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Cannabidiol Popularity Raises Questions for Clinicians
Psychiatric clinicians are often asked to treat patients with evidence-based methods, but frequently the evidence we have to guide our practice does not reflect the reality we see every day in our offices. As such, we are often forced to make clinical decisions based on a minimum amount of evidence.
Currently, many of our patients are using cannabinoids, especially cannabidiol (CBD) to treat their own symptoms—ranging from insomnia, to anxiety, to depression. What evidence is there that this will help? What are the risks? What doses of CBD should they be using? What route? How will CBD interact with other medications? I’ll be exploring these questions in my talk “Confused about Cannabidiol: A Scientific and Rational Examination of its Risks and Benefits in Psychiatry” at Psych Congress in San Diego, California. Here, I will provide a preview of my talk.
A LONG HISTORY
The Cannabis plant was noted in the Chinese medical pharmacopeia nearly 5000 years ago and was a common component in Western patient medications of the 19th century, when it was used to treat insomnia, anxiety, and pain.1 The early, racially charged (it was at this time that the word “marijuana” was used to describe the plant so as to associate its use with vilified Mexican immigrants) efforts of the 1930s to eradicate the use of the plant, most famously by the propaganda film Reefer Madness, began the process of moving the substance out of the pharmacopeia and into the ranks of banned drugs. The Controlled Substances Act (CSA) of 1970 codified this ban, making research into the benefits of cannabis more difficult with its tautological definition of a Schedule I drug as being one that has “no medical use and has a high risk of abuse.”
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At the time of its federal ban, the complexity of the cannabis plant was only just beginning to be understood, with the isolation of 9-tetrahydrocannabinol (THC), often described as the intoxicating component of cannabis, by Raphael Mechoulam in 1964.2 The presence of an endocannabinoid system in the mammalian body was unknown at the time, and the first of 2 endogenous cannabinoid receptors, CB1, was only just discovered in 1990.3,4
A CRITICAL BODILY SYSTEM
Before discussing exogenous cannabinoids, I will first review how the mammalian central nervous system expresses endocannabinoid receptors. The endocannabinoid system is critical in fine-tuning multiple other neurotransmitter systems. While most neurotransmission is anterograde, that is, a message is passed from presynaptic neuron to postsynaptic neuron, the endocannabinoids function more like salmon swimming upstream. Unlike the serotonergic or dopaminergic systems that largely propagate a signal downstream, the endocannabinoid system is a retrograde signaling mechanism.5 Another metaphor for retrograde signaling is what occurs when people move boxes in a “bucket brigade” from a house to a moving truck too quickly. When the last person in the line, whose job it is to stack the boxes in the truck, calls out “slow down” and that message is passed down the line, this is a kind of retrograde signaling.
Like more well-known systems such as serotonin, the endocannabinoid system is comprised of neurotransmitters (ligands) synthesizing enzymes for these neurotransmitters, receptors, and degrading enzymes. The CB1 receptor is the most widely distributed G protein-coupled receptor in the central nervous system. As is often the case in the history of receptor pharmacology, the discovery of the cannabinoid receptor sparked interest in discovering the endogenous ligand for this receptor. The two primary endocannabinoid neurotransmitters are anandamide (Sanskrit for “bliss,” abbreviated AEA) and 2-Arachidonoylglycerol (2-AG). AEA and 2-AG are synthesized in response to increased intracellular calcium at the postsynaptic terminal. AEA is synthesized by N-arachidonoylphosphatidylethanolamine (NAPE) and 2-AG by diacylglycerol (DAG).6
It is important to understand that these neurotransmitters are not stored in vesicles like monoamines, but rather, are made on demand and released across the synaptic cleft towards the CB1 receptors that are expressed on the presynaptic membrane. The CB1 receptor has both an orthosteric site (which is the target for AEA, 2-AG, and THC) and an allosteric site (which is the target for CBD). CB2 receptors are mostly located on immune cells7 and may modulate inflammation but are not the focus of this presentation.
THE COMPLICATED WORKINGS OF CANNABIS
The cannabis plant is a complex manufacturer of more than 500 different compounds, of which more than 100 are cannabinoids. The remainder are terpenes (which not only give cannabis its distinctive odor, but also may contribute to the psychoactivity of cannabinoids by influencing the permeability of the blood-brain barrier), phenolic compounds, steroids, and enzymes. It is important to know that these compounds often work in concert with the endocannabinoid system and with each other, known as “the entourage effect.”8,9 While THC was the first cannabinoid to be extensively studied, the increasing interest around CBD will be the focus of my presentation.
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CBD is often described as the “nonpsychoactive” cannabinoid (to distinguish it from the decidedly active THC) but a more accurate description would be “nonintoxicating,” as it is quite clear that while CBD is without the euphoriant or stimulus-distorting qualities of its THC kin, it appears to have potential benefits in the treatment of anxiety, depression, and psychosis, if early studies prove to be replicable.10,11,12
The endogenous ligands for the CB1 receptor, AEA and 2-AG, are partial agonists at this site, which is to say they partially activate the G protein-coupled receptor. THC is also a partial agonist at the orthosteric site of the CB1 receptor (some of the synthetic cannabinoids known as “spice” are full CB1 agonists, accounting for their significantly greater potency and intoxicating effects). In the absence of CBD, this receptor, partially activated, is responsible for the subjective effects of THC. Interestingly, CBD acts as a positive allosteric modulator at the CB1 receptor, so when CBD is bound to the allosteric site13 the confirmation of the orthosteric site changes, attenuating the ability of THC to activate the CB1 receptor. Subjectively, this results in a modulation of the intoxication and reduction of paranoia occasioned by THC.14 Cannabis users report that strains with a high amount of CBD (especially if the quantity of THC is low) will be less intoxicating than a strain with low concentration of CBD and high concentrations of THC.
RECENT SURGE IN POPULARITY
The nonintoxicating yet psychoactive quality of CBD has typically made it, in the eyes of the public and policymakers, a more acceptable component of the cannabis plant. Early findings showed CBD was effective against certain pediatric seizure disorders (made most famous by the development of a high CBD-strain known as “Charlotte’s Web” in honor of Charlotte Figi, a young girl in Colorado with Dravet syndrome).15
In states where cannabis is available (either in medical or recreational frameworks), the demand for CBD-rich cannabis products increased as anecdotal evidence spread in the media and on the internet about the utility of this cannabinoid for the treatment of anxiety, insomnia, and pain. (Interest in the antiproliferative, anti-inflammatory, antispasmodic, and vasorelaxation qualities of CBD led to interest across a wide degree of disease states, but is beyond the scope of this talk.) 2018 marked the first US Food and Drug Administration (FDA) approval of a Schedule 5 CBD product (Epidiolex from GW Pharmaceuticals), indicated for the pediatric seizure disorders Dravet syndrome and Lennox-Gastaut syndrome. But, the high cost ($32,000/year) has discouraged off-label exploration with this compound.
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2018 also marked the passage of the federal Farm Bill, which allows for the cultivation of industrial hemp (defined as Cannabis sativa with a THC content of less than 0.3% per dry weight) from which CBD oil can be extracted. This CBD, if grown on farms authorized by this legislation, is legal under the CSA. Further muddying the waters is that more than 30 states have now made some change to their cannabis laws. As such, in states such as my own (California), one can find CBD products in dispensaries that are extracted from plants that are still considered “marijuana” under federal law and are thus, still illegal under the CSA (though federal enforcement of these laws has been practically nonexistent in recent years). This has led to a flurry of confusion in the marketplace as large national retailers such as Bed, Bath, & Beyond and Amazon have recently begun selling “CBD oil.” Often, the language around these products makes vague health claims, which runs the risk of reprimand from the FDA, which bans unsubstantiated health claims in consumer advertising. Additionally, the FDA has made clear that CBD (as Epidiolex is now a prescriptible medicine) cannot be included in food products, as FDA-approved medications cannot be sold as food. However, as a recent picture in The New York Times of a Brooklyn café offering CBD infused lattes would indicate, enforcement is lax.
While there have been some well-controlled trials (which I will review in my presentation) that showed some benefit of high-dose CBD in the treatment of social anxiety and for improving cognitive symptoms of schizophrenia (when added to conventional antipsychotic medications), these studies often used doses in the range of 300 to 1000 mg/d, which is impractical for most patients who would be buying CBD over the counter from their local dispensary. (Products containing 250 mg of CBD cost about $50-$75 in California at the time of this writing.)There have been several small, open-label studies, adding smaller doses of CBD (2 to 100 mg/d) to ongoing medication treatments, that found the drug was well-tolerated and showed modest improvement in measures of post-traumatic stress disorder (PTSD) and insomnia. But much more well-controlled research is needed before it can be said, from the standpoint of evidence-based medicine, that low-dose CBD is an effective treatment for psychiatric ailments.
THE ROLE OF THE CLINICIAN
However, our patients are not waiting for the empiric research to be completed. Increasingly, they are coming to us asking about CBD, or have already begun using it, either alongside conventional psychiatric medications or as a substitute for them. This is, in part, a result of a growing cannabis industry that makes health claims that are not subject to FDA scrutiny. However, the dearth of evidence is largely because the CSA, in conjunction with prohibitionist drug policy, did not permit research into the claims that cannabinoids could be effective treatments for psychiatric illnesses. As such, we are at least 20 years behind where we need to be with regards to evidence. Again, our patients are not waiting for us to catch up, so what are we, as clinicians, to do?
One blanket approach is to categorically advise patients not to use cannabinoids. Historically, this has been the general approach of psychiatry, but in the current climate, with the cannabis industry and anecdotal evidence purporting benefit, is unlikely to result in anything other than patients using cannabinoids and not disclosing their use. The antipodal position is to join the panacea chorus that cannabis is useful for all manner of ailments and, because of its natural status, is inherently safe. However, the evidence showing risk of earlier development of psychosis and cognitive impairment in young people would indicate that cannabis use is certainly not without risk.
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In my talk at Psych Congress, I will discuss an attitude that I call a “pre-post marketing” approach. As cannabis has already erupted in the marketplace, attempts to prevent our patients from using it will likely be met with failure. I advocate an educational, harm-reduction approach in which we work with patients to learn from them about how they are already using cannabinoids, offer evidence about risks and what is known about the potential benefits, and then use a slow, cautious, transparent approach where we partner with patients to try to find the most optimum combination of medications, which may or may not include cannabinoids, to best treat their conditions.
If a patient chooses to use cannabinoids, they should decide if they are planning on using a single, isolated cannabinoid (such as CBD alone) or a combination (THC and CBD together). The risk of the latter is one of intoxication but the potential benefit is an amplification of the entourage effect for therapeutic benefit, particularly if low doses of THC are used. After determining the threshold of THC effects, Macallum and Russo16 suggest starting at an oral dose of 2.5 mg THC (or 1.25 mg for those who are sensitive) given 2-3 hours before bed. CBD can be added to the threshold THC dose at 0.5 mg per pound of body weight and titrated up to the desired effect, bearing in mind that higher doses will be more likely to create CYP450-mediated drug-drug interactions (Maria Mangini, PhD, FNP, personal communication, July 3, 2019).
These anecdotes should be aggregated in case reports and case series so that researchers can test these hypotheses in better controlled trials. But we can’t wait for the evidence to emerge first, as patients have already voted with their feet. The question is, will we walk with them or watch them walk away? I encourage you to join the conversation about CBD in San Diego.
PSYCH CONGRESS SNAPSHOT
Confused About Cannabidiol (CBD)? A Scientific and Rational Examination of Its Risks and Benefits in Psychiatry
FRIDAY, OCTOBER 4 | 3:15 P.M. — 4:30 P.M.
The nonintoxicating cannabinoid cannabidiol (CBD) has received considerable acclaim among patients and in the mainstream media. This session will critically examine the evidence for the claims of anxiolytic, antidepressant, and antipsychotic benefits of CBD, explore what still needs to be studied, and provide pragmatic advice for clinicians working with patients who are using CBD.
REFERENCES
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3. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990; 346(6284):561-564.
4. Munro S, Thomas KL, Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993; 365(6441): 61-65.
5. Ohno-Shosaku T, Tanimura A, Hashimotodani Y, Kano M. Endocannabinoids and retrograde modulation of synaptic transmission. The Neuroscientist. 2012; 18(2):119-132.
6. Zhornitsky S, Potvin S. Cannabidiol in humans—the quest for therapeutic targets. Pharmaceuticals (Basel, Switzerland). 2012; 5(5):529-552.
7. Turcotte C, Blanchet M, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cellular and Molecular Life Sciences. 2016; 73(23):4449-4470.
8. Aizpurua-Olaizola O, Soydaner U, .ztürk E, et al. Evolution of the cannabinoid and terpene content during the growth of cannabis sativa plants from different chemotypes. Journal of Natural Products. 2016; 79(2):324-331.
9. Andre CM, Hausman J, Guerriero G. Cannabis sativa: The plant of the thousand and one molecules. Frontiers in Plant Science. 2016; 7:19.
10. Leweke M, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry. 2012; 2:e94.
11. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochemical Research. 2005; 30(8):1037-1043.
12. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. The American Journal of Psychiatry. 2018; 175(3):225-231.
13. Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British Journal of Pharmacology. 2015; 172(20):4790-4805.
14. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. Journal of Psychopharmacology. 2013; 27(1):19-27.
15. Velasquez-Manoff M. Can CBD really do all that? The New York Times Magazine. www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html. Published May 14, 2019. Accessed June 11, 2019.
16. MacCallum Caroline, Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 2018; 49:12-19.
Andrew Penn was trained as an adult nurse practitioner and psychiatric clinical nurse specialist at the University of California, San Francisco. He is board certified as an adult nurse practitioner and psychiatric nurse practitioner by the American Nurses Credentialing Center. He has completed extensive training in Psychedelic Assisted Psychotherapy at the California Institute for Integral Studies and recently published a book chapter on this modality in The Casebook of Positive Psychiatry, published by American Psychiatric Association Press. Currently, he serves as an Associate Clinical Professor at the University of California-San Francisco School of Nursing, where he teaches psychopharmacology, and is an Attending Nurse Practitioner at the San Francisco Veterans Administration. He has expertise in psychopharmacological treatment for adult patients and specializes in the treatment of affective disorders and PTSD. As a steering committee member for Psych Congress, he has been invited to present internationally on improving medication adherence, cannabis pharmacology, psychedelic assisted psychotherapy, grief psychotherapy, treatment-resistant depression, diagnosis and treatment of bipolar disorder, and the art and science of psychopharmacologic practice.
