Marijuana is a highly controversial substance with roughly an equal number of supporters and opponents of its use for medicinal purposes. Marijuana is a dry, shredded mix of flowers, stems, seeds and leaves of the Hemp plant Cannabis sativa. New studies reporting the efficacy of medicinal marijuana in clinical conditions surface on a fairly regular basis, with the latest being a reported treatment for seizures. This constant influx of new information shows how little we know about the substance and how it works in the human body. So what do we know about this substance? While many psychoactive drugs clearly fall into the category of either stimulant, depressant or hallucinogen, Cannabis exhibits a mix of all properties, perhaps leaning the most towards hallucinogenic or psychedelic, though with other effects quite pronounced as well.
In a social context, references to religious use of Cannabis extract have been found as early as 3 BC. The immediate effects from consuming Cannabis include relaxation and mild euphoria, while side-effects include a decrease in short-term memory, impaired motor skills, dry mouth and reddening of the eyes. Pharmacologically, the principal psychoactive constituent of cannabis is tetrahydrocannabinol (THC). The chemical structure of long hydrocarbon chain makes it fat-soluble and permits entry through the blood-brain barrier, where it binds to cannabinoid receptors concentrated in hippocampus, cerebellum and basal ganglia. With the discovery of cannabinoid receptor binding a “phytocannabinoid”(plant-derived cannabinoid), the search began for an endogenous ligand since THC is not naturally found in the body. This led to the discovery of two compounds–one aptly named anandamide (ananda- meaning “internal bliss” in Sanskrit language) and 2-arachidonylglycerol (2-AG). 2-AG is present at 170 times the concentration of anandamide in some regions of the brain, and these endocannabinoids compete with THC for binding to the cannabinoid receptor. The 3-dimensional structure of THC, anandamide and 2-AG are very similar; however, unlike THC, the endogenous molecules are broken down very quickly into metabolites and, therefore, do produce a perpetual natural “high”. The cannabinoid receptor (CB1 and CB2 located in brain and immune cells respectively) are G-protein coupled receptors acting mainly through the cAMP pathway. The activation of brain CB1 by ligands causes endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission.
Apart from producing an initial feeling of “bliss”, what else do these endocannabinoids do? Anandamide plays an important role in many bodily activities such as appetite, memory, pain, depression and fertility. Interestingly, anandamide, which is synthesized in areas important for memory, actually causes forgetfulness. Cannabinoid receptor activation reduces neurotransmitter release below the levels required to trigger long-term changes in synaptic strength in the hippocampus. Cannabinoids reduce glutamate release through a G-protein-mediated inhibition of the calcium channels responsible for neurotransmitter release from hippocampal neurons.
So what other factors, apart from Cannabis, leads to activation of endocannabinoid pathway? Three compounds that strongly resemble anandamide were found in dark chocolate by Daniele Piomelli and co-workers at the Neurosciences Institute in San Diego (1). They also found compounds (N-acylethanolamines) that block the breakdown of anandamide. Piomelli speculates that part of the pleasure of chocolate comes from anandamide and the anandamide-preserving N-acylethanolamines. This of course, does not mean that chocolate can be compared to THC or marijuana since the doses are log scales apart. This observation did not stop a lawyer from trying to defend his marijuana user client, with the argument that his client had ingested huge amounts of chocolate resulting in a positive drug test (2).
Recent work shows that physical exercise such as running activates the eCB (endocannabinoid) system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans, contributing to “runners high”. A study showed that eCB signaling is dependent on the intensity of exercise, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels) (3).
Since much work needs to be done to understand the mechanism of action and true effects of Cannabis, perhaps exercise provides a way to elevate levels of this bliss molecule naturally and safely, and if not there is always chocolate….
Literature Cited
- di Tomaso. E., Beltramo, M. and Piomelli, R. (1996) Brain cannabinoids in chocolate. Nature 382, 677–8.
- Tytgat, J., Van Boven, M. and Daenens, P. (2000) Cannabinoid mimics in chocolate utilized as an argument in court. Int J Legal Med. 113, 137–9.
- Raichlen, D.A. et al. (2013) Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol. 113, 869–75.
Anupama Gopalakrishnan
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