Tetrahydrocannabinol (THC) is one of at least 113 cannabinoids identified in cannabis. THC is the principal psychoactive constituent of cannabis. With chemical name (−)-trans-Δ⁹-tetrahydrocannabinol, the term THC also refers to cannabinoid isomers.
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. THC is a lipophilic molecule and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).
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. 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.
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. 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.
Physical and chemical properties
Discovery and structure identification
In 1940, cannabidiol was isolated and identified from Cannabis sativa, and THC was isolated and described for its structure and synthesis in 1964.
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.
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.
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 regulated sources of cannabis for researchers until August 2016 when licenses were provided to growers for supplies of medical marijuana. Although cannabis is legalized for medical uses in half 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.
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. A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting adverse events, such as euphoria and dizziness.
Multiple sclerosis symptoms
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.
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.
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
Huntington disease. No reliable conclusions 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
Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.
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.
Other neurological disorders
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.
Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.
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