Cannabis and cannabinoids: Pharmacology and rationale for clinical use

It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones , and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The disc overy of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2 receptor ligands and fuelled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. Thes e are Delta(9) tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spastici ty associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 recep tor antagonists may also have clinical applications, e. g. as appetite supp ressants and in the management of schizophrenia or disorders of cognition a nd memory. So too may CB2 receptor ligands and drugs that activate cannabin oid receptors indirectly by augmenting endocannabinoid levels at cannabinoi d receptors. When taken orally, THC seems to undergo variable absorption an d to have a narrow 'therapeutic window' (dose range in which it is effectiv e without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a pati ent and indicates a need for better cannabinoid formulations and modes of a dministration. For the therapeutic potential of cannabis or CB1 receptor ag onists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected s ymptoms that is of clinical significance and, if so, whether the benefits o utweigh the risks, (b) whether cannabis has therapeutic advantages over ind ividual cannabinoids, (c) whether there is a need for additional drug treat ments to manage any of the disorders against which cannabinoids are effecti ve, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 recepto rs to produce their sought-after effects.