The major psychoactive constituent of Cannabis sativa,
delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous
cannabinoid ligands, such as
anandamide, signal through
G-protein-coupled
cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for
cannabinoids as therapeutic agents in
CNS disease where inhibition of
neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as
multiple sclerosis smoke cannabis to relieve disease-related symptoms.
Cannabinoids can alleviate
tremor and spasticity in animal models of
multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The
cannabinoid nabilone is currently licensed for use as an
antiemetic agent in
chemotherapy-induced
emesis. Evidence suggests that
cannabinoids may prove useful in
Parkinson's disease by inhibiting the excitotoxic
neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of
cannabinoids on
reactive oxygen species,
glutamate and tumour
necrosis factor suggests that they may be potent
neuroprotective agents.
Dexanabinol (HU-211), a synthetic
cannabinoid, is currently being assessed in clinical trials for
traumatic brain injury and
stroke. Animal models of mechanical, thermal and noxious
pain suggest that
cannabinoids may be effective
analgesics. Indeed, in clinical trials of postoperative and
cancer pain and
pain associated with
spinal cord injury,
cannabinoids have proven more effective than placebo but may be less effective than existing
therapies.
Dronabinol, a commercially available form of
delta(9)-THC, has been used successfully for increasing appetite in patients with
HIV wasting disease, and
cannabinoid receptor antagonists may reduce
obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive
cannabinoids such as
cannabidiol and
dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other
cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available
cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the
endocannabinoid system may also reduce adverse effects and increase the efficacy of
cannabinoid treatment. This review highlights recent advances in understanding of the
endocannabinoid system and indicates CNS disorders that may benefit from the
therapeutic effects of
cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of
cannabinoids to alleviate symptoms of these disorders.