Tetrahydrocannabinol (including six isomers)

IUPAC Name

N-(4-Methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4-yl]butanamide

Year(s) and type of review / ECDD meetings
Drug Class
ECDD Recommendation
Rescheduled from Schedule I of the 1971 Convention on Psychotropic Substances to Schedule I of the 1961 Single Convention on Narcotic Drugs
Recommendation (from TRS)
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. These molecules with their chemical designations are listed in Table 1. Most exist only for the purpose of scientific research; however, there appears to be no ongoing scientific research about their use. This entry in the Schedules does not include delta-9-tetrahydrocannabinol (dronabinol).

Table 1.

Molecules of THC with their chemical designations

Molecule Substance identification

delta-6a(10a)-THC 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol

delta-6a(7)-THC (9R,10aR)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol

delta-7-THC (6aR,9R,10aR)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3- pentyl-6H-dibenzo[b,d]pyran-1-ol

delta-8-THC (6aR,10aR)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol

delta-10-THC 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol

delta-9(11)-THC (6aR,10aR)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene3-pentyl-6H-dibenzo[b,d]pyran-1-ol

WHO review history
Isomers of THC were pre-reviewed at the fortieth ECDD meeting and recommended for a critical review.

Similarity to known substances and effects on the central nervous system
Both Δ8-THC and Δ9,11-THC 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. Δ6a,10a-THC has psychoactive effects in humans similar to those of Δ9-THC but is less potent. 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.

Dependence potential
There is no available evidence from either animal or human studies to determine the potential for dependence of any of the six isomers of THC. Moreover, there has been no definitive study of the mechanism(s) of action of the isomers and hence it is not possible to extrapolate from an understanding of the mechanism to the likely dependence potential.

Actual abuse and/or extent of abuse
Data from both human and animal studies relevant to abuse potential are at best very limited and, for some isomers, non-existent. It is not possible to assess the abuse potential of any of the isomers based on a clearly established mechanism of action. There is no evidence of actual abuse (in contrast to abuse potential) for any of the isomers studied.

In animal drug discrimination tests, Δ9,11-THC has been shown to substitute for Δ9-THC in most studies and induces characteristic CB1 agonist effects, including suppression of locomotor activity, hypothermia, antinociception and ring immobility. Δ8-THC induces characteristic CB1 agonist effects and Δ9-THC- like discriminative effects. These two compounds were less potent than Δ9-THC. In contrast, Δ10-THC failed to show Δ9-THC-like discriminative effects in an animal model.

Only very limited data on the abuse potential of these isomers in humans are available. The two isomers that were assessed, Δ8-THC and Δ6a,10a-THC, each produced similar subjective effects to those of Δ9-THC when administered by various routes.

In summary, there is evidence from animal and human studies that Δ8- THC has abuse potential of a type similar to Δ9-THC. There is much more limited evidence of abuse potential for Δ9,11-THC and Δ6a,10a-THC based on animal and human research, respectively. For Δ10-THC, the only evidence is negative and for the two remaining isomers there is no evidence.

Therapeutic usefulness
The six isomers listed under Schedule I of the 1971 Convention on Psychotropic Substances are not known to have any therapeutic uses.

Recommendations
There are currently six isomers of THC listed in Schedule I of the 1971 Convention on Psychotropic Substances. These six isomers are chemically similar to Δ9-THC, which is currently listed in Schedule II of the 1971 Convention on Psychotropic Substances. The Committee has recommended deleting Δ9-THC from this Schedule and including it in Schedule I of the 1961 Single Convention on Narcotic Drugs.

While the six isomers are chemically similar to Δ9-THC, there is little or no evidence concerning their abuse potential and acute intoxicating effects. There are no reports that the THC isomers listed in Schedule I of the 1971 Convention induce physical dependence, or that they are being abused or are likely to be abused so as to constitute a public health or social problem. There are no reported medical or veterinary uses of these isomers.

While the Committee recognized that available evidence has not demonstrated abuse and ill-effects of these isomers similar to those associated with Δ9-THC, it noted that, due to the chemical similarity of each of the six isomers to Δ9-THC, it is very difficult to differentiate any of these six isomers from Δ9-THC using standard methods of chemical analysis.

Recommendation: The Committee recommended that tetrahydrocannabinol (understood to refer to the six isomers currently listed in Schedule I of the 1971 Convention on Psychotropic Substances) be added to Schedule I of the 1961 Single Convention on Narcotic Drugs, subject to the Commission’s adoption of the recommendation to add dronabinol (delta-9- tetrahydrocannabinol) to Schedule I of the 1961 Single Convention on Narcotic Drugs.

As indicated in the Guidance on the WHO review of psychoactive substances for international control (4), to facilitate efficient administration of the international control system, it is not advisable to place a substance under more than one Convention.

■■ Recommendation: The Committee recommended that tetrahydrocannabinol (understood to refer to the six isomers currently listed in Schedule I of the 1971 Convention on Psychotropic Substances) be deleted from the 1971 Convention on Psychotropic Substances, subject to the Commission’s adoption of the recommendation to add tetrahydrocannabinol to Schedule I of the 1961 Single Convention on Narcotic Drugs.

The Committee acknowledged that placing these six isomers under the same Convention and in the same Schedule as Δ9-THC would facilitate the implementation of international control of Δ9-THC, as well as assist Member States in the implementation of control measures at country level.