There have been many speculations about the effects that cannabis, or its active ingredient delta-9-tetrahydrocannabinol, has on the central nervous system (CNS). However, while THC may be the most active chemical substance in cannabis, there are over 400 different substances in cannabis. Of these, there are approximately 66 known cannabinoids that are found exclusively on the cannabis plant. While all of these bind to the cannabinoid receptors in the brain, THC is not only the cannabinoid that binds best to the receptor but it is also the natural component that is most effective medically.
The cannabinoid receptors are also activated by the endogenous cannabinoids naturally created in the body. In humans this neurotransmitter is known as anandamide (N-arachidonoylethanolamide or AEA). THC is the phytocannabinoid (not created naturally in the body) that mimics anandamide in the body. The cannabinoid receptors are a group of G-coupled protein receptor (seven-transmembrane domain receptors) which means that there are seven transmembrane alpha-helices that detect a cannabinoid on the outside of the membrane and immediately release factors on the inside of the nerve terminal. The receptors that the cannabinoid receptors activate are known at the CB1 and CB2 receptors. The cannabinoid receptors are the only two of their kind that are known to be located in cell membranes of mammals, birds, fish and reptiles.
CB1 receptors are predominantly found in the brain in the basal ganglia and the hippocampus. They are also found in the cerebellum, and the male and female reproductive organs. The CB1 receptor is associated with feelings of euphoria, and it also has plays a role in anticonvulsive pathways. The places where these receptors are absent are the medulla oblongata and the brain stem. The brainstem and medulla oblongata are responsible for cardiovascular and respiratory functions; not having the cannabinoid receptor would leave them completely unaffected by THC, or any other cannabinoid. The lack of cannabinoid receptors on the medulla also might suggest why there has never been a case of overdose of THC, reguardless of the amount consumed or the method of consumption. Likewise, there is a lack of cannabinoid receptors on the mesocorticolimbic pathway means that there is a significantly decreased chance of physical addiction because a dopaminergic pathway is not involved.
Where the CB2 receptors are located is one of the main differences between the CB1 and CB2 receptors. The CB2 receptor is located in the immune system and the cells derived from the immune system. They are found in the highest concentration on the spleen (also found in the tonsils and thymus gland), and they function primarily for anti- inflammatory responses. The CB2 receptors are most likely active in immune suppression. While this may seem counter productive, there are many autoimmune disease where the body’s natural immunity begins to attack healthy cells. The anti-inflammatory component of the cannabis have been influential in developing treatments for demylenating disorders such as multiple sclerosis and Parkinsons’s disease.
There is large amounts of evidence that prove researchers have discovered the mechanisms of action of the cannabinoid receptors. The CB1 receptor is activated when THC binds to the active site of the receptor. This inhibits the enzyme adenylate cyclase, which is responsible for converting ATP to cAMP. Cyclic AMP (cAMP) is the secondary messenger for protein kinase A therefore passively shutting down the A-type potassium channel (rapidly activating voltage-gated channels). The A-type potassium channel is responsible for numerous functions; some of them include regulating neurotransmitter release, epithelial electrolyte transport, smooth muscle contraction, insulin secretion, heart rate, neuronal excitability, and cell volume. Another type of potassium channel that the CB1 receptor effects is the inwardly rectifying potassium channel. This is a potassium selective ion channel that is responsible for regulation neuronal activity and establishing the resting membrane potential of the cell membrane. Because this potassium channel is activated by a G-coupled protein receptor it suggests that the channel is activated by the beta and gamma subunits of the heterotrimeric G protein complex.
Another way that THC replicates the anandamide receptor system in the central nervous system is that it directly inhibits N and P/Q-type voltage dependant calcium channels and sodium channels. These channels are responsible for the release of neurotransmitters at the presynaptic cleft. Inhibiting these channels would prevent the influx of sodium and calcium and therefore inhibiting the release of neurotransmitters, L- glutamate, GABA, noradrenaline, 5-HT and acetylcholine. These neurotransmitters are normally released into the synapse and either taken back up by the synapse or by the adjacent cell, but many drugs either prevent the reuptake of neurotranmitter (therefore leaving more to be taken up by the other cell) or they modify the presynaptic terminal to release more neurotransmitter than the body would do naturally.
Lastly, one of the major mechanisms of action of THC in the brain is to activate the mitogen-activated protein (MAP) kinase enzyme. This pathway is known to contribute to regular cellular activities, including; gene expression, cell proliferation, differentiation, and ultimately the apoptotic pathway. This pathway could be instrumental in discovering the anti-tumor properties of the cannabinoids.
Scientists have found that the cannabinoids, when binding to mutated/cancerous cells that they signal the cell to “commit suicide” because it has not copied its faithfully. This would ultimately decrease the instance of cancerous cells among patients. THC has provent to regulate the release of neurotransmitters in the brain; there is evidence that THC is a neuroprotective agent.
The impact of a new study are leading researchers at the National Institutes of Mental Health in Bethesda, Maryland to discover that cannabinoidol and THC are cannabinoid receptor independent, which means that cannabinoid receptor agonists do not affect their ability to bind. They also discovered that “cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry.” This is is important in glutamate excitotoxicity because it has been show that antioxidants can prevent glutamate from reaching toxic levels. A Dutch team of scientists from Utrecht University studying how to prevent neurodegeneration by using THC found results that were similar to previous findings. They also found that “cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures.” This finding would be particularly helpful for patients suffering from cerebral ischemia because there is always a risk of creating highly reactive oxygen chemical molecules when an oxygen deprived region of the brain with oxygen.
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