Specific Medicinal Uses of Cannabis: Anticonvulsant Activity

As early as 1890, the use of cannabis was advocated for the suppression of convulsions in man. While there are some reports of the effects of smoking cannabis in this area, most effort has focused on synthetic cannabinoid derivatives.

Cannabis

Two reports indicate that regular cannabis smoking contributes to better control of seizures in epileptic patients whose disease is refractory to conventional therapy. These studies were not controlled and contained few patients.

THC

There have been no reports of the use of THC in epileptics; this compound has induced or exacerbated seizure activity in animal studies.

Cannabidiol (CBD)

Carlini and Cunha added CBD, 200–300 mg daily, to the anticonvulsant regime of eight patients with generalised secondary seizures, refractory to antiepileptic drugs. Over the 5-month observation period, improvement was noted in seven. Very similar results were reported in an earlier trial by Karler and Turkanis. In a placebo controlled study in patients with grand mal seizures, CBD produced improvement in seizure control in 7 patients, three of these showing great improvement. One patient showed some improvement on placebo however.

Summarising, there seems to be little to recommend the regular smoking of cannabis as an adjunct to conventional anticonvulsant medication. Only a few, poorly controlled studies in a limited number of patients are available and these have not demonstrated efficacy to the required standard. Indeed, in the light of the unpredictable tendency of at least one of the active constituents, THC, to cause seizures, this custom may put susceptible individuals at risk.

There is some evidence that other derivatives, notably CBD, have anticonvulsant activity in man. The precise pharmacological basis for this effect is far from clear. In experiments where CBD was shown to enhance the effect of other anticonvulsants, it is possible that this was achieved not by a direct action on receptors, but rather via a pharmacokinetic interaction in which the metabolism of the anticonvulsant was inhibited by CBD; serum levels were not measured in these experiments.

Because CBD lacks central activity but retains anticonvulsant activity and has a lower potential for tolerance, it has been suggested that this compound, or at least, other cannabinoids devoid of psychotropic activity, might be used as the basis for developing analogues with anticonvulsant activity.

Mode of Action

A deal of complex, neuropharmacological research has been undertaken in attempts to discover the reasons why CBD, a compound apparently devoid of central activity, has anticonvulsant properties, whereas THC, which undoubtedly has a central effect, has a tendency to produce, rather than prevent seizures.

THC produced seizures in rodents and rabbits. The effect was dose-related and elicited at doses comparable to those consumed by man. Metabolites of THC appeared to be more epileptogenic than the parent compound. Interestingly, CBD has been shown to antagonise the epileptogenic activity of THC — a state of affairs which may prevail when crude cannabis is smoked.

Animal studies have demonstrated anticonvulsant activity for cannabis resin and a range of synthetic analogues using artificial means to induce seizures such as electroshocks (); and chemicals. Data from comparative studies shows that CBD has anticonvulsant properties which are comparable with a range of anticonvulsants including phenytoin and ethosuximide (Karler and Turkanis, 1981). CBD has also been shown to potentiate the anticonvulsant activity of diazepam and valproic acid and phenytoin against electronically induced seizures in mice. In the latter study THC had a similar effect; when given with CBD, the effect was additive. The activity of CBD in suppressing hippocampal discharges induced by afferent stimulation was comparable with other anticonvulsants including mysoline and phenytoin at doses which produced little or no behavioural impairment.

It has been suggested that the variable response of THC is related to its central activity, whereas CBD acts by altering post-synaptic membrane conductance. Centrally, cannabinoids have been shown to reduce cortical-evoked responses and spinal reflexes, which is consistent with a neurotransmission theory for the efficacy of CBD. Other mechanisms for which there is some evidence include altered neurotransmitter release, altered transmitter equilibrium potential and altered drug/receptor interactions.

For example, brain monoamine activity may be altered. The anticonvulsant activity of cannabis resin has been decreased after pre-treatment with drugs which decrease brain serotonin levels. GABAergic pathways may also be involved, as CBD inhibited convulsions caused by GABA-inhibiting drugs such as 3-mercaptopropionic acid and hydrazine. One interesting observation by Mechoulam is that CBD and the established anticonvulsant, phenytoin share striking molecular similarities, particularly in terms of the spacing of electrondense centres; hence they may have a common or similar mode of anticonvulsant action.