High hopes for cannabinoid analgesiaBMJ 2004; 329 doi: https://doi.org/10.1136/bmj.38168.627292.0B (Published 29 July 2004) Cite this as: BMJ 2004;329:257
- Geoff Watts, science editor, BMJ1 ()
Several decades of irrational prejudice may have hampered clinical research on cannabis as a medicine, but work on the pharmacology of its active ingredients has been making steady progress. Just as the body has a natural counterpart to the opiate drugs, so too it makes its own endogenous cannabinoids. These act through receptors, of which two variants—CB1 and CB2—have been definitely identified and at least one other is suspected. The CB1 receptors are located only in the brain; their CB2 counterparts are found peripherally, and especially on the cells of the immune system. Cannabinoid receptors are present not just in vertebrates but also in molluscs, leeches, and other invertebrate groups that have been evolutionarily separate for 500 million years. The fact that natural selection has for so long conserved these receptors is an indication of their physiological importance.
Anandamide, the first natural cannabinoid to be isolated, came to light in 1992. Its precise role, and those of the other cannabinoids that have since been identified, remains uncertain; but evidence exists that all play a part in memory, appetite, the control of movement, and, especially, the modulation of pain.1 With respect to the last of these, the sites of cannabinoid action in the central nervous system are confined to specific areas, most of which—the dorsal horn of the spinal cord, for example2 3—are involved in processing pain signals. Clear parallels exist between cannabinoid and opiod receptors, and evidence is accumulating that the two systems sometimes interact,4 and may operate synergistically. One unproved but intriguing idea is that endocannabinoids may set the “analgesic tone” of the body, with the level of their production acting as a kind of pain thermostat.
The perception of pain is controlled by neurotransmitter systems within the central nervous system, but peripheral tissues also have mechanisms for relieving and preventing pain. Cannabinoids may therefore have two distinct roles in relation to pain. The evidence comes from animal experiments showing that cannabinoids lower the response of pain neurones in the spinal cord and also in parts of the thalamus in the brain. The possibility that cannabinoid receptor subtypes act synergistically hints at a potentially valuable strategy: the development of a new class of analgesic drug comprising a mixture of synthetic CB1 and CB2 agonists. Alternatively, devising agents to slow the breakdown of natural cannabinoids might potentiate their analgesic effects.5
The brain has many more CB1 than opioid receptors, and interest in the therapeutic potential of cannabinoids has prompted the development of several synthetic variants, of which dronabinol is one.1 Many of these compounds bind to both CB1 and CB2 receptors, but differences between the two suggest that it should be possible to design drugs that would attach to only one of them. This might offer a means of producing more selective biological actions, including analgesia without some of the psychotropic effects that might disturb people whose wish was to be pain-free but not “high.”
A review by the US Institute of Medicine has commented on how little we know about cannabinoids in comparison with opiates.2 A comparison between the history of research into the two groups, the review added, “suggests good reason for optimism about the future of cannabinoid drug development.”