Tetrahydrocannabinol

"THC" redirects here. For other uses, see THC (disambiguation).
Tetrahydrocannabinol (THC)
INN: dronabinol
Systematic (IUPAC) name
(−)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
Clinical data
Trade names Marinol
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability		 8–10% (Relatively low risk of tolerance)[1]
Addiction
liability		 Low
Routes of
administration		 Orally, local/topical, transdermal, sublingual, inhaled
Legal status
Legal status
Pharmacokinetic data
Bioavailability 10–35% (inhalation), 6–20% (oral)[3]
Protein binding 97–99%[3][4][5]
Metabolism Mostly hepatic by CYP2C[3]
Biological 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
CAS Number 1972-08-3 YesY
ATC code A04AD10 (WHO)
PubChem CID 16078
IUPHAR/BPS 2424
DrugBank DB00470 YesY
ChemSpider 15266 YesY
UNII 7J8897W37S YesY
ChEBI CHEBI:66964 N
ChEMBL CHEMBL465 YesY
Synonyms  (6aR,10aR)-delta-9-tetrahydrocannabinol
Chemical data
Formula C21H30O2
Molar mass 314.469 g/mol
Specific rotation −152° (ethanol)
Physical data
Boiling point 157 °C (315 °F) [6]
Solubility in water 0.0028,[7] (23 °C) mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Tetrahydrocannabinol (THC, dronabinol by INN), or more precisely its main isomer (−)-trans-Δ9-tetrahydrocannabinol, is the principal psychoactive constituent (or cannabinoid) of cannabis. It can be an amber or gold colored glassy solid when cold, which becomes viscous and sticky if warmed.

Like most pharmacologically-active secondary metabolites of plants, THC in Cannabis is assumed to be involved in self-defense, perhaps against herbivores.[8] THC also possesses high UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.[9][10][11]

THC, along with its double bond isomers and their stereoisomers, 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.[12] Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV).

A pharmaceutical formulation is available by prescription in the U.S. and Canada under the brand name Marinol.

Medical uses

Not to be confused with Droperidol.

Dronabinol is the INN for a pure isomer of THC, (–)-trans-Δ9-tetrahydrocannabinol,[13] which is the main isomer found in cannabis. It is used to treat anorexia in people with HIV/AIDS as well as for refractory nausea and vomiting in people undergoing chemotherapy. It is safe and effective for these uses.[14][15]

THC is also 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.[16][17]

Adverse effects

A hybrid Cannabis strain (White Widow) (which contains one of the highest amounts of Cannabidiol), flower coated with trichomes, which contain more THC than any other part of the plant
Closeup of THC-filled trichomes on a Cannabis sativa leaf

Acute toxicity

There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol.[18] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction (heart attack);[19][20] however, oral administration does not have this effect. Information about the toxicity of THC is primarily based on results from non-human studies. The toxicity depends on the route of administration and the laboratory animal.

The estimated lethal dose of intravenous dronabinol in humans is 30 mg/kg,[21] meaning lethality is unlikely. The typical medicinal dosage administered is two 2.5 mg capsules daily for an 80 kg man (~170 lb). A lethal dose for such a person would be approximately 960 of those capsules infused intravenously. Non-fatal overdoses have occurred: "Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules."[21]

A meta analysis of clinical trials conducted using standardized cannabis extracts or THC conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least two trials. There was a single death rated by the investigator as "possibly related" to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the subjects from the epilepsy trials.[22]

Overdose

An overdose of dronabinol usually presents with lethargy, decreased motor coordination, slurred speech, and postural hypotension. The FDA estimates the lethal human dose of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70 kg).[23]

Pharmacology

Mechanism of action

For a review of the mechanisms behind endocannabinoid synaptic transmission, see Endocannabinoid system.

The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki=10nM[24]), located mainly in the central nervous system, and the CB2 receptor (Ki=24nM[24]), mainly expressed in cells of the immune system.[25] The psychoactive effects of THC are primarily mediated by its activation of CB1G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.[26]

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). 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 efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[27] THC is a lipophilic molecule[28] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[29][30]

THC, similarly to cannabidiol, albeit less potently, is an allosteric modulator of the μ- and δ-opioid receptors.[31]

Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.[27] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.[25]

Pharmacokinetics

THC is metabolized mainly to 11-OH-THC by the 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.[32] 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.[33]

Physical and chemical properties

Discovery and structure identification

The discovery of THC, by a team of researchers from Hebrew University Pharmacy School, was first reported in 1964,[34] with substantial later work reported by Raphael Mechoulam in June 1970.[35]

Solubility

An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[7] THC, CBD, CBN, CBC, CBG and over 113 other molecules make up the phytocannabinoid family.[36][37]

Biosynthesis

Biosynthesis of THCA

In the Cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC, THC-COOH). Geranyl pyrophosphate and olivetolic acid react, catalysed by an enzyme to produce cannabigerolic acid,[38] 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.[39][40]

Detection in body fluids

Main article: Cannabis drug testing

THC, 11-OH-THC and THC-COOH 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.[41][42][43]

History

THC was first isolated in 1964 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science.[34][44][45]

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.

On May 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.[46] 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 Δ9-tetrahydrocannabinol (also referred to as Δ9-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 (See also United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances).

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.[47]

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 constituted 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".[48]

At its 33rd meeting, 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 potential.[49]

Society and culture

Brand names

Not to be confused with Droperidol.

Dronabinol is marketed as Marinol,[50] a registered trademark of 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. Dronabinol is available as a prescription drug (under Marinol[51]) in several countries including the United States, Germany, South Africa and Australia.[52] In the United States, Marinol is a 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 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol's U.S. Food and Drug Administration (FDA) approvals for medical use has raised much controversy[53] as to why natural THC is considered a schedule I drug.[54]

Comparisons with medical cannabis

Further information: Medical cannabis

Female cannabis plants contain at least 113 cannabinoids,[55] including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis;[56] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.[57]

It takes over one hour for Marinol to reach full systemic effect,[58] compared to seconds or minutes for smoked or vaporized cannabis.[59] Some people accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages. Many people using Marinol 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. For that reason, alternative THC-containing medications based on botanical extracts of the cannabis plant such as nabiximols are being developed. 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."[60] Mr. Kleiman's opinion notwithstanding, clinical trials comparing the use of cannabis extracts with Marinol in the treatment of cancer cachexia have demonstrated equal efficacy and well-being among subjects in the two treatment arms.[61] United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, except synthetics like nabilone.[62]

Research

Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became legalized in Colorado, Washington state, Oregon, Alaska, and Washington D.C.[63]

In April 2014 the American Academy of Neurology published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders.[22] The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality.[22] The study found evidence supporting the effectiveness of the cannabis extracts that were tested and THC in treating certain symptoms of multiple sclerosis, but found insufficient evidence to determine the effectiveness of the tested cannabis products in treating several other neurological diseases.[22]

Several of the clinical trials exploring the safety and efficacy of "oral cannabis extract" that were reviewed by the AAN were conducted using "Cannador", made by the Institute for Clinical Research (IKF) in Berlin,[64] which is a capsule with a standardized Cannabis sativa extract; the cannabis grown in Switzerland and processed in Germany.[65]:88 Each capsule of Cannador contains 2.5mg Δ9- tetrahydrocannabinol and cannabidiols are standardized to a range 0.8–1.8mg.[66]

Multiple sclerosis symptoms

Neurodegenerative disorders

Other neurological disorders

See also

References

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