CBD and PSYCHEDELICS (such LSD) bind to the same serotonin receptor, which produces psychedelic altered states, but CBD is antipsychotic and does not produce hallucinations.
Serotonin is commonly referred to as the “happy neurotransmitter” in a manner that drives scientists furious. This issue is especially problematic as faults in the’serotonin hypothesis’ of depression – the assumption that depression is caused by a serotonin shortage that a pill (a serotonin reuptake inhibitor) may remedy – become increasingly apparent. 1 Serotonin is a complicated chemical in the brain and periphery with a huge and convoluted receptor system comprised of seven primary subtypes that govern an extensive array of physiological processes. To call serotonin the happy chemical is a gross oversimplification.
The significance of serotonin extends beyond positive mental experiences. The serotonin molecule controls the release of a plethora of other neurotransmitters in all bilateral animals, including worms and insects, where it has been conserved as an evolutionary through-line. 2 Serotonin is involved in activities as diverse as aggression, learning, appetite, sleep, cognition, and reward activity. It is commonly abbreviated as 5-HT due to its chemical name, 5-hydroxytryptamine. The serotonin receptors have become pharmacological targets for a variety of neuropsychiatric and gastrointestinal illnesses. 90% of 5-HT is situated in the gastrointestinal tract, where it governs intestinal motility.
In the late 1940s, biochemist Maurice Rapport isolated serotonin and described its chemical structure. 1979 saw the discovery of two unique serotonin receptor binding sites in the rat brain: 5-HT1 and 5-HT2 (later renamed 5-HT1A and 5-HT2A). Cannabidiol (CBD), a non-psychoactive, promiscuous cannabis component, binds directly to both of these receptors.
CBD has weak binding affinity for the traditional cannabinoid receptors, CB1 and CB2, however numerous subtypes of serotonin receptors are CBD’s primary docking sites. Additionally, the 5-HT2A receptor mediates the effects of LSD, mescaline, and other hallucinogens. But CBD and LSD work differently on 5-HT2A, the psychedelic receptor, resulting in notably distinct effects.
CBD AND PSYCHEDELICS: RECEPTOR CLUSTERS
The 2005 discovery that CBD interacts directly with these (and other) 5-HT receptors suggests a link between the endocannabinoid and serotonergic systems that scientists are actively investigating. Both endogenous cannabinoids and serotonin are highly conserved across animal taxa and are associated with a large “super family” of G-protein coupled receptors in the brain and periphery. Moreover, there is extensive communication between these two neurotransmitter systems, which are involved in similar physiological functions throughout the body, including the alleviation of anxiety, the reduction of pain, the relief of nausea and headaches, and the regulation of internal temperature.
G-protein coupled receptors, which are imbedded on the cell surface, are so complex that the study of their signaling pathways has already generated six Nobel Prizes for figuring out various aspects of the picture. The activation of a G-protein coupled receptor by an extracellular signal causes the release of a second messenger molecule within the cell. These intracellular molecules function like Western Union messengers that transmit signals across the entire cell. Roughly fifty percent of all current medications target G-protein coupled receptors, demonstrating their importance to human health.
Before scientists discovered that these transmembrane-bound proteins might “dimerize” into receptor complexes with unique signals, it was believed that G-protein coupled receptors functioned as solitary actors. (A “dimer” is the chemical structure generated when two of these receptors that float around the lipid membrane combine to form a functional unit.) In 2002, researchers from the University of Washington in Seattle found that CB1 cannabinoid receptors occasionally form “homomeric” complexes with one other.
Although we may not fully comprehend the physiological effects of receptor dimerization, one thing is clear: Receptors of various sorts can tangle and dimerize with one another. Neuroprotective benefits were mediated by a “heteromer” combination composed of a 5-HT1A serotonin receptor and a CB2 cannabinoid receptor, according to a 2013 study conducted by Spanish researchers on newborn piglets and ischemia (an injury that disrupts blood flow). This occurs when two distinct receptor types fuse and frequently accomplish actions that neither of them could independently.
CBD AND PSYCHEDELICS: GIVE-AND-TAKE
Interactions and feedback between the endocannabinoid and serotonergic systems are broad. Anandamide, an endogenous cannabinoid, exhibits action at the 5-HT1A receptor. CBD, which has been defined as a “moderate affinity agonist at the human 5-HT1A receptor,” also binds to this receptor.
An agonist activates a receptor, while an antagonist inhibits it. CBDA, the unheated “acid” form of cannabidiol found in unprocessed cannabis, is a more potent 5-HT1A agonist than CBD. CBDA demonstrates considerable promise as an antiemetic and treatment for anticipatory sickness.
When injected into many brain regions, CBD enhances neurotransmission mediated by 5-HT1A. Activation of the 5-HT1A receptor by CBD has been demonstrated to reduce blood pressure, body temperature, heart rate, and discomfort. The British Journal of Pharmacology published in 2013 that 5HT1A mediates the beneficial effects of CBD in animal models of liver damage, anxiety, sadness, pain, and nausea.
The most abundant G-protein coupled receptors in the central nervous system are CB1 cannabinoid receptors, which are activated by THC and not CBD. Numerous brain regions contain CB1 receptors, including the dorsal raphe nucleus, the principal source of serotonin in the forebrain. Stimulating these serotonergic neurons reduces anxiety and combats depression in animal studies. Restricting them results in depressive states.
It was discovered that mice bred to lack CB1 expression in this serotonin-producing brain area were more nervous than their wild-type counterparts.
Long-term cannabis stimulation downregulates 5-HT1A receptors, according to an article published in the International Journal of Neuropsychopharmacology in 2006 by Matthew Hill et al. By inhibiting serotonin receptors, the effects of various cannabinoids, such as “the conditioning of fear memory, emotional memory consolidation, antinociception [painkilling], catalepsy, hypothermia, and the activation of the hypothalamic-pituitary-adrenal axis in mice,” are diminished.
CBD AND PSYCHEDELICS: FALLING DOWN AND FORGETTING
CBD is likewise active at the 5-HT2A receptor, albeit reportedly to a lesser extent than at the 5-HT1A receptor.
The activation of 5-HT2A has been associated to a variety of symptoms, including migraines, mood problems, and hallucinations. This subtype of serotonin receptor is renowned for its significance to the psychedelic experience. LSD, mescaline, and psilocybin mushroom constituents are powerful agonists that bind to 5-HT2A, and when this occurs, the wonderful mystery tour begins.
Notably, a high amount of cannabis resin (hashish) consumed orally can induce LSD-like symptoms, including vivid, kaleidoscopic hallucinations. According to Dr. Ethan Russo, “significant experimental data” suggests that THC is hallucinatory while the similarly related cannabinoid, cannabidiol (CBD), inhibits such activity.
Perhaps the 5-HT2A receptor mediates the hallucinatory effects of THC. THC does not bind directly to 5-HT2A, unlike CBD. However, as previously mentioned, THC activates the CB1 cannabinoid receptor directly. The CB1 receptors form heterodimer complexes with 5-HT2A receptors, according to a fascinating article released by PLoS Biology in 2015. This indicates that CB1 and 5-HT2A receptors can interact and operate as a single entity.
Intriguingly, the interaction of these receptors activates signaling pathways that neither receptor alone would produce. Whether or not this can explain the hallucinatory effects of high-dose cannabis extracts is a topic of conjecture. CB1/5-HT2A heteromer complexes, however, are responsible for both the analgesic and amnesic effects of THC, as demonstrated by behavioral tests on mice.
Specifically when it comes to CBD and Psychedelics, the study published in PLOS Biology discovered that these cannabinoid/serotonin heteromers are “expressed and functionally active in certain brain areas associated with memory impairment.” Chronic cannabis usage was subsequently connected to the increase of CB1/5-HT2A heteromer complexes in human olfactory cells, as reported in Molecular Neurobiology.
Some cannabis advocates may be offended by the claim that prolonged use of their favorite herb causes short-term memory loss, but the scientific evidence is difficult to refute. Cannabis generally impairs memory in mice and humans, making it more difficult to recall aspects of a movie or, in the case of rodents, to navigate a maze as quickly.
However, the effects of THC on memory are not necessarily negative. In truth, forgetfulness is not an impairment but rather one of the most essential medicinal benefits of marijuana. Cannabinoids may be exactly what a veteran needs to forget a triggering experience or at least lessen the memory’s grasp.
It appears that these heteromer complexes mediate some of the cognitive deficits and advantages associated to THC.
CBD, THC, AND 5-HT3A INTERACTION
Because it is unique among serotonin receptors, the 5-HT3A receptor needs at least a brief mention. 5-HT3A, unlike all other subtypes of serotonin receptor, is not a G-protein coupled receptor. 5-HT3A operates instead as an ion channel.
An ion channel regulates the flow of ions across the cell membrane, hence regulating the brain’s quick electrical messages.
5-HT3A receptors, which are located in both the peripheral and central nervous systems, are implicated in both mood disorders and the transmission of pain signals. Antidotes that block the 5-HT3A receptor are used to relieve nausea and vomiting caused by chemotherapy.
THC and CBD are both highly effective negative allosteric modulators of 5-HT3A receptors. This indicates that THC and CBD interact with the 5-HT3A receptor in a manner that modifies its conformation, or shape, making it less likely to bind and be triggered by its native ligand, serotonin.
This may partially explain the anti-nausea properties of THC and CBD. Curiously, the natural cannabinoid anandamide also induces this type of inhibition. In conjunction with the serotonin system, plant cannabinoids and endogenous cannabinoids alleviate yet another human illness.
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