Understanding the multiple functions of endocannabinoid signaling in the brain offers insight into the pharmacological effects of cannabis and other exogenous cannabinoids, their therapeutic potential and undesirable adverse effects. An overview in depth “on demand” endocannabinoid modulation of excitatory and inhibitory synaptic transmission and regulatory functions in the brain.
Brain development, neurogenesis, psychiatric disorders: Endocannabinoid signaling is crucial for brain development, and guides neural stem cell survival and proliferation, cell fate decisions and the motility and differentiation of ensuing neuronal and glial cells. Developmental endocannabinoid signaling, from fetus to young adult, may be susceptible to cannabis use during pregnancy and adolescence. Endocannabinoids and cannabis-altered endocannabinoid signaling may contribute to neuropsychiatric diseases that are of developmental origins
and in which modifications to signaling have been observed: autism, schizophrenia, bipolar disorder and depression. The central role of the cannabinoid system in promoting adult neurogenesis in the hippocampus and the lateral ventricles provides insight into the processes underlying post-developmental neurogenesis in the mammalian brain. Both THC and CBD inhibit neurogenesis in adolescent or adult rodent brain, a process of potential relevance to a wide range of cannabis-induced adverse events.
Neuroprotection: Cannabinoids and CB1, CB2 receptors display neuroprotective effects in the brain by preventing or decreasing the severity of damage resulting from mechanical, blood flow, or other forms of injury. Genetic ablation of the CB1 receptor exacerbates ischemic stroke, with CB2 agonists providing anti-inflammatory properties and CB1 activation promoting hypothermia. The use of cannabis for this purpose is compromised by psychoactive effects and the development of tolerance to its neuroprotective effects.
Cannabinoids and sensory function (olfaction, auditory, pain): The endocannabinoid system contributes to olfactory, auditory and pain sensations. There is extensive anatomical overlap of the opioid and cannabinoid receptor systems, and it appears probable that functional interactions between them occur in the production of analgesia.
Appetite and nausea: A number of nuclei in the medulla are involved in the regulation of appetite and nausea. These nuclei coordinate sensory input from the brainstem, vagal complex, vestibular organs, and peripheral organs. Endocannabinoids and CB1 agonists inhibit vagal fibers to promote eating and CB1 antagonists to decrease or inhibit food intake.
Sleep: Endogenous and exogenous cannabinoids, including cannabis and THC, affect sleep patterns. There is evidence that cannabis or cannabinoids have therapeutic benefit in sleep disorders.
Affective disorders: The endocannabinoid system has mood elevating, anti-depressant and anxiolytic effects. The anxiolytic response to cannabis is biphasic, implying that cannabis dosing is a critical factor in minimizing risk of anxiety, depression and maximizing benefit.
Seizure activity: The endogenous cannabinoid system inhibits seizure susceptibility. Therefore it is unsurprising that exogenous cannabis has antiseizure activity. However, if THC levels are high or cannabis is consumed by susceptible individuals, THC may promote seizures. CBD has therapeutic potential as antiepileptic drug without the psychoactive effects, or potential for pro-seizure activity of whole plant cannabis.
Motor function: The endocannabinoid system plays a complex role in regulating motor pathways, which conceivably are relevant to symptomatic relief, or to addressing the underlying pathology in a wide range of neurological diseases characterized by motor impairment. CB1 receptors are abundant in brain regions that regulate motor function and coordination, including the basal ganglia, cerebellum. CB1 receptors are down-regulated in several neurological conditions.
Cognitive functions: Cannabinoids can both facilitate and degrade learning processes dependent upon the process involved. Endocannabinoids apparently facilitate various forms of learning and memory processes in a number of brain regions. The endogenous cannabinoid system is also implicated in extinguishing learning of aversive situations. On the other hand, THC and cannabis decrease working memory, apparently by actions in the hippocampus, a brain region critical for learning and memory. The memory decrements induced by THC or cannabis resemble hippocampal lesions. These impairments may result from suppression of glutamate release in the hippocampus, which is responsible for the establishment of synaptic plasticity.
Appreciation to Harvard Medical School for the information
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