Once a widely ignored phytocannabinoid, cannabidiol (CBD) now attracts great therapeutic interest, especially in epilepsy and cancer. As with many rising trends, various myths and misconceptions have accompanied the heightened public interest and intrigue. CBD is a 21-carbon terpenophenolic (plant metabolite with biological activity important for human health) compound exclusive to Cannabis, after its decarboxylation from a cannabidiolic acid precursor (Figure 1).
Figure 1. Cannabidiol (CBD) Production, Biosynthesis and Metabolism. CBD is biosynthesised in hemp or Cannabis sativa and is produced in greatest concentration in capitate glandular trichomes in the unfertilised female flowering tops of the plant. Its main precursors are olivetolic acid and geranyl pyrophosphate, which produce cannabigerolic acid (CBGa) and then cannabidiolic acid (CBDa) via catalysis by CBDa synthase, an enzyme co-dominant with delta-9-tetrahydrocannabinolic acid (THCa) synthase. Subsequently decarboxylation via light exposure, heating or ageing results in CBD. In vivo (in a living organism), first-pass hepatic metabolism produces 7-hydroxy-cannabidiol, whose specific pharmacology has yet to be ascertained. While exposure to strong acids can produce an isomerisation (conversion into an isomer of itself) of CBD to tetrahydrocannabinol (THC), this reaction does not occur in humans.
Understanding how CBD exerts its myriad effects on human physiology is a work in progress. Scientists have identified over 60 different molecular pathways through which CBD operates. CBD is the most common phytocannabinoid in hemp and second-most prevalent in Cannabis. It has proven extremely versatile pharmacologically, displaying the unusual ability to antagonise or nullify the action of cannabinoid receptor type 1 (CB1) in the presence of THC, despite having little binding affinity and supporting its modulatory effect on THC-associated adverse events such as anxiety, tachycardia, hunger and sedation. CBD and THC have similar molecular structures, but CBD does not directly stimulate CB1 and CB2, the canonical cannabinoid receptors, like THC does).
Data emerging from international cannabinoid research indicates CBD interacts directly with CB1 in ways that are therapeutically relevant, but CBD parks at a different docking site on CB1, functionally distinct from THC’s orthosteric binding site (the active site; allosteric bind elsewhere on the protein surface). CBD attaches to an allosteric binding site on the CB1 receptor. When CBD docks, it does not initiate a signalling cascade. But it does impact how CB1 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 signalling.
The effects are mediated by a wide variety of signalling mechanisms including activity on cannabinoid receptors, 5-HT1A (subtype serotonin receptor; involved in mechanism of action of anxiolytic, anti-depressant and anti-psychotic medications), the orphan GPR55 (G Protein-Coupled Receptor 55), GPR18, TRPV1 (the capsaicin receptor or vanilloid receptor 1 which contributes to CBD’s anti-psychotic effect), the nuclear receptor PPAR-gamma (regulates gene expression) and other transient receptor potential (TRP) channels. CBD is a GPR55 and GPR18 antagonist (blocking agent), possibly supporting a therapeutic role in disorders of cell migration, notably endometriosis. CBD is anti-convulsant, anti-nausea, cyto-preservative for normal cells, enhances adenosine (a potent biological mediator that affects numerous cell types) receptor signalling and prevents prion accumulation and neuronal toxicity. CBD and THC are both neuroprotective, evidenced in a 1998 study, Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants, and are a treatment and preventative for Alzheimer’s. CBD is an analgesic, a neuroprotective anti-oxidant, more potent than ascorbate or tocopherol, acts as a TRPV1 agonist analogous to capsaicin but without noxious effect, while also inhibiting uptake of anandamide (AEA).
In 2005, it was demonstrated CBD had agonistic activity which may underlie its anti-anxiety activity, reduction of stroke risk and anti-nausea effects. Recent studies demonstrated that CBD has a prospective role as an anti-depressant; inhibits synthesis of lipids in sebocytes and produces apoptosis at higher doses in a model of acne; and, displays powerful activity against methicillin-resistant Staphylococcus aureus (MRSA). CBD has been linked to the speedier healing of bone fractures. The Journal of Bone and Mineral Research published a study, Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts, which shows the administration of CBD significantly helps heal bone fractures.
Newfound interest in CBD has been accompanied by an alarming number of mischaracterisations. Across the United States (US), many start-ups and retailers have jumped on the CBD bandwagon, touting CBD derived from industrial hemp as the next big thing, a miracle oil with medicinal properties, without making people feel “stoned”. But along with a growing awareness of CBD as a potential health aid there has been a proliferation of misconceptions. These include apparent confusion as to the correct assignation of CBD’s psychopharmacological activity, where does it belong in the politically correct drug war catechism, alleged sedative effects, its mechanism of action as an antagonist at CB1, its legal status in US commerce, its metabolic fate in human administration, medicinal versus recreational cannabinoids, ‘bad’ versus ‘good’ cannabinoids, effectiveness of single-molecule compounds, state law ineffectiveness in serving patients and, CBD isn’t CBD, as it really does matter where it comes from. Better understanding of these issues will be of great importance for patients, recreational consumers, physicians and legislators as they further consider the role and disposition of this versatile phytocannabinoid.
Misconception: Cannabidiol is non-psychoactive and non-psychotropic – CBD is frequently mischaracterised in lay, electronic and scientific sources as ‘non-psychoactive’ or ‘non-psychotropic’ in comparison to THC, but these terms are inaccurate, given its prominent pharmacological benefits on anxiety, schizophrenia, addiction and possibly even depression. CBD should be re-labelled, perhaps as being less ‘illuminating’ than THC. Lacking associated reinforcement, craving, compulsive use, etc., that would indicate a significant ‘drug abuse’ liability, CBD certainly isn’t a suitable ‘drug of abuse’, nor is THC, for that matter, as neither has the same mechanism of action as drugs of addiction, like cocaine, for example, do.
CBD Molecular Formula: C21H30O2
There is serious interest among drug companies in allosteric modulation of the Endocannabinoid System (ECS). 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.
Properly used, the psycho- or neuroactivity of Cannabis carries with it many important treatment options. Rev. Dr Kymron deCesare of Steep Hill Lab Inc., said in 2015 that a good friend living with ADHD focussed on sativa strains containing significant amounts of the terpenes, pinene, limonene and terpinolene (in a strain like Super Silver Haze) and their mind became energetic, clear-headed and project-oriented, turning the unfocussed, chaotic ADHD mind into a mildly focussed OCD. Research into allosteric modulation of the ECS is still in its early phases. Allosteric modulators of CB1 were first discovered in 2005 and ten years would elapse before scientists at Dalhousie University in Halifax, Canada, reported in the British Journal of Pharmacology that CBD is a negative allosteric modulator of CB1 in vitro. This means CBD lowers the ceiling on the ability of THC and endogenous cannabinoids to stimulate CB1.
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 psycho- or neuroactivity 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 is a pharmacological agent of wondrous diversity, an absolute archetypal ‘dirty drug’ (a substance used as a medication that may bind to many different molecular targets or receptors in the body with a wide range of effects and reactions), encompassing analgesic, anti-depressant, anti-inflammatory, anti-oxidant, anti-emetic, anxiolytic (anti-anxiety), anti-psychotic, anti-convulsant, neuroprotective, immuno-modulatory and cytotoxic effects (in breast cancer, for example). If CBD can relieve anxiety or depression or psychosis, then obviously CBD 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 or neuroactive like THC” rather than repeating the familiar and somewhat misleading refrain that “CBD is not psychoactive”. The identification of CBD as a negative allosteric modulator that binds directly to CB1 challenges antiquated assumptions about CBD and sheds new light on its medicinal potential. In turn, as scientific understanding and therapeutic experience deepens, the description of CBD as non-psychoactive or non-neuroactive may fall by the wayside.
Misconception: Psychoactivity is inherently an adverse side effect – According to politically correct drug war catechism, the Cannabis high is an unwanted side effect. ‘Big Pharma’ is keen on synthesising medically active Cannabis-like molecules that don’t make people high, although it’s not obvious why mild euphoric feelings are intrinsically negative for a sick person or a healthy person, for that matter. In ancient Greece, the word euphoria meant “having health”, a state of well-being. The euphoric qualities of Cannabis, far from being an unwholesome side effect, are deeply implicated in the therapeutic value of the plant. “We should be thinking of Cannabis as a medicine first” said Dr Tod Mikuriya, “that happens to have some psychoactive properties, as many medicines do, rather than as an intoxicant that happens to have a few therapeutic properties on the side”.
Misconception: CBD Is Sedating – Some early anecdotal literature cited a low incidence of sedation after CBD administration, and contemporaneously, this side effect is frequently attributed to CBD. However, low to moderate doses are distinctly alerting, as proven in its ability to counteract sedative effects of THC, delay sleep time as documented via electro-encephalography and reduce THC-associated ‘hangover’. Numerous studies in normal subjects have been free of sedative effects. By contrast, CBD formulated as the pharmaceutical Epidiolex (an investigational Cannabis extract with traces of THC, other cannabinoids and some terpenoids), employed in very high doses of 25 mg/kg/day or more to treat intractable epilepsy has produced sedation under conditions of poly-pharmacy, especially when co-administered with clobazam (benzodiazepine), which resolves after reduction of the dose of clobazam.
Whereas pure CBD is not sedating, many CBD-containing Cannabis and hemp chemovars do display this liability. This is not attributable to CBD concentration per se, but rather to the predominance of high levels of myrcene in many commercial varieties. Myrcene, a monoterpenoid, displays a prominent narcotic-like profile that is seemingly responsible for the ‘couch-lock’ phenomenon frequently associated with modern Cannabis phenomenology. Selective breeding of low myrcene chemovars reduces or eliminates this liability, yielding Cannabis plants or extracts that are more suitable to the patient who must also work or study.
Misconception: CBD Is a CB1 Antagonist Like Rimonabant – Rimonabant (Acomplia) a synthetic CB1 inverse agonist that was marketed briefly in Europe to treat obesity and metabolic syndrome was removed from the market due to numerous serious associated adverse events, including anxiety, suicidal ideation, nausea and even anew cases of multiple sclerosis. This situation produced a chilling effect on development programs for other CB1 inverse agonists and even extended to harsh scrutiny of the natural compounds, CBD and tetrahydrocannabivarin (THCv), which, in contradistinction, act as neutral antagonists at CB1. The mechanism of action of CBD seems, rather, to stem from negative allosteric modulation of CB1, particularly in the presence of THC and it produces none of the rimonabant-type adverse events.
Misconception: CBD is legal in all 50 US states – In keeping with its versatile pharmacology without associated drug abuse liability or serious side effects, CBD is unscheduled in most nations. This is not the case in the US (nor in Australia*), where pharmacology notwithstanding, CBD has been a forbidden Schedule I agent with its own Drug Enforcement Administration (DEA) number and designation as a THC analogue. In spite of continuing prohibition, domestic commerce in CBD in one form or another is rampant, previously accompanied by claims that its extraction from hemp refuse was a legal process. In 2016 the DEA considered CBD oil to be a federally illegal Schedule I drug, but there were temporary safeguards in place that protected patients in many states from federal prosecution over possession of the oil.
Misconception: CBD Turns into THC in the Body – This false claim has been invoked online and has gained currency and perhaps even credibility, after publication of an article in which it was demonstrated that CBD could be converted to THC after prolonged exposure to ‘simulated’ gastric acid. While this isomerisation reaction has been known for decades, first reported in 1940 and later in the 1960’s, there is no evidence the reaction occurs in humans in vivo. First, no known enzyme exists that can catalyse such a bioconversion. In addition, pharmacokinetic and metabolism studies in human clinical trials refute such a reaction. In a double-blind placebo-controlled study of CBD in Huntington disease, fourteen patients were administered oral doses over six weeks. No plasma levels of THC were found. Similarly, a 2012 randomised, controlled study compared CBD, THC and placebo in sixteen healthy males. Neither THC nor its primary hepatic metabolite, 11-hydroxy-THC, was noted after CBD administration. There seems to be no compelling evidence CBD undergoes cyclisation or bioconversion to THC in humans. A review in 2016, Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans, came to the conclusion enough data exists to be reassured the acidic gastric environment during normal gastrointestinal transit does not “expose patients treated with oral CBD to levels of THC and other psychoactive cannabinoids that exceed the threshold for a physiological response”.
Misconception: CBD is medical. THC is recreational – Often people seek “CBD, the medical part” of the plant, “not THC, the recreational part” that gets you high. Actually, THC, “The High Causer” has awesome therapeutic properties and should become known as, THC, “The Healing Cannabinoid”. In 2006, Scientists at the Scripps Research Institute (San Diego, California) reported that THC inhibits an enzyme implicated in the formation of beta-amyloid plaque, the hallmark of Alzheimer’s-related dementia. The US federal government recognises single-molecule synthetic THC (Marinol) as an anti-nausea compound and appetite booster, deeming it a Schedule III drug, a category reserved for medicinal substances with little abuse potential. Side effects of synthetic THC include;
- mood changes;
- dizziness, trouble concentrating;
- feeling “high”;
- weakness, lack of coordination;
- anxiety, confusion;
- stomach pain, nausea, vomiting, diarrhea;
- warmth or tingly feeling; or,
- sleep problems (insomnia).
But whole plant Cannabis, the only natural source of THC, continues to be classified as a dangerous Schedule I drug in the US with no medical value.
Misconception: THC is the bad cannabinoid. CBD is the good cannabinoid – The drug warrior’s strategic retreat: Give ground on CBD while continuing to demonise THC. Diehard Cannabis prohibitionists are exploiting the good news about CBD to further stigmatise THC with CBD framed as the good cannabinoid. Why? Because CBD doesn’t make you high like THC. This demonisation is moralistic, reefer madness. In 2014, Project CBD penned a foundational science paper, A Tale of Two Cannabinoids, in favour of whole plant Cannabis therapeutics.
Misconception: CBD is most effective without THC – THC and CBD as the power couple of Cannabis compounds work best together. Scientific studies have established that CBD and THC interact synergistically to enhance each other’s therapeutic effects. British researchers have shown that CBD potentiates THC’s anti-inflammatory properties. Scientists in San Francisco, California determined that a combination of CBD and THC has a more potent anti-tumoural effect than either compound alone when tested on brain cancer and breast cancer cell lines. Extensive clinical research has demonstrated that CBD combined with THC is also more beneficial for neuropathic pain than either compound as a single molecule.
Misconception: Single-molecule pharmaceuticals are superior to ‘crude’ whole plant medicinals – According to the US federal government, specific components of the Cannabis plant (THC and CBD) have medical value, but the plant itself does not have medical value. Uncle Sam’s single-molecule blinders reflect a cultural and political bias that privileges Big Pharma products. Single-molecule medicine is the predominant corporate way, the FDA-approved way, but it’s not the only way and it’s not necessarily the optimal way to benefit from Cannabis therapeutics. Cannabis contains several hundred compounds, including various flavonoids, aromatic terpenes and many minor cannabinoids in addition to THC and CBD. Each of these compounds has specific healing attributes, but when combined they create the “Entourage Effect”; the therapeutic impact of the whole plant is greater than the sum of its single-molecule parts. The FDA, however, isn’t in the business of approving plants as medicine.
Misconception: CBD-only’ laws adequately serve the US patient population – Fifteen US state legislatures have passed “CBD only” (or, more accurately, “low THC”) laws and other states are poised to follow suit. Some states restrict the sources of CBD-rich products and specify the diseases for which CBD can be accessed; others do not. Ostensibly these laws allow the use of CBD-infused oil derived from hemp or Cannabis that measures less than 0.3% THC. But a CBD-rich remedy with little THC doesn’t work for everyone. Parents of epileptic children have found that adding some THC (or THCa, the raw unheated version of THC) helps with seizure control in many instances. For some epileptics, THC-dominant strains are more effective than CBD-rich products. The vast majority of patients are not well served by CBD-only laws. They need access to a broad spectrum of whole plant Cannabis remedies, not just the low THC medicine. One size doesn’t fit all with respect to Cannabis therapeutics and neither does one compound or one product or one strain.
Misconception: CBD is CBD—It doesn’t matter where it comes from – Yes it does matter. The flower-tops and leaves of some industrial hemp strains may be a viable source of CBD, but hemp is by no means an optimal source. CBD-rich products should be made using only organic, whole plant Cannabis because this offers the best safety profile and superior medicinal benefits. Industrial hemp typically contains far less CBD than CBD-rich Cannabis. Huge amounts of industrial hemp are required to extract a small amount of CBD, thereby raising the risk of toxic contaminants because hemp is a “bio-accumulator” that draws heavy metals and other toxins from the soil. Single-molecule CBD synthesised in a lab or extracted and refined from industrial hemp-derived CBD and refined CBD powder lack critical medicinal terpenes and secondary cannabinoids found in Cannabis oil. These compounds interact with CBD and THC to enhance their therapeutic and medicinal benefits. In the US it’s against federal law to use hemp leaves and flowers to make medicinal products.
In conclusion, CBD is an intriguing agent of unparalleled pharmacological diversity that is nevertheless surprisingly benign in all its observed effects. Its use has become widespread in certain geographical areas, particularly in ‘legal’ states in the US and it is on the threshold of becoming an approved pharmaceutical agent in intractable epilepsies (even though whole plant works at least twice as well, without side-effects that pharmaceuticals seem to inherently attract). Given this current nouvelle richesse (new wealth) following its long history of obscurity, it is incumbent upon the scientific and medical communities to understand better the mechanisms of action of CBD, its limitations and particularly the myths and misconceptions that its meteoric rise in popularity have engendered.
Expanded from Cannabidiol Claims and Misconceptions, with Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects, Are cannabidiol and delta-9- tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review, Effect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and earlymorning behavior in young adults, Neural basis of delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition, Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial, Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor, Current therapeutic cannabis controversies and clinical trial design issues, Identification of psychoactive degradants of cannabidiol in simulated gastric and physiological fluid, Even high doses of oral cannabidiol do not cause THC-like effects in humans, Acute effects of a single, oral dose of d9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers, Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy, Is CBD Really Non-Psychoative?, Cannabidiol (CBD), Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016, and CBD Misconceptions
*CBD was added to the Australian Government Poisons Standard (the SUSMP), Standard for the Uniform Scheduling of Medicines and Poisons, under Schedule 4 in June, 2015;
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis.
Additionally, in the SUSMP of November 2016, the Therapeutic Goods Administration (TGA) updated the entry for Tetrahydrocannabinols in Schedule 8 (Controlled Drug – Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence) to read;
# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:
- a) included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
- b) imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
- c) in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
- i) it is in a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
- ii) in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
(A) Not for internal use; or
(B) Not to be taken; or
iii) in products for purposes other than for internal human use containing 50 mg/kg or less of tetrahydrocannabinols; or
- iv) separately specified in the NABIXIMOLS entry in this Schedule.
Formerly, THC had sat in Schedule 9, Prohibited Substance – Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.