Cannabis has been used recreationally for millennia and is the third most commonly used the drug after tobacco and alcohol; there are an estimated 3 million frequent users in the United Kingdom alone. There has been a steady stream of medical claims throughout history that cannabis eases limb-muscle spasms, migraine, and pain. Although there is evidence of medical use in Europe from the 13th century, it became more popularised in the early 19th century when cannabis was noted to have anticonvulsive, analgesic, antianxiety, and antiemetic properties.

The main function of the endocannabinoid system is to regulate synaptic neurotransmission. The CB1 endocannabinoid system regulates synaptic neurotransmission of excitatory and inhibitory circuits. In response to depolarisation and Ca2+ fluxes and in some instances postsynaptic group I metabotrophic-glutamate-receptor activation, endocannabinoids are released that inhibit further neurotransmitter via stimulation of presynaptic CB1 receptors. As a regulator of neurotransmission, the cannabinoid system seems to influence many different functions. There is experimental evidence that cannabinoids affect the activity of most neurotransmitters.

What actually happens after stimulation depends on the location of the receptor within the excitatory or inhibitory neural circuit being stimulated. The sometimes paradoxical findings that cannabis suppresses or induces certain phenotypical signs (eg, convulsions, tremor) is probably because these signs are controlled by different neuronal circuits. Many neurological diseases occur due to inappropriate neuronal signals leading to too much excitation, too little inhibition, or vice versa.

However, sometimes patients with disorders such as post-traumatic fear responses also have to “remember to forget” and here stimulation of the cannabinoid system may be useful to extinguish certain aversive memories. Thus, cannabis may have positive and negative outcomes, and therefore its clinical use must balance these effects against the nature of the disorder.

The clinical potential of the cannabinoids is large; some people suggest that cannabis could be the “aspirin of the 21st century”. Therefore, most experimental studies have concentrated on measurable physiological effects, and, as a result, the understanding of the underlying biology is improving. Most claims made by patients suggest that cannabis may be useful in symptom management and there is now experimental support for the clinical investigation of cannabis in the control of pain and spasticity in multiple sclerosis.

Cannabinoids inhibit pain in virtually every experimental pain paradigm either via CB1 or by a CB2-like activity in supra-spinal, spinal, or peripheral regions, dependent on the type of nociceptive pathway being studied. This finding is consistent with high concentrations of CB1 receptors on primary afferent nociceptors, particularly in the dorsal spinal cord, whereas peripheral CB2-like receptors have been implicated in the control of “inflammatory” pain.

One of the main claims for cannabis is the alleviation of painful spasms and spasticity. This effect is currently difficult to assess objectively, owing to a lack of sensitive and reliable outcome measures. In an experimental model of multiple sclerosis, there is evidence of tonic control of spasticity and tremor by cannabinoids. Although cannabis may contain additional therapeutic compounds to THC, the main antispastic activity seems to be mediated through CB1 and comparable efficacy may be obtained with single pharmacological reagents.

Non-cannabis-derived cannabinoids can inhibit spasticity by an unknown CB independent mechanism. Although CB1 agonism can inhibit spasticity, the important experimental observation was that CB1 receptor antagonists made spasticity transiently worse, which suggests inhibition of a tonically active, endogenous control mechanism. Indeed, inhibition of the degradation pathways of endocannabinoids by targeting of the endocannabinoid transporter or fatty-acid-amide hydrolase degradation of the endocannabinoids led to a significant antispastic effect similar to strong CB1 agonists. Importantly, such compounds do not bind directly to CB1 and thus have little inherent psychoactivity. In addition, there seems to be local upregulation of endocannabinoids in and around lesions. Therefore, degradation inhibitors may offer some site selectivity not afforded by cannabinoid receptow agonists. Similar dysregulation of the cannabinoid system is found in experimental pain and experimental models of Huntington’s and Parkinson’s diseases. Manipulation of the endocannabinoid system may be possible in a range of neurological disorders including stroke.

Bladder hyper-reflexia, a common problem in neurological disorders such as multiple sclerosis, has been treated by local administration of VR1 agonists. This symptom can also be inhibited experimentally by cannabinoids, which lack the irritancy of VR1 agonists. Recent work has suggested that VR1 stimulated effects initiate cannabinoid-receptor mediated tone and are part of a downstream effector pathway of capsaicin-induced control of bladder hyper-reflexia. As we understand more about how cannabinoid receptors interact, a combination of agents might be used to limit the cannabinoid dose and thus limit the adverse effects. However, these studies highlight one fundamental problem with cannabis as a drug: the main target for most therapeutic activities is CB1 and this is the same receptor that causes the adverse effects. Dissociation of the adverse effects from the therapeutic effects of cannabis may never be possible despite frequent claims to the contrary.

Although the current clinical use of cannabinoids focuses on symptom management, the biology of the cannabinoid system suggests that there may be other benefits in the treatment of neurological disease, notably the slowing of progression in neurodegenerative disorders.

As we learn more about the pharmacological activities of compounds in cannabis and their biological targets outside the cannabinoid system, varieties of cannabis might be tailored to different diseases or used in combination with known drugs. Whatever the future holds, there are many challenges to be overcome before we view cannabinoids as routine medicine in neurological disorders.

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