Tetrahydrocannabinol

Substance identification
The isomers of THC include six molecules that are identified in Schedule I of the Convention on Psychotropic Substances of 1971 including their stereochemical variants.

Chemistry
Methods have been developed for synthesis of these isomers.

Ease of convertibility into controlled substances
It is possible to convert (−)-trans-Δ8-THC into (−)-trans-Δ9-THC in laboratory facilities.

General pharmacology
Δ8-THC and Δ9(11)-THC each produce Δ9-THC-like pharmacological effects in some animal models, whereas Δ10-THC does not. In humans, Δ8-THC is active when administered via several different routes, for example, oral, intravenous and inhalation. One stereoisomer of Δ6a,10a-THC ((S)-(−)- Δ6a,10a-THC) has psychoactive effects in humans similar to those of Δ9-THC but is quantitatively less potent (1:3 to 1:6), while the (R)-(+)-Δ6a,10a-THC, a second stereoisomer was inactive. Δ6a(10a)-THC also produces Δ9-THC-like effects when smoked, but the effects are less marked and have a shorter duration than those of Δ9 THC. None of the other isomers have been tested in humans.

Toxicology
Very little information exists on the toxicology of these isomers. There are limited preclinical toxicity data, and the isomers have not been administered to humans for extended periods. Limited toxicology data are available only for Δ8-THC, Δ6a,10a-THC and Δ9 (11)-THC.

The oral median lethal dose (LD50) of Δ8-THC in rats is 2000 mg/kg. Subcutaneous administration of Δ8-THC (up to 40 mg/kg) in rats prior to conception or during gestation did not have teratogenic effects. From the limited data available, Δ8-THC does not appear to be mutagenic.

In mice, intravenous administration of 200 mg/kg Δ6a,10a-THC did not promote mortality. Δ6a,10a-THC does not reduce locomotor activity in mice.

When administered to humans via smoking, Δ6a,10a-THC has much lower psychoactivity than Δ9-THC. The effects of smoking 15 mg Δ6a,10a-THC are less marked and have a shorter duration than a 12-mg dose of Δ9-THC. Δ6a,10a THC produced symptoms of light-headedness, numbness and tingling in the extremities and face, fatigue, cold perspiration, drowsiness and a feeling of relaxation. Impairment of thinking and the perception of time were less pronounced than with Δ9-THC.

Δ9 (11)-THC has an intravenous LD50 of 93 mg/kg in mice, which is double that found for Δ9-THC.

Adverse reactions in humans
Only Δ8-THC and Δ6a,10a-THC have been tested in humans. The acute intoxicating effects of these molecules are similar in quality but less potent than acute doses of Δ9-THC. These molecules are not available for medical or non- medical purposes, so little is known about their adverse effects in humans.

Dependence potential
No reports are available of studies that have assessed the potential of THC isomers for inducing physical dependence in laboratory animals or humans

Abuse potential
Data on the specific abuse potential of the six isomers are sparse. Of the six THC isomers reviewed here, preclinical assessment of abuse liability of three isomers has been evaluated for their pharmacological similarity to Δ9-THC, particularly in discrimination tests for substitution of the Δ9-THC discriminative stimulus. Δ9(11)-THC demonstrated the cannabimimetic tetrad of characteristic Δ9-THC-like effects, including suppression of locomotor activity, hypothermia, antinociception and ring immobility in animal studies, and was found to be several-fold less potent than Δ9-THC for each dependent measure. It has also been shown to produce Δ9-THC-like discriminative effects but at lower potency than Δ9-THC. 43

Δ8-THC also produces Δ9-THC-like discriminative effects but at lower potency, and induces the characteristic tetrad of Δ9-THC-like effects as described in the paragraph above.

Δ10-THC, the third isomer that has been tested, did not produce Δ9-THC- like discriminative effects.

Few studies addressing the abuse potential of THC isomers have been undertaken in humans. The information on abuse potential of THC isomers is based primarily on early observational studies in which their subjective or physiological effects in human volunteers were compared to those reported following Δ9-THC administration. Of the six THC isomers reviewed here, only Δ8-THC and Δ6a,10a-THC have been tested in humans. The acute intoxicating effects of these substances are similar to those of Δ9-THC, but they are less potent.

Therapeutic applications, extent of therapeutic use and
epidemiology of medical use No medical or veterinarian use of these isomers has been reported.

Listing in the WHO Model List of Essential Medicines
None of the isomers is listed in the WHO EML (20th list) or the WHO Model List of Essential Medicines for Children (6th list).

Marketing authorizations (as a medicinal product)
There are no known marketing authorizations for these isomers.

Industrial use
These isomers have no known legitimate industrial use.

Non-medical use, abuse and dependence
No case reports of abuse or dependence relating to the use of these isomers were available. Between 1995 and 2014, one study reported a change in the potency of seized cannabis products in the USA. The data showed that before 2009, Δ8-THC had not been detected in cannabis seizures in the USA. A gradual increase in Δ8- THC content was observed from 0 1% to 0 7% in 2014. However, compared to Δ9-THC, Δ8-THC content was lower by a factor of 10, and increasing potency of Δ8-THC did not appear to impact Δ9-THC concentrations.

Nature and magnitude of public health problems related to
misuse, abuse and dependence These isomers appear not to have been available for use. At present no public health problems (for example, driving under the influence of drugs or comorbidities) have been associated with their use.

Licit production, consumption and international trade
There is no known licit production of these isomers.

Illicit manufacture and traffic and related information
There appears to be no illicit manufacture or traffic of these isomers.

Current international controls and their impact
These isomers are included in Schedule I of the Convention on Psychotropic Substances of 1971.

Current and past national controls
The extent to which the isomers of THC, other than Δ9-THC, are controlled depends on the exact wording of the legislation in each jurisdiction.

WHO review history
The isomers of Δ9-THC have never been subject to a critical review or pre-review by the ECDD.

Recommendation
There are currently six isomers of THC listed in Schedule I of the 1971 Convention. Of the six THC isomers reviewed here, the abuse potential of only two, Δ8-THC and Δ6a,10a-THC, have been evaluated in a few human studies. These studies found that the acute intoxicating effects of these substances are similar to those of Δ9- THC, but they are less potent.

There are no reports that THC isomers induce physical dependence. There are no reported medical or veterinary uses of these isomers.

There is no evidence that any of these listed isomers are being abused or are likely to be abused so as to constitute a public health or social problem. However, the Committee noted the potential difficulty of differentiating these six isomers (listed in Schedule 1 of the 1971 Convention) from Δ9-THC (listed in Schedule II of the 1971 Convention) using standard methods of chemical analysis owing to their chemical similarities. The Committee further noted that this is an important factor to consider in the scheduling of these isomers.

The Committee concluded that there is sufficient information to recommend a critical review of the isomers of THC at a future ECDD meeting and to explore further the relevance of their current scheduling within the 1971 Convention.