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The cannabis plant synthesizes more than 100 cannabinoids that can interact with the body’s endocannabinoid system and elicit varying clinical effects. In recent years, cannabidiol (CBD), a nonintoxicating compound found in cannabis, has garnered increasing attention and popularity among patients for the treatment of pain, insomnia, and anxiety, though more data are needed from well-controlled trials to confirm any real therapeutic benefits.1
Without clear evidence-based recommendations and methods to apply in everyday practice, this uptake in CBD use has placed clinicians in a difficult position.
At Psych Congress 2019, held October 3 to 6 in San Diego, California, Andrew Penn, RN, MS, NP, PMHNP-BC, associate clinical professor at the School of Nursing at the University of California, San Francisco, spoke to this topic in his presentation, Confused About Cannabidiol (CBD)? A Scientific and Rational Examination of Its Risks and Benefits in Psychiatry, in which he discussed current evidence for the therapeutic potential of CBD, as well as the clinician’s role in advising patients who choose to use cannabinoids.2
CBD vs THC
Before describing existing evidence for CBD therapies, Mr Penn explained an important correction to how many perceive CBD vs tetrahydrocannabinol (THC), the principal psychoactive component of cannabis. “The difference between [THC and CBD] is not black and white… THC is not the bad guy, CBD is not the good guy — it is much more complicated than that.”2
On the neural network level, THC reduces activity at both the default mode and the salience networks of the brain, creating the intoxicating effects of cannabis. In strains of cannabis that are high in CBD and low in THC, CBD corrects some of this disruption, limiting THC’s intoxicating effects.2
Is CBD an Actual Medicine?
The first CBD product was approved by the United States Food and Drug Administration (FDA) in 2018 with indications for Dravet syndrome and Lennox-Gastaut syndrome. Interest in CBD as a treatment for these conditions was heightened after the highly publicized story of Charlotte Figi, a young girl with Dravet syndrome for whom a high-CBD strain of cannabis was designed as a therapy for her debilitating seizures.2
Outside of these indications, there is a plethora of anecdotal data that point to many therapeutic benefits of CBD, but clinical trial data are lacking. “In the absence of data, we have stories,” said Mr Penn in his presentation, adding that the scientific community is far behind cannabis users in understanding possible benefits of the drug.2
Is CBD Legal?
Cannabis remains illegal under US federal law, though the government does not strictly enforce this position and many states are moving toward cannabis legalization.
Until the Agriculture Improvement Act of 2018 (also known as the 2018 farm bill) was enacted, CBD was a Schedule I drug. The Hemp Farming Act of 2018 declared that CBD is legal when derived from THC-free hemp plants (<0.3% THC dry weight) grown according to state laws and US Department of Agriculture regulations.3
CBD can be extracted from both hemp and cannabis. Hemp-derived CBD is legal under federal law if produced according to terms of the 2018 farm bill but may be illegal under state law. In US states that have legalized cannabis, CBD derived from cannabis is legal but may remain illegal under federal law.2
Is CBD Safe?
High doses of CBD have been well tolerated in existing studies, but data at this point are equivocal.2
In one small double-blind crossover study, researchers examined the pharmacologic effects of THC and CBD in the same healthy participants. While THC increased heart rate, intoxication, and physical and mental sedation 2 hours after administration, CBD did not increase any of these factors more than placebo.4
With regard to drug-drug interactions, good in vivo studies are needed, but some data suggest CBD/THC have potential interactions with ketoconazole, theophylline, and clobazam.5-8
Is CBD an Anxiolytic?
There is some evidence that CBD is associated with reduced social anxiety and reduced limbic and paralimbic activity related to anxiety disorders,9 but there is still a dearth of evidence supporting the use of CBD for anxiety-related conditions.
In one study examining the effects of a single dose of CBD or placebo on generalized social anxiety associated with public speaking, healthy volunteers who were pretreated with CBD before speaking (n=12) were found to have significantly lower anxiety levels, discomfort in speech performance, and cognitive impairment compared with those who received placebo.10 Other research found similar effects with a moderate dose of CBD before public speaking: CBD 300 mg significantly reduced subjective measures of anxiety and exhibited less sedative effects than clonazepam.11
How Does CBD Affect Sleep?
Despite much anecdotal evidence from patients using CBD to aid in sleep,2 a case series of individuals with anxiety or sleep issues using CBD (25-175 mg/d) in addition to usual treatment showed more significant and sustained improvements in anxiety than sleep.12 Another study on the topic found that compared with placebo, low-dose oral CBD/THC was associated with slightly longer sleep time and fewer awakenings but did not increase time in deep sleep or help patients fall asleep any faster.2,13
Does CBD Exert Antidepressant Effects?
There is no evidence in humans for any antidepressant effects of CBD.2 Some animal studies have indicated antidepressant effects with CBD treatment, but these effects were attenuated after certain antidepressants had already been administered, blocking the subsequent activity of CBD at the cellular level.2,14
Could CBD Be Therapeutic for PTSD, Autism, or Eating Disorders?
One small study (N=11) found that when added to usual care in patients with posttraumatic stress disorder (PTSD), open-label use of CBD was linked to PTSD symptom reduction and significant improvement in nightmares over the course of 8 weeks.15 These effects may be related to elevation of anandamide availability with CBD, as anandamide signaling mediated by the cannabinoid receptor CB1 is disrupted in PTSD.2
Most data that exist for the effect of CBD on behavioral issues in children with autism are anecdotal.2 However, researchers who conducted a retrospective study of young patients with autism spectrum disorder (N=60; age range, 5.0-17.5 years) found that treatment with CBD-rich cannabis improved behavioral outbreaks and was generally well tolerated.16
With regard to eating disorders, a role for CBD has not been explored; however, there is potential in this area, as endocannabinoid signaling is likely related to regulation of appetite.2
Translating Research Into Practice: What Should We Tell Our Patients?
CBD can be inhaled, delivered orally, or applied topically. Clinicians should advise patients who want to use CBD to choose oral formulations over inhaled products given emerging evidence of vaping-induced pulmonary injury.2 As a reference point, Mr Penn indicated a maximum recommended dose of CBD of 0.25 mg/kg. Dosing should be started low and titrated upward on an individual basis.2
“The way I see CBD in psychiatric practice right now is that we are really in an in-between space where we have a small handful of studies, usually looking at very large doses of CBD in disease states like schizophrenia and anxiety, and we do not have good clinical data on smaller doses, which are more representative of what patients are generally taking and what they can access through dispensaries,” Mr Penn told Psychiatry Advisor, adding “It creates this disconnect between what we are seeing in our offices and what the small amount of research has shown us. Until we get more data, we have to work with our patients and find out what they are doing and, ideally, report that into a larger space and publish it so that other clinicians can learn from it.”
“At this point I do not see CBD replacing existing medications in most cases, but instead being added to them. To somebody who has patients who are coming into their office, I would invite them, first of all, to get curious and to try and understand what the patient is trying to do [with CBD] and then to…encourage the patient to understand what they are taking and to understand how much of the cannabinoids are in it. [Clinicians should also] talk about side effects and benefits,” he said.
“To keep an open mind is really important because, in the absence of good data, we can be extremists and say ‘you should never do that,’ but patients are going to do it anyway,” explained Mr Penn. “Or we can say ‘let’s try to figure this out together.’ That collaborative approach is what I am advocating for.”
For more coverage of Psych Congress 2019, click here.
References
1. Penn A. Cannabidiol popularity raises questions for clinicians. Psych Congress Newsroom. September 4, 2019. http://www.psychcongress.com/article/cannabidiol-popularity-raises-questions-clinicians. Accessed October 2, 2019.
2. Penn A. Confused about cannabidiol (CBD)? A scientific and rational examination of its risks and benefits in psychiatry. Presented at: Psych Congress 2019; October 3-6, 2019; San Diego, CA.
3. H.R.5485 – Hemp Farming Act of 2018. Congress.gov. https://www.congress.gov/bill/115th-congress/house-bill/5485?r=48. Accessed October 5, 2019.
4. Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18(32):4966-4979.
5. Stott C, White L, Wright S, Wilbraham D, Guy G. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;3:236.
6. Zendulka O, Dovrtělová G, Nosková K. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206-226.
7. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86-95.
8. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-1251.
9. Crippa JAS, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011; 25(1):121-130.
10. Bergamaschi MM, Queiroz RHC, Chagas MHN, et al. Cannabidol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36(6):1219-1226.
11. Zuardi AW, Rodrigues NP, Silva AL, et al. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol. 2017;8:259.
12. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: a large case series. Perm J. 2019;23:18-041.
13. Nicholson AN, Turner C, Stone BM, Robson PJ. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol. 2004; 24(3):305-313.
14. Sales AJ, Crestani CC, Guimarães FS, Joca SRL. Antidepressant-like effect induced by cannabidiol is dependent on brain serotonin levels. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:255-261.
15. Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the treatment of post-traumatic stress disorder: a case series. J Altern Complement Med. 2019;25(4):392-397.
16. Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief report: cannabidiol-rich cannabis in children with autism spectrum disorder and severe behavioral problems-a retrospective feasibility study. J Autism Dev Disord. 2019;49(3):1284-1288.
