Dronabinol: Substances recommended for changes in scheduling

Substance identifi cation

 Dronabinol (INN) is (6aR,10aR) -6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3- pentyl-6-H-dibenzo [b, d]pyran-1-ol. It is the (6aR,10aR)-stereoisomer of delta-9-tetrahydrocannabinol and is also designated (-)-trans-delta-9-tetrahydrocannabinol.

Other stereoisomers of delta-9-tetrohydrocannabinol are: (6aR,10aS)-, (6aS,10aR)- and (6aS,10aS)-, also known as (-)-cis-, (+)-cis- and (+)- trans-, respectively. Delta-9-tetrohydrocannabinol has two racemates, (6aRS,10aRS)- and (6aRS,10aSR)-, also known as (±)-trans- and (±)-cis-, respectively.

Originally, all isomers of tetrahydrocannabinol were included in Schedule I of the 1971 Convention. This was later amended to include seven named constitutional isomers and their respective stereochemical variants. The term “constitutional isomers” used above has recently been introduced by the International Union of Pure and Applied Chemistry (IUPAC) to replace the traditionally used term “positional isomers”. The term “stereochemical variants” used in the 1971 Convention and mentioned above is equivalent to the term “stereoisomers”, which is at present much more widely used in the chemical and related literature. Both terms cover geometric isomers and optical isomers.

Previous review
 Delta-9-tetrahydrocannabinol was included in Schedule I of the 1971 Convention at the time of its adoption. At its twenty-sixth meeting, the Committee recommended that dronabinol be moved to Schedule II, while keeping the other isomers and their stereochemical variants in Schedule I (4). This proposal was rejected at the 11th Special Session of the Commission on Narcotic Drugs, and the Committee reviewed the question again at its twenty-seventh meeting when it recommended that all the stereochemical variants of delta-9-tetrahydrocannabinol be rescheduled to Schedule II (5). This recommendation was adopted by the United Nations Commission on Narcotic Drugs at its 34th session (6). At its thirty-second meeting, the Committee pre-reviewed dronabinol and recommended its critical review for consideration of the rescheduling on the grounds that the rate of abuse of dronabinol was extremely low (7).

Delta-9-tetrahydrocannabinol was critically reviewed by the Expert Committee on Drug Dependence at its thirty-third meeting in September 2002 (3). On the basis of the available data the Committee considered that dronabinol should be rescheduled to Schedule IV of the 1971 Convention. However, no further procedural steps were taken. Therefore, the existing critical review report was updated, including information from recent scientifi c publications, to enable the Committee to fi nalize the process of critical review.

Similarity to known substances and effects on the central nervous system
 Dronabinol is the main active principle of cannabis and has similar effects on mood, perception and the cardiovascular system. The cannabis plant contains a “natural mixture” of around 70 different cannabinoids, and also contains fl avonoids and terpenes, as well as many other substances. Therefore the pharmacological properties of natural cannabis and dronabinol are not identical.

Dependence potential
 Animal studies have demonstrated that, like other drugs of abuse, dronabinol acts as a drug reinforcer. Physical dependence, as shown by withdrawal syndrome following chronic administration, has also been demonstrated. Reinforcing effects and physical dependence have also been described in human studies.

Actual abuse and/or evidence of likelihood of abuse
 The abuse of dronabinol is currently rare and there have been very few specifi c reports of its occurrence. In response to the WHO questionnaires only the United States mentioned instances of abuse of delta-9-tetrahydrocannabinol. At present, the quantity produced by licit manufacture is limited. In the United States, which is the major manufacturing country, the abuse of dronabinol medicinal preparations is reported to be very low and there are no reports of diversion of the pharmaceutical product.

Therapeutic usefulness
 Dronabinol preparations have been used in a limited number of countries in the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments and in the treatment of anorexia associated with weight loss in patients with acquired immunodefi ciency syndrome (AIDS). It has also been indicated in the treatment of chronic pain (e.g. in multiple sclerosis, neuropathic disorders and arthritis), neurological disorders and appetite loss in cachexia, and is being evaluated for use in various other clinical situations.

Recommendation
 The Committee reconsidered the recommendation of the thirty-third Expert Committee after considering the updated critical review report. The Committee concluded that dronabinol constitutes a substantial risk to public health. However this risk is different from those related to cannabis - controlled under the 1961 Convention. The substance has a moderate therapeutic usefulness and as a result of continuing clinical research its medical use is likely to increase. Therefore, the Committee recommended that dronabinol (INN) and its stereoisomers should be rescheduled from Schedule II to Schedule III of the 1971 Convention.

To avoid legal and forensic chemical problems that may arise in some countries when placing stereoisomers of the same substance under different control systems, the Committee indicated that the recommendation pertains to all stereoisomeric forms of delta-9-tetrahydrocannabinol as specifi ed above.

WHO EXPERT COMMITTEE ON DRUG DEPENDENCE
 WHO Technical Report Series

http://www.who.int/medicines/areas/quality_safety/WHO_TRS_942.pdf