CBD – how non-psychoactive is it really? CBD interacts directly with the CB1 cannabinoid receptor in therapeutically significant ways while moderating the psychoactive effects of THC, according to the data.

It is still a work in progress to comprehend how cannabidiol (CBD) exerts its numerous impacts on human physiology. Scientists have identified over sixty distinct biochemical mechanisms by which CBD functions. CBD binds to numerous receptors in the brain, including serotonin 5HT1A (which contributes to CBD’s anti-anxiety impact), TRPV1 (which contributes to CBD’s anti-psychotic effect), the nuclear receptor PPAR-gamma (which regulates gene expression), and the orphan receptor GPR55, among others.

CBD and tetrahydrocannabinol (THC) have similar chemical structures, however CBD does not directly excite canonical cannabinoid receptors CB1 and CB2 in the same way that THC does. THC, the primary psychoactive component of marijuana, induces intoxication by binding to CB1, the most abundant protein receptor in the brain and central nervous system.

THC fits snuggly into a particular pocket on the CB1 receptor called a “orthosteric” binding site. Lock-and-key is an apt metaphor for orthosteric binding: THC, the chemical key, fits into the CB1 receptor lock and activates it, initiating a signaling cascade that suppresses the release of other neurotransmitters on a cellular level (thereby protecting the brain from too much excitation). This is one of the several reasons why THC is a fantastic therapeutic drug.

The orthosteric binding site of CB1 is also the “keyhole” for THC’s endogenous relatives, anandamide (the first endocannabinoid identified in the human brain) and 2AG (our most abundant endocannabinoid). These endogenous cannabinoid chemicals, comparable to the brain’s own marijuana, occupy the same orthosteric binding pocket as THC and trigger some of the same signaling processes.


CBD – how non-psychoactive is it really? Since the CB1 receptor was discovered in 1988, it has been a tenet of cannabinoid research that CBD, unlike THC, has a low affinity for binding to CB1. However, this idea is based on outdated science.

CBD interacts directly with the CB1 receptor in ways that are therapeutically meaningful, according to new findings emerging from the international cannabinoid research community. CBD, however, docks at a unique location on CB1 that is functionally separate from the orthosteric binding site utilized by THC. CBD binds to a region on the CB1 receptor known as an allosteric binding site.

Cannabidiol, an allosteric modulator of CB1, does not initiate a signaling cascade when it binds to the receptor. However, it does influence the response of the CB1 receptor to activation by THC and endogenous cannabinoids. Allosteric modification of CB1 alters the conformation (shape) of the receptor, which can have a profound effect on cell signaling efficiency.

Numerous receptors for various types of messenger molecules, which influence the activity of the cell, are present on the membrane of every cell. Not infrequently, a receptor has two different binding sites or loci that can be triggered by multiple medicines and endogenous substances. A medication activates the orthosteric site, but an allosteric modulator can either increase or reduce a receptor’s ability to convey a signal, depending on how the allosteric modulator alters the receptor’s conformation.

To extend the metaphor of the lock and key: The allosteric binding site, when active, makes the orthosteric binding site simpler or more difficult to open. Positive allosteric modulators alter the geometry of the receptor to enhance receptor signaling, whereas negative allosteric modulators inhibit receptor transmission.


CBD – how non-psychoactive is it really? Numerous medications target orthosteric receptor-stimulating binding sites. Additionally, Big Pharma has commercialized a number of synthetic allosteric modulators of different receptor systems (Mimpara, Piracetam, and Selzentry, for example). Pharmaceutical corporations are keenly interested in allosteric manipulation of the endocannabinoid system. Theoretically, if not in fact, allosteric modulators can prime the system for amplification or inhibition by astonishingly fine-tuning receptor transmission.

According to Big Pharma dogma, full activation of CB1 can provide therapeutic benefits, but THC’s psychoactivity innately restricts its medical utility. In medical dictionaries, getting high is defined as a negative side effect. Allosteric manipulation increases the possibility of boosting CB1 receptor activation without inducing unsettling distress or unnecessary bliss.

The University of Aberdeen in Scotland has developed a positive allosteric modulator of CB1 for the treatment of pain and neurological disorders. This new medicine, dubbed “ZCZ011,” produced no euphoric effects when tested on mice, but it reduced neuropathic and inflammatory pain by enhancing the CB1 receptor’s responsiveness to anandamide, an endogenous cannabinoid.

Allosteric regulation of the endocannabinoid system research is still in its infancy. In 2005, the first allosteric modulators of CB1 were found. Scientists from Dalhousie University in Halifax, Canada, published in the British Journal of Pharmacology that cannabidiol is a negative allosteric modulator of CB1 in vitro after ten years had passed. This indicates that CBD reduces the maximum stimulation of CB1 by THC and endogenous cannabinoids.

The Canadian study team determined the precise molecular niche where CBD resides at the CB1 receptor, a protein composed of 472 amino acids strung together in a twisted chain that loops seven times around the cell membrane. Scientists can precisely modify CB1 receptors by targeting a single amino acid. The mutational analysis data identified locations 98 and 107 on the CB1 amino acid chain as the CBD docking sites.


CBD – how non-psychoactive is it really? Negative allosteric regulation of CB1 is conceptually comparable to a light dimmer switch. CBD modifies cognition and improves mood; it provides mood lighting for the brain and dims the “strobe light” that causes seizures. As a negative allosteric modulator of the CB1 receptor, CBD shows promise for treating conditions associated with endocannabinoid excess or overactivity (obesity, metabolic disorders, liver disease, cardiovascular issues), whereas a positive allosteric modulator that enhances CB1 receptor signaling may be beneficial for diseases associated with endocannabinoid deficiency (such as anorexia, migraines, irritable bowel, fibromyalgia, and PTSD).

Notably, allosteric modulators cannot often affect receptor conformation unless the orthosteric binding site is simultaneously activated. CBD can only affect CB1 receptor activation in the presence of THC or another cannabinoid at the orthosteric binding site. CBD’s efficacy as an allosteric modulator in whole-plant cannabis treatments needs the presence of THC.

THC and CBD function together; they are the dynamic duo of cannabis medicine. Given the close interactions between these two plant components, does it make sense to credit psychoactivity solely to one (THC) and not the other (CBD)? Is it correct to suggest that CBD is “psychoactive-free”?

Researchers have shown that CBD has antipsychotic, anxiolytic (anxiety-relieving), and antidepressant properties. If CBD may alleviate anxiety, sadness, or psychosis, then it is evident that cannabidiol is a powerful mood-altering chemical, even if it does not provide much euphoria. Perhaps it would be more accurate to clarify that CBD is “not psychoactive in the same way that THC is,” rather than repeating the oft-repeated but sometimes inaccurate phrase “CBD is not psychoactive.”

Cannabidiol’s emergence as a negative allosteric modulator that binds directly to the CB1 receptor challenges outdated beliefs about CBD and throws new light on its therapeutic potential. In turn, as our scientific knowledge and therapeutic experience grows, the categorization of CBD as non-psychoactive may become obsolete.


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