, with median time to peak of 1.0 to 2.5 hours at different doses. [21] [3] In some cases, peak levels may not occur for as long as 6 hours. [3] Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration. [21] There is a slight increase in dose proportionality in terms of peak and area-under-the-curve levels of THC with increasing oral doses over a range of 2.5 to 10 mg. [21] A high-fat meal delays time to peak concentrations of oral THC by 4 hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered. [21] A high-fat meal additionally increases absorption of THC via the lymphatic system and allows it to bypass first-pass metabolism. [31] 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. [31]

The bioavailability of THC when smoking or inhaling is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%). [22] [32] [3] The large range and marked 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). [22] [32] THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10 minutes. [3] [32] 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. [22] [32] Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration. [22] The bioavailability of THC with inhalation is increased in heavy users. [3]

Transdermal administration of THC is limited by its extreme water insolubility. [22] Efficient skin transport can only be obtained with permeation enhancement. [22] Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration. [22]

Distribution

The volume of distribution of THC is large and is approximately 10 L/kg (range 4–14 L/kg), which is due to its high lipid solubility. [21] [22] [32] The plasma protein binding of THC and its metabolites is approximately 95 to 99%, with THC bound mainly to lipoproteins and to a lesser extent albumin. [21] [3] THC is rapidly distributed into well-vascularized organs such as lung, heart, brain, and liver, and is subsequently equilibrated into less vascularized tissue. [22] [32] It is extensively distributed into and sequestered by fat tissue due to its high lipid solubility, from which it is slowly released. [31] [22] [32] THC is able to cross the placenta and is excreted in human breast milk. [22] [3]

Metabolism

The metabolism of THC occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4. [33] [34] CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC. [21] Pharmacogenomic research has found that oral THC exposure is 2- to 3-fold greater in people with genetic variants associated with reduced CYP2C9 function. [21] When taken orally, THC undergoes extensive first-pass metabolism in the liver, primarily via hydroxylation. [21] The principal active metabolite of THC is 11-hydroxy-THC (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC. [31] [22] [21] This metabolite is further 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. [31] [35]

Elimination

More than 55% of THC is 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. [36]

Estimates of the elimination half-life of THC are variable. [22] THC was reported to have a fast initial half-life of 6 minutes and a long terminal half-life of 22 hours in a population pharmacokinetic study. [22] [32] Conversely, the Food and Drug Administration label for dronabinol reports an initial half-life of 4 hours and a terminal half-life of 25 to 36 hours. [21] Many studies report an elimination half-life of THC in the range of 20 to 30 hours. [3] 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36 hours relative to 25 to 36 hours in one study. [3] The elimination half-life of THC is longer in heavy users. [22] This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use. [22]

Chemistry

Overview

CategoryCompoundTHC-relationship
Analogs Dimethylheptylpyran an analog of THC
Analogs Levonantradol an analog of THC
Analogs Nabilone a novel synthetic cannabinoid analog (neocannabinoid) that mimics THC. [37]
Analogs Nabitan an analog of THC
Analogs Tinabinol an analog of THC and dimethylheptylpyran
Derivatives 9-Hydroxyhexahydrocannabinol (9-OH-HHC)a semi-synthetic derivative of THC
Derivatives Hexahydrocannabinol (HHC)a hydrogenated derivative of THC
Derivatives THC morpholinylbutyrate a synthetic derivative of THC
Esters THC hemisuccinate the hemisuccinate ester of THC that's water soluble and has rectal bioavailability to reach CNS
Esters THC-O-acetate the acetate ester of THC
Esters THC-O-phosphate a water-soluble organophosphate ester derivative
Homologues Parahexyl a homologue of THC
Homologues Tetrahydrocannabihexol (THCH)a hexyl homologue of THC
Homologues Tetrahydrocannabiorcol (THCC)a homologue of THC and THCV
Homologues Tetrahydrocannabutol (THCB)a homologue of THC
Homologues Tetrahydrocannabiphorol (THCP)the heptyl homologue of THC
Homologues Tetrahydrocannabivarin (THCV)a homologue of THC
Isomers Cis-THC an isomer of THC
Isomers Δ-3-Tetrahydrocannabinol (Delta-3-THC)a synthetic isomer of THC
Isomers Δ-4-Tetrahydrocannabinol (Delta-4-THC)a synthetic isomer of THC
Isomers Delta-7-Tetrahydrocannabinol a synthetic isomer of THC
Isomers Delta-8-Tetrahydrocannabinol a double bond isomer of THC
Isomers Delta-10-Tetrahydrocannabinol a positional isomer of THC
Metabolites 3'-Hydroxy-THC a minor active metabolite of THC
Metabolites 8,11-Dihydroxytetrahydrocannabinol an active metabolite of THC
Metabolites 11-Hydroxy-Δ-8-THC an active metabolite of THC
Metabolites 11-Hydroxy-THC the main active metabolite of THC
Metabolites 11-Hydroxyhexahydrocannabinol an active metabolite of THC and a metabolite of the trace cannabinoid hexahydrocannabinol (HHC)
Metabolites 11-Nor-9-carboxy-THC the main secondary metabolite of THC
Precursor Tetrahydrocannabinolic acid (THCA)the biosynthetic precursor for THC
Prodrug THC-VHS a synthetic prodrug of THC

Solubility

As with many aromatic terpenoids, THC has a very low solubility in water, but good solubility in lipids and most organic solvents, specifically hydrocarbons and alcohols. [8]

Total synthesis

A total synthesis of the compound was reported in 1965; that procedure called for the intramolecular alkyl lithium attack on a starting carbonyl to form the fused rings, and a tosyl chloride mediated formation of the ether. [38] [ third-party source needed ]

Biological function

As a phytochemical, THC is assumed to be involved in the plant's evolutionary adaptation against insect predation, ultraviolet light, and environmental stress. [39] [40] [41]

Biosynthesis

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, [42] which is cyclized by the enzyme THC acid synthase to give THCA. Over time, or when heated, THCA is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops. [43] [44] It can also be produced in genetically modified yeast. [45]

Biosynthesis of THC THC biosynthesis labeled.svg
Biosynthesis of THC

History

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. [46] [47] [48] [49] THC was first isolated from Cannabis by Raphael Mechoulam in 1964. [50] [51] [52] [53]

Society and culture

Comparisons with medical cannabis

Female cannabis plants contain at least 113 cannabinoids, [54] including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis, [55] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis. [56]

Drug testing

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. [57] [58] [59] There is ongoing research to create devices capable of detecting THC in breath. [60] [61]

Regulation

THC, along with its double bond isomers and their stereoisomers, [62] 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 WHO. Based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III. [63] 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 [64] 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 FDA as an appetite stimulant for people with AIDS and an antiemetic for people receiving chemotherapy under the trade names Marinol and Syndros. [65]

In 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the convention, citing its medical uses and low abuse and addiction potential. [66] In 2019, the Committee recommended transferring Δ9-THC to Schedule I of the Single Convention on Narcotic Drugs of 1961, but its recommendations were rejected by the United Nations Commission on Narcotic Drugs. [67]

In the United States

As of 2023, 38 states, four territories, and the District of Columbia in the United States allow 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. [68] 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). [69] [70]

In Canada

As of October 2018 when recreational use of cannabis was legalized in Canada, some 220 dietary supplements and 19 veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions. [14]

Research

The status of THC as an illegal drug in most countries imposes restrictions on research material supply and funding, such as in the 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. [71] 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. [72]

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. [73] A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting adverse events, such as dizziness. [74]

Multiple sclerosis symptoms

Neurodegenerative disorders

Other neurological disorders

Potential for toxicity

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. [76]

See also

Related Research Articles

<span class="mw-page-title-main">Medical cannabis</span> Cannabis sativa L. (marijuana; hemp) used medicinally

Medical cannabis, medicinal cannabis or medical marijuana (MMJ) refers to cannabis products and cannabinoid molecules that are prescribed by physicians for their patients. The use of cannabis as medicine has a long history, but has not been as rigorously tested as other medicinal plants due to legal and governmental restrictions, resulting in limited clinical research to define the safety and efficacy of using cannabis to treat diseases.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 100 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive phytocannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).

<span class="mw-page-title-main">Cannabidiol</span> Phytocannabinoid discovered in 1940

Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple forms of epilepsy. It was discovered in 1940 and, as of 2024 clinical research on CBD included studies related to the treatment of anxiety, addiction, psychosis, movement disorders, and pain, but there is insufficient high-quality evidence that CBD is effective for these conditions. CBD is sold as an herbal dietary supplement and promoted with yet unproven claims of particular therapeutic effects.

<span class="mw-page-title-main">Tetrahydrocannabivarin</span> Homologue of tetrahydrocannabinol

Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes. THCV was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">THC-O-acetate</span> Acetate ester of tetrahydrocannabinol (THC)

THC-O-acetate is the acetate ester of THC. The term THC-O-acetate and its variations are commonly used for two types of the substance, dependent on which cannabinoid it is synthesized from. The difference between Δ8-THC and Δ9-THC is bond placement on the cyclohexene ring.

<span class="mw-page-title-main">11-Hydroxy-THC</span> Active metabolite of Δ9-THC

11-Hydroxy-Δ9-tetrahydrocannabinol, usually referred to as 11-hydroxy-THC is the main active metabolite of tetrahydrocannabinol (THC), which is formed in the body after Δ9-THC is consumed.

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

Δ9-Tetrahydrocannabutol is a phytocannabinoid found in cannabis that is a homologue of tetrahydrocannabinol (THC), the main active component of Cannabis. Structurally, they are only different by the pentyl side chain being replaced by a butyl side chain. THCB was studied by Roger Adams as early as 1942

<span class="mw-page-title-main">11-Nor-9-carboxy-THC</span> Main secondary metabolite of THC

11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, often referred to as 11-nor-9-carboxy-THC or THC-11-oic acid, is the main secondary metabolite of tetrahydrocannabinol (THC) which is formed in the body after cannabis is consumed.

<span class="mw-page-title-main">Dronabinol</span> Generic name of Δ9-THC in medicine

Dronabinol, sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep apnea reliever and is approved by the U.S. Food and Drug Administration (FDA) as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.

<span class="mw-page-title-main">Tetrahydrocannabinolic acid</span> THC precursor

Tetrahydrocannabinolic acid is a precursor of tetrahydrocannabinol (THC), an active component of cannabis.

Trauma contributed to promoting the use and potential abuse of cannabis. Conversely, cannabis use has been associated with the intensity of trauma and PTSD symptoms. While evidence of efficacious use of cannabis is growing in novelty, it is not currently recommended.

<span class="mw-page-title-main">Δ-8-Tetrahydrocannabinol</span> Isomer of tetrahydrocannabinol

Δ-8-tetrahydrocannabinol is a psychoactive cannabinoid found in the cannabis plant. It is an isomer of delta-9-tetrahydrocannabinol, the compound commonly known as THC, with which it co-occurs in hemp; natural quantities of ∆8-THC found in hemp are low. Psychoactive effects are similar to that of Δ9-THC, with central effects occurring by binding to cannabinoid receptors found in various regions of the brain.

<span class="mw-page-title-main">THC hemisuccinate</span> Synthetic derivative of tetrahydrocannabinol

THC hemisuccinate is a synthetic derivative of tetrahydrocannabinol, developed in the 1990s. It is a water-soluble prodrug ester which is converted into THC inside the body, and was developed to overcome the poor bioavailability of THC when taken by non-inhaled routes of administration. In medical applications it has mainly been formulated as rectal suppositories.

<span class="mw-page-title-main">11-Hydroxy-Δ-8-THC</span> Metabolite of delta-8-THC

11-Hydroxy-Δ-8-tetrahydrocannabinol is an active metabolite of Δ8-THC, a psychoactive cannabinoid found in small amounts in cannabis. It is an isomer of 11-OH-Δ9-THC, and is produced via the same metabolic pathway. It was the first cannabinoid metabolite discovered in 1970.

<span class="mw-page-title-main">11-Hydroxyhexahydrocannabinol</span> Chemical compound

11-Hydroxyhexahydrocannabinol is an active metabolite of tetrahydrocannabinol (THC) and a metabolite of the trace cannabinoid hexahydrocannabinol (HHC).

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

Tetrahydrocannabihexol is a phytocannabinoid, the hexyl homologue of tetrahydrocannabinol (THC) which was first isolated from Cannabis plant material in 2020 along with the corresponding hexyl homologue of cannabidiol, though it had been known for several decades prior to this as an isomer of the synthetic cannabinoid parahexyl. Another isomer Δ8-THCH is also known as a synthetic cannabinoid under the code number JWH-124, though it is unclear whether this occurs naturally in Cannabis, but likely is due to Δ8-THC itself being a degraded form of Δ9-THC. THC-Hexyl can be synthesized from 4-hexylresorcinol and was studied by Roger Adams as early as 1942.

Cannabinoids are compounds found in the cannabis plant or synthetic compounds that can interact with the endocannabinoid system. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (Delta-9-THC), the primary intoxicating compound in cannabis. Cannabidiol (CBD) is another major constituent of some cannabis plants. Conversion of CBD to THC can occur when CBD is heated to temperatures between 250–300 °C, potentially leading to its partial transformation into THC.

<span class="mw-page-title-main">8-Hydroxyhexahydrocannabinol</span> Cannabinoid metabolite

8-Hydroxyhexahydrocannabinols are active primary metabolites of hexahydrocannabinol (HHC) in animals and trace phytocannabinoids. The 8-OH-HHCs are produced in notable concentrations following HHC administration in several animal species, including humans. They have drawn research interest for their role in HHC toxicology and stereoisomeric probes of the cannabinoid drug/receptor interaction.

Conversion of cannabidiol (CBD) to tetrahydrocannabinol (THC) can occur through a ring-closing reaction. This cyclization can be acid-catalyzed or brought about by heating.

References

  1. ↑ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ↑ "Marinol" (PDF). Food and Drug Administration . Archived from the original (PDF) on 2014-05-13. Retrieved 2014-03-14.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Grotenhermen F (2003). "Pharmacokinetics and pharmacodynamics of cannabinoids". Clinical Pharmacokinetics. 42 (4): 327–60. doi:10.2165/00003088-200342040-00003. PMID   12648025. S2CID   25623600.
  4. ↑ The Royal Pharmaceutical Society of Great Britain (2006). "Cannabis". In Sweetman SC (ed.). Martindale: The Complete Drug Reference: Single User (35th ed.). Pharmaceutical Press. ISBN   978-0-85369-703-9.[ page needed ]
  5. ↑ "Tetrahydrocannabinol – Compound Summary". National Center for Biotechnology Information. PubChem. Archived from the original on 12 January 2014. Retrieved 12 January 2014. 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%.
  6. ↑ Gaoni Y, Mechoulam R (April 1964). "Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish". Journal of the American Chemical Society. 86 (8): 1646–47. doi:10.1021/ja01062a046.
  7. ↑ Adams R, Cain CK, McPhee WD, Wearn RB (August 1941). "Structure of Cannabidiol. XII. Isomerization to Tetrahydrocannabinols". Journal of the American Chemical Society. 63 (8): 2209–13. doi:10.1021/ja01853a052.
  8. 1 2 Garrett ER, Hunt CA (July 1974). "Physiochemical properties, solubility, and protein binding of delta9-tetrahydrocannabinol". Journal of Pharmaceutical Sciences. 63 (7): 1056–64. doi:10.1002/jps.2600630705. PMID   4853640.
  9. ↑ Pichersky E, Raguso RA (November 2018). "Why do plants produce so many terpenoid compounds?". The New Phytologist. 220 (3): 692–702. Bibcode:2018NewPh.220..692P. doi:10.1111/nph.14178. hdl: 2027.42/146372 . PMID   27604856.
  10. ↑ "THC Chemistry by Alexander Shulgin - January 21, 1995". www.druglibrary.org. Archived from the original on 2020-11-12. Retrieved 2020-11-12.
  11. ↑ "Marinol (Dronabinol)" (PDF). U.S. Food and Drug Administration. September 2004.
  12. ↑ "Sativex Oromucosal Spray – Summary of Product Characteristics". UK Electronic Medicines Compendium. March 2015. Archived from the original on 2016-08-22. Retrieved 2017-06-01.
  13. ↑ Multiple Sclerosis Trust. October 2014 Sativex (nabiximols) – factsheet Archived 2015-09-20 at the Wayback Machine
  14. 1 2 "Health products containing cannabis or for use with cannabis: Guidance for the Cannabis Act, the Food and Drugs Act, and related regulations". Government of Canada. 11 July 2018. Archived from the original on 19 October 2018. Retrieved 19 October 2018.
  15. ↑ "В Україні легалізували використання медичного канабісу, але не всього" [In Ukraine, some medical cannabis has been legalized, but not all]. УП.Життя (UP.Life) (in Ukrainian). 9 April 2021. Archived from the original on 9 April 2021. Retrieved 10 April 2021.
  16. 1 2 Ng T, Keshock MC (2024). "Tetrahydrocannabinol (THC)". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   33085321 . Retrieved 2024-08-20.
  17. ↑ "Short-Term Effects of Cannabis Consumption | Washington State Liquor and Cannabis Board". lcb.wa.gov. Retrieved 2024-08-20.
  18. ↑ Thompson GR, Rosenkrantz H, Schaeppi UH, Braude MC (July 1973). "Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys". Toxicology and Applied Pharmacology. 25 (3): 363–72. Bibcode:1973ToxAP..25..363T. doi:10.1016/0041-008X(73)90310-4. PMID   4199474. In dogs and monkeys, single oral doses of Δ9-THC and Δ8-THC between 3000 and 9000/mg/kg were nonlethal.
  19. ↑ Hartung B, Kauferstein S, Ritz-Timme S, Daldrup T (April 2014). "Sudden unexpected death under acute influence of cannabis". Forensic Science International. 237: e11–e13. doi:10.1016/j.forsciint.2014.02.001. PMID   24598271.
  20. ↑ Nahas GC (1 January 1972). "UNODC - Bulletin on Narcotics - 1972 Issue 2 - 002". United Nations: Office on Drugs and Crime: 11–27. Archived from the original on 2022-12-11. Retrieved 2022-12-11.
  21. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Highlights of prescribing information" (PDF). www.accessdata.fda.gov.
  22. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Lucas CJ, Galettis P, Schneider J (November 2018). "The pharmacokinetics and the pharmacodynamics of cannabinoids". Br J Clin Pharmacol. 84 (11): 2477–2482. doi:10.1111/bcp.13710. PMC   6177698 . PMID   30001569.
  23. 1 2 Bow EW, Rimoldi JM (28 June 2016). "The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation". Perspectives in Medicinal Chemistry. 8: 17–39. doi:10.4137/PMC.S32171. PMC   4927043 . PMID   27398024.
  24. 1 2 Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 (Suppl 1): S13–S18. doi: 10.1038/sj.ijo.0803272 . PMID   16570099.
  25. ↑ Elphick MR, Egertová M (March 2001). "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC   1088434 . PMID   11316486.
  26. ↑ Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA (November 2009). "Hydroxylation and further oxidation of delta9-tetrahydrocannabinol by alkane-degrading bacteria". Applied and Environmental Microbiology. 75 (22): 7135–41. Bibcode:2009ApEnM..75.7135R. doi:10.1128/AEM.01277-09. PMC   2786519 . PMID   19767471. 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.
  27. ↑ Ashton CH (February 2001). "Pharmacology and effects of cannabis: a brief review". The British Journal of Psychiatry. 178 (2): 101–06. doi: 10.1192/bjp.178.2.101 . PMID   11157422. 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.
  28. ↑ Huestis MA (August 2007). "Human cannabinoid pharmacokinetics". Chemistry & Biodiversity. 4 (8): 1770–804. doi:10.1002/cbdv.200790152. PMC   2689518 . PMID   17712819. THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver.
  29. ↑ Pertwee RG (January 2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC   2219532 . PMID   17828291.
  30. ↑ Eymery MC, McCarthy AA, Hausmann J (February 2023). "Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling". Life Science Alliance. 6 (2): e202201595. doi:10.26508/lsa.202201595. PMC   9834664 . PMID   36623871.
  31. 1 2 3 4 5 Tagen M, Klumpers LE (August 2022). "Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC". Br J Pharmacol. 179 (15): 3915–3933. doi: 10.1111/bph.15865 . PMID   35523678.
  32. 1 2 3 4 5 6 7 8 Foster BC, Abramovici H, Harris CS (November 2019). "Cannabis and Cannabinoids: Kinetics and Interactions". Am J Med. 132 (11): 1266–1270. doi:10.1016/j.amjmed.2019.05.017. PMID   31152723. S2CID   173188471.
  33. ↑ Qian Y, Gurley BJ, Markowitz JS (2019). "The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications". Journal of Clinical Psychopharmacology. 39 (5): 462–71. doi:10.1097/JCP.0000000000001089. PMID   31433338. S2CID   201118659.
  34. ↑ Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (March 2007). "Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes". Life Sciences. 80 (15): 1415–19. doi:10.1016/j.lfs.2006.12.032. PMID   17303175.
  35. ↑ Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A (April 2017). "Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis". Drug Testing and Analysis. 9 (4): 626–33. doi:10.1002/dta.1998. PMID   27341312. S2CID   27488987. Archived from the original on 2023-01-05. Retrieved 2022-12-02.
  36. ↑ Huestis MA (2005). "Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9-Tetrahydrocannabinol, Cannabidiol and Cannabinol". Handbook of Experimental Pharmacology. 168 (168): 657–90. doi:10.1007/3-540-26573-2_23. ISBN   978-3-540-22565-2. PMID   16596792.
  37. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018677s011lbl.pdf
  38. ↑ Mechoulam R, Gaoni Y (July 1965). "A Total Synthesis of Dl-Delta-1-Tetrahydrocannabinol, the Active Constituent of Hashish". Journal of the American Chemical Society. 87 (14): 3273–75. doi:10.1021/ja01092a065. PMID   14324315.
  39. ↑ Pate DW (1994). "Chemical ecology of Cannabis". Journal of the International Hemp Association. 2 (29): 32–37. Archived from the original on 2018-12-21. Retrieved 2017-12-09.
  40. ↑ Pate DW (1983). "Possible role of ultraviolet radiation in evolution of Cannabis chemotypes". Economic Botany. 37 (4): 396–405. Bibcode:1983EcBot..37..396P. doi:10.1007/BF02904200. S2CID   35727682.
  41. ↑ Lydon J, Teramura AH, Coffman CB (August 1987). "UV-B radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes". Photochemistry and Photobiology. 46 (2): 201–06. doi:10.1111/j.1751-1097.1987.tb04757.x. PMID   3628508. S2CID   7938905. Archived from the original on 2020-06-27. Retrieved 2019-07-04.
  42. ↑ Fellermeier M, Zenk MH (May 1998). "Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol". FEBS Letters. 427 (2): 283–85. Bibcode:1998FEBSL.427..283F. doi: 10.1016/S0014-5793(98)00450-5 . PMID   9607329.
  43. ↑ Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, et al. (2009). "Identification of candidate genes affecting Delta9-tetrahydrocannabinol biosynthesis in Cannabis sativa". Journal of Experimental Botany. 60 (13): 3715–26. doi:10.1093/jxb/erp210. PMC   2736886 . PMID   19581347.
  44. ↑ Baker PB, Taylor BJ, Gough TA (June 1981). "The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products". The Journal of Pharmacy and Pharmacology. 33 (6): 369–72. doi:10.1111/j.2042-7158.1981.tb13806.x. PMID   6115009. S2CID   30412893.
  45. ↑ Luo X, Reiter MA, d'Espaux L, Wong J, Denby CM, Lechner A, et al. (March 2019). "Complete biosynthesis of cannabinoids and their unnatural analogues in yeast" (PDF). Nature. 567 (7746): 123–26. Bibcode:2019Natur.567..123L. doi:10.1038/s41586-019-0978-9. PMID   30814733. S2CID   71147445. Archived (PDF) from the original on 2022-01-14. Retrieved 2021-12-30.
  46. ↑ Adams R (1942). "Marihuana: Harvey Lecture, February 19, 1942". Bulletin of the New York Academy of Medicine. 18 (11): 705–730. PMC   1933888 . PMID   19312292.
  47. ↑ Adams R, Loewe S, Smith CM, McPhee WD (March 1942). "Tetrahydrocannabinol Homologs and Analogs with Marihuana Activity. XIII 1". Journal of the American Chemical Society. 64 (3): 694–697. doi:10.1021/ja01255a061. ISSN   0002-7863.
  48. ↑ US 2419937,Roger A,"Marihuana active compounds",issued 6 May 1947, assigned to Individual
  49. ↑ Adams R, Hunt M, Clark JH (1940). "Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp". Journal of the American Chemical Society. 62: 196–200. doi:10.1021/ja01858a058.
  50. ↑ Mechoulam R (June 1970). "Marihuana chemistry". Science. 158 (3936): 1159–66. Bibcode:1970Sci...168.1159M. doi:10.1126/science.168.3936.1159. PMID   4910003.
  51. ↑ Gaoni Y, Mechoulam R (1964). "Isolation, structure and partial synthesis of an active constituent of hashish". Journal of the American Chemical Society. 86 (8): 1646–47. doi:10.1021/ja01062a046.
  52. ↑ "Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel". February 2007. Archived from the original on 2011-04-30.
  53. ↑ Geller T (2007). "Cannabinoids: A Secret History". Chemical Heritage Newsmagazine. 25 (2). Archived from the original on 19 June 2008.
  54. ↑ Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, et al. (February 2016). "Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes". Journal of Natural Products. 79 (2): 324–31. doi:10.1021/acs.jnatprod.5b00949. PMID   26836472. Archived from the original on 2023-01-05. Retrieved 2022-12-02.
  55. ↑ Pickens JT (April 1981). "Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content". British Journal of Pharmacology. 72 (4): 649–56. doi:10.1111/j.1476-5381.1981.tb09145.x. PMC   2071638 . PMID   6269680.
  56. ↑ Morales P, Hurst DP, Reggio PH (2017). "Molecular Targets of the Phytocannabinoids: A Complex Picture". Phytocannabinoids. Progress in the Chemistry of Organic Natural Products. Vol. 103. pp. 103–31. doi:10.1007/978-3-319-45541-9_4. ISBN   978-3-319-45539-6. PMC   5345356 . PMID   28120232.
  57. ↑ Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, et al. (December 2009). "Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC". Clinical Chemistry. 55 (12): 2180–89. doi:10.1373/clinchem.2008.122119. PMC   3196989 . PMID   19833841.
  58. ↑ Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, et al. (May 2010). "Concentrations of delta9-tetrahydrocannabinol and 11-nor-9-carboxytetrahydrocannabinol in blood and urine after passive exposure to Cannabis smoke in a coffee shop". Journal of Analytical Toxicology. 34 (4): 196–203. doi: 10.1093/jat/34.4.196 . PMID   20465865.
  59. ↑ Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1644–48.
  60. ↑ Wallace A (January 2, 2020). "Testing drivers for cannabis is hard. Here's why". CNN Business. Archived from the original on 26 February 2020. Retrieved 26 February 2020.
  61. ↑ Mirzaei H, O'Brien A, Tasnim N, Ravishankara A, Tahmooressi H, Hoorfar M (May 2020). "Topical review on monitoring tetrahydrocannabinol in breath". Journal of Breath Research. 14 (3): 034002. Bibcode:2020JBR....14c4002M. doi:10.1088/1752-7163/ab6229. PMID   31842004. S2CID   209388839.
  62. ↑ Mazzoccanti G, Ismail OH, D'Acquarica I, Villani C, Manzo C, Wilcox M, et al. (November 2017). "Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra high performance supercritical fluid chromatography". Chemical Communications. 53 (91): 12262–65. doi:10.1039/C7CC06999E. hdl: 11573/1016698 . PMID   29072720.
  63. ↑ "The UN Drug Control Conventions". 8 October 2015. Archived from the original on 3 February 2018. Retrieved 3 December 2015.
  64. ↑ "Drug Schedules; Schedule 1". United States Drug Enforcement Administration. US Drug Enforcement Administration, Department of Justice. 1 December 2017. Archived from the original on 7 May 2021. Retrieved 14 January 2018.
  65. ↑ "Marinol (Dronabinol)" (PDF). US Food and Drug Administration. September 2004. Archived (PDF) from the original on 10 February 2017. Retrieved 14 January 2018.
  66. ↑ "WHO Expert Committee on Drug Dependence". World Health Organization. Archived from the original on January 7, 2005. Retrieved 12 January 2014.
  67. ↑ Riboulet-Zemouli K, Krawitz MA, Ghehiouèche F (2021). "History, Science, and Politics of International Cannabis Scheduling, 2015–2021". FAAAT editions . Rochester, NY. SSRN   3932639 – via SSRN.
  68. ↑ "State Medical Cannabis Laws". National Conference of State Legislatures. 3 February 2022. Archived from the original on 11 December 2018. Retrieved 10 December 2022.
  69. ↑ "Drug scheduling: Marijuana (Cannabis)". US Department of Justice, Drug Enforcement Administration. 2022. Archived from the original on 10 December 2022. Retrieved 10 December 2022.
  70. ↑ "Controlled Substances" (PDF). usdoj.gov. Archived (PDF) from the original on April 21, 2021. Retrieved December 11, 2022.
  71. ↑ "Medical Marijuana". Multidisciplinary Association for Psychedelic Studies. Archived from the original on 14 April 2012. Retrieved 12 January 2014.
  72. ↑ Mead A (May 2017). "The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law". Epilepsy & Behavior. 70 (Pt B): 288–91. doi: 10.1016/j.yebeh.2016.11.021 . PMID   28169144. Archived from the original on 2022-10-21. Retrieved 2018-01-26.
  73. 1 2 3 4 5 6 7 8 Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. (April 2014). "Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology". Neurology. 82 (17): 1556–63. doi:10.1212/WNL.0000000000000363. PMC   4011465 . PMID   24778283.
  74. 1 2 Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. (2015). "Cannabinoids for Medical Use: A Systematic Review and Meta-analysis". JAMA. 313 (24): 2456–73. doi: 10.1001/jama.2015.6358 . hdl: 10757/558499 . PMID   26103030.
  75. ↑ Krishnan S, Cairns R, Howard R (April 2009). Krishnan S (ed.). "Cannabinoids for the treatment of dementia". The Cochrane Database of Systematic Reviews. 2009 (2): CD007204. doi:10.1002/14651858.CD007204.pub2. PMC   7197039 . PMID   19370677.
  76. ↑ Reece AS, Hulse GK (July 2016). "Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity". Mutation Research. 789: 15–25. Bibcode:2016MRFMM.789...15R. doi:10.1016/j.mrfmmm.2016.05.002. PMID   27208973.
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