Non Psychoactive CBD Oil

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Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant <i>Cannabis sativa</i> L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the c … The cannabis-derived chemical is non-psychoactive, and – while federally illegal – has been hailed as a cure for disease<br> New scientific data shows that CBD interacts directly with the CB1 cannabinoid receptor in ways that are therapeutically relevant while modulating the psychoactive effects of THC.

Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature

Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.

Keywords: Cannabis sativa; cannabidiol; degradation; psychotropic effects; tetrahydrocannabinol.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Chemical structures of ( a…

Chemical structures of ( a ) cannabinol (CBN) including the numbering system, (…

Chemical structures of (a) cannabinol (CBN) including the numbering system, (b) Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and (c) cannabidiol (CBD).

Google trends analysis for cannabidiol…

Google trends analysis for cannabidiol (CBD) (Data source: Google Trends [23]).

Chemical structures of ( a…

Chemical structures of ( a ) hexahydrocannabinol (HHC), ( b ) cannabigerol (CBG)…

Chemical structures of (a) hexahydrocannabinol (HHC), (b) cannabigerol (CBG) and (c) cannabichromene (CBC).

Overview of various chemical conversions…

Overview of various chemical conversions of cannabidiol (CBD) to different conversion products and…

Overview of various chemical conversions of cannabidiol (CBD) to different conversion products and the respective conditions, which are reported in the literature.

Chemical structures of ( a…

Chemical structures of ( a ) cannabidiolic acid (CBDA) and ( b )…

Chemical structures of (a) cannabidiolic acid (CBDA) and (b) Δ 9 -tetrahydrocannabinolic acid (Δ 9 -THCA).

What is CBD? The ‘miracle’ cannabis compound that doesn’t get you high

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.

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 perception of its widespread medical benefits have made the chemical a rallying cry for legalization advocates.

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.

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So far, CBD is the most promising compound from both a marketing and a medical perspective. Many users believe it helps them relax, despite it not being psychoactive, and some believe regular doses help stave off Alzheimer’s and heart disease.

While studies have shown CBD to have anti-inflammatory, anti-pain and anti-psychotic properties, it has seen only minimal testing in human clinical trials, where scientists determine what a drug does, how much patients should take, its side effects and so on.

Despite the government ruling, CBD is widely available over the counter in dispensaries in states where marijuana is legal.

CBD first came to public attention in a 2013 CNN documentary called Weed. The piece, reported by Dr Sanjay Gupta, featured a little girl in Colorado named Charlotte, who had a rare life-threatening form of epilepsy called Dravet syndrome.

At age five, Charlotte suffered 300 grand mal seizures a week, and was constantly on the brink of a medical emergency. Through online research, Charlotte’s desperate parents heard of treating Dravet with CBD. It was controversial to pursue medical marijuana for such a young patient, but when they gave Charlotte oil extracted from high-CBD cannabis, her seizures stopped almost completely. In honor of her progress, high-CBD cannabis is sometimes known as Charlotte’s Web.

CBD has been sought for its healing properties. Illustration: George Wylesol

After Charlotte’s story got out, hundreds of families relocated to Colorado where they could procure CBD for their children, though not all experienced such life-changing results. Instead of moving, other families obtained CBD oil through the illegal distribution networks.

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.)

Epidiolex was developed by the London-based GW Pharmaceuticals, which grows cannabis on tightly controlled farms in the UK. It embarked on the Epidiolex project in 2013, as anecdotes of CBD’s value as an epilepsy drug began emerging from the US.

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.

Fortunately, like THC, CBD appears to be well tolerated; as far as I can tell, there are no recorded incidents of fatal CBD overdoses.

Is CBD Really Non-Psychoactive?

Data shows that CBD interacts directly with the CB1 cannabinoid receptor in therapeutically relevant ways while modulating THC’s psychoactive effects.

Data shows that CBD interacts directly with the CB1 cannabinoid receptor in therapeutically relevant ways while modulating THC’s psychoactive effects.

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.

CBD and tetrahydrocannabinol ( THC ) have similar molecular structures, but CBD does not directly stimulate CB1 and CB2 , the canonical cannabinoid receptors, like THC does. THC , marijuana’s principal psychoactive component, makes a person feel high by binding to CB1 , the most abundant protein receptor in the brain and central nervous system.

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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.

CB1 ’s orthosteric binding site is also the “keyhole” for THC ’s endogenous cousins, anandamide (the first endocannabinoid compound discovered in the mammalian brain) and 2AG (our most abundant endocannabinoid). Likened to the brain’s own marijuana, these endogenous cannabinoid compounds fit into the same orthosteric binding pocket as THC and activate some of the same signaling mechanisms.

New Data Versus Old Science

Since the CB1 receptor was discovered in 1988, it’s been an article of faith among cannabinoid researchers that CBD , unlike THC , has little binding affinity for CB1 . But this notion is based on old science.

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.

When cannabidiol, an allosteric modulator of CB1 , docks at the receptor, it does not initiate a signaling cascade. But it does impact how the CB1 receptor responds to stimulation by THC and the endogenous cannabinoids. Allosteric modulation of CB1 changes the conformation (shape) of the receptor, and this can have a dramatic impact on the efficiency of cell signaling.

Every cell membrane has lots of receptors for many types of messenger molecules, which influence the activity of the cell. It’s not uncommon for a receptor to have two distinct binding sites or loci that can be activated by various drugs and endogenous compounds. The orthosteric site is the switch that a drug turns on, whereas an allosteric modulator can either amplify or decrease a receptor’s ability to transmit a signal depending on how the allosteric modulator changes the conformation of the receptor.

To extend the lock-and-key metaphor: If the orthosteric binding site is the lock on a door, then the allosteric binding site, when activated, makes the lock easier or more difficult to open. A “positive allosteric modulator” changes the shape of the receptor in a way that potentiates receptor signaling, while a “negative allosteric modulator” will reduce receptor transmission.

Healing Without the High?

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.

Full-on stimulation of CB1 can deliver therapeutic benefits, but THC ’s psychoactivity intrinsically limits its medical utility, according to Big Pharma catechism. For the medical constabularies, getting high is by definition an adverse side effect. Allosteric modulation raises the prospect of increasing CB1 receptor activity without causing disconcerting dysphoria or needless euphoria.

Scientists at the University of Aberdeen in Scotland have synthesized a positive allosteric modulator of CB1 to treat pain and neurological disorders. When researchers at Virginia Commonwealth University tested the compound on mice, this experimental drug, known as “ ZCZ011 ,” had no psychoactive effects of its own, but reduced neuropathic and inflammatory pain by boosting the CB1 receptor’s response to anandamide, an endocannabinoid compound.

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Research into allosteric modulation of the endocannabinoid system is still in its early phases. Allosteric modulators of CB1 were first discovered in 2005. Ten years would elapse before scientists at Dalhousie University in Halifax, Canada, reported in the British Journal of Pharmacology that cannabidiol is a negative allosteric modulator of CB1 in vitro. This means that CBD lowers the ceiling on the ability of THC and endogenous cannabinoids to stimulate CB1 .

The Canadian research team identified the exact molecular niche where CBD parks at the CB1 receptor, a protein which consists of 472 amino acids strung together in a crumpled chain that wraps around the cell membrane seven times. Scientists can mutate CB1 receptors with precision, targeting one amino acid at a time. Data generated by mutational analysis pinpointed positions 98 and 107 on CB1 ’s amino acid chain as the key docking loci for CBD .

A Dimmer Switch

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 ).

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 .

THC and CBD work in tandem; they are the power couple of cannabis therapeutics. Given the intimate synergies between these two plant compounds, how much sense does it make to attribute psychoactivity exclusively to one ( THC ) and not the other ( CBD )? Is it really accurate to say that CBD is a “non-psychoactive” substance?

Researchers have demonstrated that CBD confers antipsychotic, anxiolytic (anxiety-reducing), and antidepressant effects. If CBD can relieve anxiety or depression or psychosis, then obviously cannabidiol is a profound mood-altering substance, even if it doesn’t deliver much by way of euphoria. Perhaps it would be better to say that CBD is “not psychoactive like THC ,” rather than repeating the familiar and somewhat misleading refrain that “ CBD is not psychoactive.”

The identification of cannabidiol as a negative allosteric modulator that binds directly to the CB1 receptor challenges antiquated assumptions about CBD and sheds new light on its medicinal potential. In turn, as our scientific understanding and therapeutic experience deepens, the description of CBD as non-psychoactive may fall by the wayside.

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.

Copyright, Project CBD . May not be reprinted without permission.

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