Continued Cannabis Confusion

FROM THE EDITOR

In April, Delaware became the 22nd state to legalize the recreational use of cannabis. Hence the scale has moved slightly closer to 50% of our United States legalizing this Schedule I recreational drug. As a physician, scientist, and citizen, I continue to support the federal legalization of cannabis for many reasons. As I have written previously,¹ I believe cannabis should be regulated in the United States in a manner similar to alcohol and tobacco. The US Food and Drug Administration (FDA) should steer clear of cannabis unless it is evaluating 1 specific component of cannabis that has been appropriately purified, analyzed, and studied in clinical trials for a specific indication, and it has crossed the necessary threshold of benefits outweighing risks for the indication.

In fact, this is already the case for cannabidiol (CBD). In 2018, the FDA approved CBD (Epidiolex) for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex in patients 1 year or older.² The 39-page FDA product insert for Epidiolex was updated in January 2023, and it provides all of the clinical and pharmacological information any prescriber should expect and rely upon for any prescribed drug. However, CBD is the lonely exception, as the other 500 or so molecules in cannabis have no such product insert or reliable data.

CBD Oppositional to THC

In nature, cannabis contains more than 100 unique cannabinoid molecules.³ CBD and delta-9-tetrahydrocannabinol (THC) are the 2 most common and the most discussed in the scientific literature by medical clinicians, in dispensaries, and in social conversations. Three other cannabinoids have been well characterized as unique molecules with pharmacologically distinct profiles, but with much still to be understood: delta-9-tetrahydrocannabivarin, cannabichromene, and cannabigerol.⁴

Let’s look at what we currently know about CBD and THC and attempt to resolve some of the continued confusion over these 2 cannabinoids. The Table highlights the established differences between CBD’s and THC’s effects on humans. The original plant, Cannabis sativa, which has been harvested since approximately 4000 BC, has roughly equal amounts of CBD and THC. The cannabis circulating around high schools and college campuses in the 1960s commonly contained 2% CBD and 2% THC. Over the past 60 years, the systematic breeding of different strains has created a menu of plants with wide-ranging ratios of CBD and THC—with up to 30% THC and as little as 0.2% CBD (or less).⁵

Significantly, THC binds as a partial agonist to both the human cannabinoid 1 and 2 receptors (CB1 and CB2), displacing the endogenous cannabinoids. In contrast, CBD binds as a noncompetitive antagonist at the CB1 receptor, as an inverse agonist at the CB2 receptor, and as a partial agonist at the serotonin 5-HT1A receptor. CBD also inhibits the enzyme that metabolizes the endogenous cannabinoid anandamide and inhibits anandamide’s reuptake, hence increasing anandamide levels in the brain. THC depletes anandamide.⁶

The CBD:THC Ratio

As mentioned previously, naturally occurring cannabis generally has equal quantities of CBD and THC. However, in today’s booming cannabis market, which has created a significant source of tax revenue in states that have legalized it, the CBD-to-THC ratio (CBD:THC) can vary widely. CBD lacks the psychotomimetic, anxiogenic, and amnestic effects that are seen with THC. A growing literature supports the hypothesis that higher CBD:THC decreases the risks of psychotic and cognitive adverse events by THC.

A recent article in Neuropsychopharmacology by Englund et al (2023) set out to test this hypothesis by using a double-blind, within-subject, randomized trial of varying ratios of CBD and THC; the primary outcome was change in delayed verbal recall, and secondary outcomes included change in severity of psychotic symptoms.⁷ The participants included 46 healthy, infrequent cannabis users. They received an initial baseline assessment, followed by 4 visits during which participants received randomized concentrations of CBD and THC, and repeat assessments. At all 4 visits, each participant inhaled vaporized cannabis with 10 mg of THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) of CBD. The treatment with 10 mg THC and 0 mg CBD demonstrated impaired delayed verbal recall and induced positive psychotic symptoms. All 3 doses of CBD demonstrated no significant decrease in these THC-only symptoms.

CBD May Improve Psychosis and Cognition

It would seem, then, at first read, that the conclusion by Englund et al (2023) negates the growing literature that supports the protective effects of CBD when administered with THC, as well as the antipsychotic properties of CBD. However, the article highlights the importance of understanding the design of any clinical study. The maximum dose of CBD used was only 30 mg. A previous study, though, demonstrated that 1000 mg per day of CBD—added as an adjunct in patients with schizophrenia who had responded only partially to antipsychotic medication— showed a greater decrease in positive psychotic symptoms than the placebo arm.⁸

A monotherapy study involving 39 individuals with an acute exacerbation of schizophrenia dosed up to 800 mg/day of CBD was compared with up to 800 mg/day of amisulpride for 4 weeks in a double-blind, randomized, parallel-arm comparison. By study’s end, a significant reduction in positive symptoms was seen in both groups, with no significant difference in efficacy. Improvement in positive symptoms on the Positive and Negative Syndrome Scale at day 28 was –9.0 in the CBD group and –8.4 in the amisulpride group.⁹

Englund et al (2013) investigated the effect of pretreatment with 600 mg oral CBD versus placebo on the development of psychosis and cognitive impairment in 48 healthy participants 210 minutes before intravenous administration of 1.5 mg of THC.¹⁰ Clinically significant positive psychotic symptoms were less common in the group pretreated with CBD compared with placebo (odds ratio, 0.22). Additionally, post-THC paranoia was lower in the CBD participants compared with the placebo participants (t = 2.28; P < .05). Finally, episodic memory (measured with the Hopkins Verbal Learning Task – revised) decreased less, compared with baseline, in the CBD pretreated group (–0.4) than in the placebo group (–10.6).

These studies are just a sampling of a large volume of literature on cannabis— specifically, CBD and THC. One lesson learned so far is that the dose of CBD needs to be much higher than that of THC to achieve clinically relevant effects. Doses of CBD in these 3 studies ranged from 600 mg/day to 1000 mg/day. This is in sharp contrast to the clear psychotomimetic and cognitive dysfunction that can occur with just 10 mg of THC.

Concluding Thoughts

When it comes to cannabis, we have a lot to learn. When I hear that word, I imagine an unknown subset of more than 500 molecules from 3 major families (cannabinoids, terpenes, and flavonoids) dancing around the brain in varying concentrations. Regardless, it is the third most commonly used drug in the United States, after alcohol and nicotine, and its use is rapidly growing and likely here to stay. At least with alcohol and nicotine, we know exactly what we are dealing with: well-characterized single molecules with predictable pharmacokinetics and pharmacodynamics. With cannabis, all that is predictable is confusion, even if we do know a little about its 2 most common molecules, CBD and THC. Through the process of obtaining FDA approval for CBD, we have learned a lot more about its purified form.

It is likely very significant that THC is a partial agonist at both the CB1 and CB2 receptors, while CBD binds as a noncompetitive antagonist and inverse agonist at these same 2 receptors. Clinical studies suggest that THC binds much more tightly than CBD; therefore, a much higher dose of CBD compared with THC is likely necessary for them to compete at these receptors. CBD and THC also appear to have oppositional effects on the endogenous cannabinoid anandamide. This should be a high-priority area for further research.

Characterizing drug-drug interactions for THC remains a huge unmet need. It has been established that THC is metabolized by CYP3A4 and CYP2C9. There is plenty of speculation, but few solid data, on which cytochrome P450 metabolic enzymes THC may inhibit or induce. CBD, on the other hand, has detailed studies on its drug-drug interactions that are well documented in the Epidiolex FDA product insert.

We know a little, and we need to learn a lot more. Given the growing use and legalization of THC, it is our responsibility as medical professionals to lessen our confusion and increase our knowledge and confidence about cannabis and its effects on our patients.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; and Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Miller J. Cannabis confusion. Psychiatric Times. 2021;38(8).

2. Prescribing information. Jazz Pharmaceuticals. Updated January 2023. Accessed May 15, 2023. https://pp.jazzpharma.com/pi/epidiolex.en.USPI.pdf

3. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241-254.

4. National Academies on Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press; 2017.

5. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613-619.

6. Rong C, Lee Y, Carmona NE, et al. Cannabidiol in medical marijuana: research vistas and potential opportunities. Pharmacol Res. 2017;121:213-218.

7. Englund A, Oliver D, Chesney E, et al. Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios. Neuropsychopharmacology. 2023;48(6):869-876.

8. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175(3):225-231.

9. Davies C, Bhattacharyya S. Cannabidiol as a potential treatment for psychosis. Ther Adv Psychopharmacol. 2019;9:2045125319881916.

10. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19-27.