In late June, the US Food and Drug Administration could approve the Epidiolex, a pharmaceuticalized form of CBD for several severe pediatric seizure disorders. According to data recently published in the New England Journal of Medicine, the drug can reduce seizures by more than 40%. If Epidiolex wins approval it would be the first time the agency approves a drug derived from the marijuana plant. (The FDA has approved synthetic THC to treat chemotherapy-related nausea.)
While parents treating their children with CBD had to proceed based on trial and error, like a folk medicine, they also had to wonder whether dispensary purchased CBD was professionally manufactured and contained what the package said it did. GW brought a scientific understanding and pharmaceutical grade manufacturing to this promising compound.
In early May, a federal court declined to protect cannabidiol (CBD), a chemical produced by the cannabis plant, from federal law enforcement, despite widespread belief in its medical value.
CBD has been sought for its healing properties. Illustration: George Wylesol
The ruling was contrary to existing evidence, which suggests the chemical is safe and could have multiple important uses as medicine. Many cannabis advocates consider it a miracle medicine, capable of relieving conditions as disparate as depression, arthritis and diabetes.
The first thing to know about CBD is that it is not psychoactive; it doesn’t get people high. The primary psychoactive ingredient in marijuana is tetrahydrocannabinol (THC). But THC is only one of the scores of chemicals – known as cannabinoids – produced by the cannabis plant.
Despite the government ruling, CBD is widely available over the counter in dispensaries in states where marijuana is legal.
It should be noted that allosteric modulators typically are unable to alter receptor conformation unless the orthosteric binding site is also stimulated. CBD can modulate CB1 receptor signaling only when THC or another cannabinoid compound is active at the orthosteric binding site. In terms of whole plant cannabis therapeutics, CBD ’s efficacy as an allosteric modulator requires the co-presence of THC .
Jahan Marcu is Chief Science Officer at Americans for Safe Access with 14 years of experience in Cannabis research and regulations. Ali S. Matthews is the pen name of an endocannabinoid researcher currently studying allosteric modulators and the mammalian brain, who wishes to protect the privacy and identity of his federally funded laboratory. Martin A. Lee is the director of Project CBD and the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.
Understanding how cannabidiol ( CBD ) exerts its myriad effects on human physiology is a work in progress. Thus far, scientists have identified more than 60 different molecular pathways through which CBD operates. It is known, for example, that CBD acts through multiple receptor-independent channels and it also binds to various receptors in the brain, including serotonin 5HT1A (which contributes to CBD ’s anti-anxiety effect), TRPV1 (which contributes to CBD ’s anti-psychotic effect), the nuclear receptor PPAR -gamma (regulates gene expression), and the orphan receptor GPR55 , among others.
Healing Without the High?
Negative allosteric modulation of CB1 is conceptually similar to a dimmer switch on a light fixture. CBD alters cognition and improves mood; it creates mood lighting for the brain and dims the ‘strobe light’ triggering seizures. As a negative allosteric modulator of the CB1 receptor, CBD shows particular 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 could be helpful for diseases linked to endocannabinoid deficits (such as anorexia, migraines, irritable bowel, fibromyalgia, and PTSD ).
THC fits snugly into a special pocket – an “orthosteric” binding site – on the CB1 receptor. The image of lock-and-key is apropos for orthosteric binding: THC , the molecular key, fits into the CB1 receptor lock and turns it on, which triggers a signaling cascade on a cellular level that inhibits the release of other neurotransmitters (thereby protecting the brain from too much excitation). It’s one of the many reasons why THC is such a remarkable therapeutic substance.
New data emerging from the international cannabinoid research community indicates that CBD interacts directly with the CB1 receptor in ways that are therapeutically relevant. But CBD parks at a different docking site on CB1 that is functionally distinct from THC ’s orthosteric binding site. CBD attaches to what’s known as an “allosteric” binding site on the CB1 receptor.
Numerous pharmaceuticals target orthosteric binding sites for receptor stimulation. Big Pharma has also brought to market several synthetic allosteric modulators of other receptor systems (Mimpara, Piracetam, and Selzentry, for example). There is serious interest among drug companies in allosteric modulation of the endocannabinoid system. In theory, if not practice, allosteric modulators can prime the system for amplification or inhibition by fine-tuning receptor transmission with amazing subtlety.
• Psychoactive: “A substance affecting the mind”.
This becomes easier to understand once we look at the definitions of both terms:
Psychoactive substances are more common than you think
With an understanding of how CBD might influence the mind, we now come back to the original question: Is CBD psychoactive?
Psychotropic substances affect our mental state, our sense of reality, and our perception of the world. Although it’s a term that can refer to prescription drugs, it’s most commonly used to describe recreational drugs.
Working along the same lines as chocolate, CBD is thought to influence serotonin receptors and help in the regulation of tension, uneasiness and low mood. Obviously, with any mechanism involving sophisticated neurochemicals, there are a lot of variables to explore. Researchers are keen to understand the full scope of the interaction between CBD and 5-HT receptors, with studies underway.