Cannabis smoking produces a relaxant effect which most users value and it has been suggested that the beneficial effects of cannabis and THC observed in neurological disorders such as motor tics, dystonias and Huntingdon’s chorea are due to sedative and anxiolytic actions. In addition, sedation is by far the most common side effect of cannabis, and in particular THC, observed in clinical trials against a range of disorders. This has lead to the suggestion that cannabis and some cannabinoids may be useful in disorders accompanied by anxiety and/or insomnia.
Sethi et al. () noted a reduction of anxiety in 50 chronic cannabis users compared to controls, in terms of scores on the Taylor Manifest Anxiety Scale. Oral preparations of cannabis have a sedative or tranquillising effect in man, accompanied by diminished anxiety at doses much lower than those producing psychoactivity. However, anxiety and panic, possibly due to depersonalisation, intoxication and loss of control, can also feature as side effects. These symptoms have been observed after smoking or oral ingestion of cannabis, but particularly after intravenous administration of aqueous extracts. This may be due to the rapid onset of altered mental state induced under these conditions. Which effect is produced appears to be independent of age, previous cannabis use or setting, but may be associated with the degree of interpersonal support.
Initial studies in man showed THC to be not much different from conventional hypnotics. Single doses decreased REM sleep and increased stage 4 sleep; some REM rebound was observed on discontinuation of the drug. When THC was given to healthy insomniacs in doses of 10, 20 or 30 mg sleep latency was reduced but subjects experienced dose-related dysphoria prior to falling asleep and similar symptoms the following day. When given as a dose of 20 mg for several consecutive nights, THC reduced REM sleep but upon discontinuation, mild insomnia ensued, with a slight degree of REM rebound.
Marijuana extract, given chronically in daily equivalent THC doses ranging from 70 to 200 mg, reduced REM activity, but with the development of some degree of tolerance. Abrupt withdrawal led to marked REM rebound.
While single dose studies in anxious volunteers have shown little therapeutic benefit three trials have demonstrated some anxiolytic effect after repeated doses. In the first, 11 anxious patients received 1–2.5 mg nabilone or placebo, twice daily, for one week in a double-blind, randomised, cross-over study. Nabilone was superior to placebo as judged by scores on the Hamilton Anxiety Rating and the Clinical Global Impression scales. In the second study, 25 psychoneurotic anxiety patients were given either 1 mg nabilone or placebo, three times a day for 28 days. Nabilone was significantly superior to placebo after four days of treatment, as judged by scores on the Patient and Clinical Global Impression and Hamilton Anxiety Rating scales. Nabilone also appeared to improve other psychosomatic symptoms and concomitant depression suffered by some patients. The third trial was placebo-controlled and double-blind; 2 mg nabilone was compared to 5 mg diazepam in experimentally induced anxiety in 36 volunteers with high levels of trait anxiety. Both drugs relieved experimentally-induced anxiety but diazepam was superior. Nabilone was associated with more side effects than diazepam and as nabilone was tested at the highest practicable dose, the drug was deemed unlikely to be able to compete with existing anxiolytic drugs.
In an early study CBD doses of 40, 80, and 160mg were compared to placebo and 5mg nitrazepam in 15 insomniac volunteers. Only subjects receiving 160mg CBD reported sleeping significantly longer than those taking the placebo.
Animal and human experiments have demonstrated that this compound has only weak anxiolytic properties (approximately one thirtieth to one sixtieth of the activity of diazepam); it is therefore unlikely that cannabidiol will ever be considered for clinical use.
In summary, its seems unlikely that cannabis or the cannabinoids will ever be accepted as satisfactory anxiolytics or hypnotics. The changes in sleep produced by these compounds (decreased sleep latency, decreased REM sleep, increased slow wave sleep) are not unique and use is accompanied by tolerance, rebound insomnia and dysphoric reactions experienced both before falling asleep and as hangover the next day. Occasional reports of excitement and panic and the inability to identify susceptible patients is problematic.
Mode of Action
The mode of action of the cannabinoids, both as anxiolytics and hypnotics is unclear. Results from animal experiments suggest that both the prostaglandin system and central benzodiazepine receptors are involved.