Delta-9-tetrahydrocannabinol

Substance identification
To date, more than 500 naturally occurring compounds have been identified in the cannabis plant, including cannabinoids (more than 100 chemicals unique to the plant), terpenoids and alkaloids. Δ9-THC is thought to be the principal intoxicant constituent of Cannabis sativa.

Delta-9-tetrahydrocannabinol refers to the following four stereoisomers:

■■ (−)-trans-delta-9-tetrahydrocannabinol (also known as dronabinol)

■■ (+)-trans-delta-9-tetrahydrocannabinol

■■ (−)-cis-delta-9-tetrahydrocannabinol

■■ (+)-cis-delta-9-tetrahydrocannabinol

The stereoisomer (−)-trans-Δ9-THC is the only one that occurs naturally in the cannabis plant and is generally the only stereoisomer that has been studied. Dronabinol is the INN for this isomer. Where the term "Δ9-THC" is used in this report without further specification, it refers to (−)-trans-Δ9-THC or dronabinol. If reference is made to a different isomer, this will be explicitly specified.

For therapeutic use, dronabinol is supplied as gelatine capsules (Marinol®) for oral use, and as an oral solution (Syndros®).

WHO review history
Delta-9-tetrahydrocannabinol (Δ9-THC) and its stereochemical variants, with one variant being dronabinol ((−)-trans-Δ9-THC), are currently in Schedule II of the 1971 Convention on Psychotropic Substances. Δ9-THC, together with its stereochemical variants, was originally included in Schedule I of the 1971 Convention at the time of its adoption.

■■ In 1989, the WHO ECDD recommended, based on the critical review of dronabinol undertaken at its twenty-sixth meeting in 1988, that dronabinol be moved to Schedule II while keeping the other isomers and stereochemical variants in Schedule I. WHO’s proposal to transfer dronabinol to Schedule II was rejected by the CND at its eleventh special session in 1990.

■■ At its twenty-seventh meeting in 1990, the ECDD carried out a critical review of updated information on Δ9-THC. It recommended that Δ9- THC and its stereochemical variants be rescheduled from Schedule I to Schedule II of the 1971 Convention. This was proposed in order to avoid a distinction between Δ9-THC and its stereochemical variants, their placement under different Schedules and to prevent potential legal and forensic analytical problems. This recommendation was adopted by the CND at its thirty-fourth session in 1991.

■■ At its thirty-third meeting in 2002, Δ9-THC was again critically reviewed by the ECDD. The Committee recommended that dronabinol and its stereochemical variants be rescheduled from Schedule II to Schedule IV of the 1971 Convention. However, no further procedural steps were taken, i.e. there was no formal communication of this recommendation from WHO to the CND.

■■ At its thirty-fourth meeting in 2006, the ECDD carried out an assessment of an updated critical review of dronabinol. The Committee concluded that although dronabinol constitutes a substantial risk to public health, this risk is different from those related to cannabis, which is controlled under the 1961 Convention. The substance was found to have moderate therapeutic usefulness, and an increase in its medical use was likely as a result of continuing clinical research. Therefore, the Committee recommended that dronabinol and its stereochemical variants be rescheduled from Schedule II to Schedule III of the 1971 Convention. ■■ In March 2007, at its fiftieth session, the CND decided by consensus not to vote on the recommendation of WHO to transfer dronabinol and its stereochemical variants from Schedule II to Schedule III of the 1971 Convention. Furthermore, the CND requested WHO, in consultation with INCB, as appropriate, to undertake, for consideration by the Commission, a review of dronabinol and its stereochemical variants when additional information became available (CND Decision 50/2).

■■ At its thirty-fifth meeting in 2012, the ECDD discussed the CND’s recommendations of 2007. The Committee did not carry out a review of dronabinol, but reinstated the recommendation made at its thirty- fourth meeting to move dronabinol and its stereochemical variants from Schedule II to Schedule III of the 1971 Convention. The ECDD decided that its earlier decision on dronabinol and its stereochemical variants should stand, since it was unaware of any new evidence that was likely to materially alter the scheduling recommendation made at its thirty-fourth meeting. This recommendation was communicated by the Director-General of WHO to the UN Secretary-General in October 2012.

■■ The CND reconsidered this issue in March 2013 at its fifty-sixth session. Concern was expressed by several delegations that, despite the recommendation received from WHO, no decision had yet been taken by the Commission to reschedule dronabinol and its stereochemical variants. A number of delegations noted that they were not able to support the recommendation made by WHO regarding dronabinol, as that recommendation could hinder efforts to prevent international cannabis abuse and could send a confusing message regarding the harm associated with the use of cannabis. It was suggested that WHO should continue reviewing dronabinol.

■■ In March 2014, based on the recommendation made by the ECDD at its thirty-fifth meeting in 2012, the CND voted against moving dronabinol and its stereochemical variants from Schedule II to Schedule III of the 1971 Convention.

■■ At its thirty-eighth meeting in 2016 the ECDD requested that Δ9- THC be pre-reviewed together with cannabis and cannabis resin, extracts and tinctures of cannabis, cannabidiol and isomers of THC.

■■ At its fortieth meeting in June 2018 the ECDD evaluated the above-mentioned pre-reviews and recommended to proceed to the critical reviews of cannabis and cannabis resin, extracts and tinctures of cannabis, Δ9-THC and isomers of THC at the forty-first meeting in November 2018.

Similarity to other known substances and effects on the central nervous
system In humans, Δ9-THC has very similar pharmacological and subjective effects to those of cannabis. Users may exhibit euphoria, laughter and increased talkativeness. Δ9-THC increases appetite, causes dry mouth and occasional dizziness and alters visual, olfactory and auditory perceptions. Δ9-THC can cause subtle cognitive deficits such as impairment of attention and short-term memory. Higher doses of Δ9-THC are associated with anxiety, panic, confusion and disorientation in some users. Δ9-THC can also provoke transient psychosis- like phenomena in some healthy participants.

Δ9-THC has very low potential to produce lethal effects. It has been calculated that a lethal dose for a 70-kg human would be approximately 4 g and that such a dose would not typically be achieved in a human following oral consumption, smoking or vaporizing the substance.

Acute exposure of humans to Δ9-THC produces tachycardia; however, tolerance may occur to these effects, and decreases in blood pressure and heart rate may occur with subsequent exposures. Δ9-THC is a bronchodilator. While in vitro and in vivo studies in animals demonstrate that high doses of Δ9-THC can modulate the immune system in complex ways, two studies in humans in which low doses of Δ9-THC were administered, found no significant effects on the immune system.

Oral Δ9-THC is reported to cause impairment of driving skills in both driving simulators and on roads. Doses of 10 and 20 mg of Δ9-THC increased standard deviation of lateral position (indicative of loss of road-tracking control) and time taken to adapt speed (indicative of increased reaction times).

Dependence potential
In animal models, marked tolerance develops to the effects of Δ9-THC. The effects of spontaneous withdrawal following cessation of chronic administration appear relatively mild, but antagonist-precipitated withdrawal is characterized by clear somatic signs such as tremor and ataxia.

Tolerance has also been demonstrated in humans and there is evidence of a withdrawal syndrome on cessation following administration for a period as short as 4 days. The doses of Δ9-THC administered in the studies demonstrating withdrawal exceeded the doses used in clinical trials for therapeutic applications. Sleep disruption appears to be the most prominent symptom of withdrawal from Δ9-THC.

Actual abuse and/or evidence of abuse
Pharmaceutical products containing Δ9-THC do not appear to be abused. Orally administered pharmaceutical preparations containing Δ9-THC appear to have only weak reinforcing properties in humans, with low and variable rates of self- administration. Smoked cannabis is much preferred. Evidence concerning the medical use of Δ9-THC shows no diversion of the pharmaceutical product for nonmedical purposes and no evidence of abuse.

There is no significant evidence concerning the reinforcing effects of smoked or vaporized pure Δ9-THC in humans. However, newer (nonmedical) preparations of the cannabis plant, principally as extracts, contain very high concentrations of Δ9-THC, sometimes exceeding 80%. Such preparations, including butane hash oil, are administered by inhalation of vapour after heating. Previously, the only relatively pure Δ9-THC preparations were medicinal. The development of high-purity Δ9-THC products is associated with significant health risks, including increased risk of dependence.

Therapeutic usefulness
Δ9-THC (dronabinol) is approved in a number of countries for indications including anorexia associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS) and for nausea and vomiting associated with cancer chemotherapy in patients who do not gain adequate relief from conventional antiemetic treatment.

Δ9-THC has been explored for other indications. For example, it has demonstrated at least partial effectiveness in decreasing neuropathic pain, reducing anxiety in patients with chronic pain, increasing weight gain in patients with anorexia nervosa, decreasing pain intensity and increasing patient satisfaction when given as an adjunct to opioids for chronic pain, reducing spasticity in patients with multiple sclerosis, and for improving tics (or a trend towards such improvement) in patients with Tourette’s syndrome.

Δ9-THC (dronabinol) is not listed on the WHO EML (twentieth list) or the WHO Model List of Essential Medicines for Children (sixth list).

Recommendation
The main psychoactive substance in the cannabis plant is one of the four stereoisomers of Δ9-THC. This substance has therapeutic uses and is sometimes known by its International Nonproprietary Name dronabinol. It is currently placed in Schedule II of the 1971 Convention on Psychotropic Substances.

At the time of the adoption of the 1961 Single Convention on Narcotic Drugs, scientific research had not identified Δ9-THC as the main psychoactive compound in cannabis. Subsequently, Δ9-THC was included in the 1971 Convention on Psychotropic Substances at its inception. In previous ECDD reviews, the active and naturally occurring stereoisomer of Δ9-THC known as dronabinol had been considered in a synthetic form as a pharmaceutical preparation. Following a recommendation from the ECDD at its twenty- seventh meeting, dronabinol was placed in Schedule II of the 1971 Convention on Psychotropic Substances. However, the CND did not adopt a subsequent recommendation to place dronabinol in Schedule III of the 1971 Convention on Psychotropic Substances.

The Committee noted that whereas in these previous ECDD reviews Δ9- THC, and especially its active stereoisomer dronabinol, had been considered in a synthetic form as a pharmaceutical preparation, Δ9-THC today also refers to the main psychoactive component of cannabis and the principal compound in illicit cannabis-derived psychoactive products. Some of these products contain Δ9-THC at concentrations as high as 90%. Butane hash oil is an example of a cannabis-derived product containing high-purity Δ9-THC, which has recently emerged and is used by heating and inhalation of the vapour. In derived forms of such high purity, Δ9-THC produces ill-effects, dependence and abuse potential that is at least as great as that produced by cannabis, which is placed in Schedule I of the 1961 Single Convention on Narcotic Drugs.

A substance liable to similar abuse and productive of similar ill-effects to those of a substance already scheduled within the 1961 Single Convention on Narcotic Drugs would normally be scheduled in the same way as that substance. As Δ9-THC is liable to similar abuse to cannabis and has similar ill-effects, it meets the criteria for inclusion in Schedule I of the 1961 Single Convention on Narcotic Drugs. It was further recognized that cocaine, the principal active compound in coca is placed together with coca leaf in Schedule I of the 1961 Single Convention on Narcotic Drugs. Futhermore, morphine, the principal active compound in opium, is placed with opium in the same Schedule. Placing Δ9-THC, the principal active compound in cannabis, in the same Schedule as cannabis would be consistent with this approach.

■■ Recommendation: The Committee recommended that dronabinol and its stereoisomers (delta-9- tetrahydrocannabinol) be added 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. Accordingly:

■■ Recommendation: The Committee recommended the deletion of dronabinol and its stereoisomers (delta-9-tetrahydrocannabinol) from the 1971 Convention on Psychotropic Substances, Schedule II, subject to the Commission’s adoption of the recommendation to add dronabinol and its stereoisomers (delta-9- tetrahydrocannabinol) to Schedule I of the 1961 Single Convention on Narcotic Drugs.

Based on requests received from Member States and information received from other United Nations agencies, the Committee understood that placing Δ9-THC under the same Convention and in the same Schedule as cannabis – Schedule I of the 1961 Single Convention on Narcotic Drugs – would greatly facilitate the implementation of the control measures of the conventions in Member States.