CRx MAGAZINE

Spring 2020

Cannabis in the Treatment of PTSD

Cannabis shows promise for posttraumatic stress disorder, but questions remain.

Posttraumatic stress disorder (PTSD) is a potentially debilitating mental health condition for which it’s difficult to obtain adequate treatment. The lack of effective, accessible treatment options has led to increasing interest in cannabis as an alternative for symptom relief, especially among combat veterans. Cannabis is now legal in more than one-half of US states as a medical treatment for PTSD,1 and there’s no shortage of anecdotal reports to suggest that it works. But is there research to support the claims?

Unfortunately, the enthusiasm for cannabis as a potential treatment for PTSD is ahead of the science. The most up-to-date research suggests that cannabis could be effective for PTSD, but there are too many unanswered questions to know for certain what impact it has and whether the benefits outweigh the harms.

PTSD: A Picture of the Problem
PTSD is a relatively common condition. Estimates suggest that the prevalence is between 1% to 3.5% of the general population,2,3 but certain subgroups are at considerably higher risk. Approximately 15% of assault survivors suffer from PTSD,4 and prevalence is between 19% and 24% among combat veterans.5,6

The characteristic symptoms of PTSD fall into four categories: 1) reexperience of the trauma, such as through flashbacks, nightmares, and intrusive memories; 2) avoidance of trauma reminders, such as refusal to talk about the trauma; 3) negative changes in mood and beliefs, such as feelings of guilt or shame related to the trauma; and 4) hyperarousal.7

First-line treatment options for PTSD include psychotherapy as well as pharmacotherapies. Psychotherapy focuses on reprocessing the memories associated with the trauma, but trauma-focused psychotherapy can be hard to access, and there remains a stigma associated with it, meaning it’s underutilized.7 As for pharmacotherapy, VA and Department of Defense guidelines recommend antidepressants, but many patients experience no improvement from approved drugs.8 According to one report, the number of patients who received a benefit from existing pharmacotherapies is as low as 1 out of every 9 patients.9

Meanwhile, an array of anecdotal accounts and case reports claim that cannabis use may decrease symptoms of PTSD. Self-report data shows that individuals diagnosed with PTSD are more likely than the general population to use cannabis, and they often use it specifically for the purpose of coping with their condition.10

The Theoretical Basis for a Role of Cannabis in Treating PTSD
The cannabis plant contains dozens of different cannabinoids—chemicals that act on the endocannabinoid system in the brain and that have neuromodulatory effects. The endocannabinoid system is known to have a central role in regulating fear, stress, and anxiety, all of which are relevant to PTSD.11 Hence, there’s reason to believe that influencing the endocannabinoid system could influence PTSD symptoms.

The two best-known and well-studied cannabinoids are THC, the main psychoactive component of cannabis, and CBD, which is nonintoxicating but has various medicinal effects. The effects of these two cannabinoids differ, but both are thought to be potentially relevant for PTSD. Regarding THC, this molecule acts directly on the CB1 receptor. Preclinical research shows that stimulation of CB1 receptors reduces fear-related behavior, stress responses, and anxiety.7 In rats, activation of CB1 receptors after exposure to stress has been shown to prevent the development of PTSD-like behavior.12 In mice, activation of CB1 receptors both inhibits retrieval of negative memories and encourages their extinction, suggesting the possibility that THC could reduce flashbacks and nightmares in PTSD.13,14 On the other hand, both preclinical and clinical studies have shown that high doses of THC can actually promote anxiety, indicating that dosage matters.7

Importantly, individuals with PTSD are known to have a higher expression of CB1 receptors than do individuals without PTSD.7 It’s also known that CB1 receptors are particularly prevalent in both the amygdala and the hippocampus, which is significant because PTSD is characterized by increased activity in the amygdala (an area of the brain closely associated with fear responses), as well as by decreased volume of the hippocampus (the brain’s memory center). A number of the symptoms associated with PTSD are thought to be caused by these abnormalities in the amygdala and the hippocampus, and the fact that CB1 receptors are highly expressed in these areas suggests that THC could act on the endocannabinoid system to affect PTSD. Indeed, various studies have shown that THC can significantly reduce the amygdala’s response to signals of threat.11

Unlike THC, CBD does not have a strong direct action on CB1 receptors. However, an array of research indicates that CBD reduces anxiety. This impact has been shown in preclinical studies under a variety of paradigms, but it has also been demonstrated in several clinical studies.7 In addition, CBD has been shown in humans to promote fear extinction, which is significant because impaired fear extinction is thought to be a fundamental feature of PTSD.15 Preclinical literature also suggests that CBD has beneficial effects on depression.16

Cannabis and PTSD: What Evidence Reveals
As demonstrated previously, there’s a theoretical basis for believing that cannabinoids could influence the pathophysiology of PTSD and reduce associated symptoms.8 But how much hard evidence is there that cannabis is a viable treatment for PTSD?

Multiple review articles in the past three years have come to the same conclusion: All existing research in humans has significant flaws in design and methodology.7,8,11,17

There’s a “strong scientific rationale [for using cannabis to treat PTSD symptoms], but clinical trials have been rare,” says Chandni Hindocha, PhD, a research associate in the clinical psychopharmacology unit at University College London and the lead author of a 2020 systematic review on cannabis and PTSD. Of the 10 studies included in Hindocha’s review, only one was a randomized controlled trial, and it was a small pilot study. Apart from that single trial, all of the evidence regarding cannabis and its impact on PTSD is limited to uncontrolled or open-label trials, observational studies, retrospective studies, and case reports.11

“We found that cannabinoids may decrease PTSD symptomology, in particular sleep disturbances and nightmares,” Hindocha says. However, “every identified study had medium to high risk of bias and was of low quality. So the question now is, when we do really good science on this issue, do these results remain?”

Several of the existing studies are worth highlighting. Perhaps the key study to note is the randomized controlled trial just mentioned, which Hindocha says has the strongest design of any study available on cannabis for treatment of PTSD. This trial was a double-blind crossover study of 10 Canadian military personnel who had PTSD and were experiencing treatment-resistant nightmares. The question at issue was whether nabilone—a synthetic form of cannabis that mimics the effects of THC—could reduce frequency and intensity of nightmares associated with PTSD. The researchers found that subjects receiving nabilone indeed saw a significant reduction in nightmares compared with the placebo group, and they experienced significant increases in scores of general well-being and global improvement. The sample size was quite small, and the study relied on a pharmaceutical cannabis preparation rather than the more common herbal preparations, but the finding provides important evidence that stimulation of cannabinoid receptors potentially can have a positive impact on PTSD symptoms.18

Among case reports, one of the more noteworthy studies is a 2018 retrospective case series of 11 participants with PTSD who were recruited from an outpatient psychiatric clinic. All subjects were given CBD on a flexible dosing regimen on an open-label basis. After eight weeks of treatment, 10 of the 11 patients showed a decrease in severity of PTSD symptoms according to the PTSD Checklist (PCL-5). (The mean total percentage decrease in PCL-5 score was 28%.) In this study, CBD appeared to help reduce nightmares in particular, which were a commonly reported symptom. However, a key weakness of the study is that concurrent psychiatric medications were added, removed, or changed during the course of the study; in addition, the sample size was small and there was no placebo or control group. Thus, it’s unclear how many of the benefits were due to the placebo effect or to other medications.19

Population-level epidemiological research on cannabis use and PTSD outcomes is in short supply. The only study in this category was published in 2020 and was based on data from the Canadian Community Health Survey Mental Health Cycle. However, its findings are promising. The data set contained information on a nationally representative sample of more than 24,000 Canadians, of whom 420 had been diagnosed with PTSD. Previous research had already demonstrated a strong relationship between having PTSD and having a major depressive episode or suicidal thoughts, but the researchers wanted to know whether cannabis use would modify this association. They found that cannabis use was associated with a reduced likelihood of experiencing major depression or suicidal ideation among individuals with PTSD.20

“Among the cannabis nonusing population, there was a strong association between having PTSD and experiencing depression or experiencing suicidal ideation,” says Stephanie Lake, MSc, a research assistant with the British Columbia Centre on Substance Use and a PhD candidate in the School of Population and Public Health at the University of British Columbia, who’s also the lead author of the study. But, in the population that did use cannabis, “there was no significant association between PTSD and depression/suicide.”

Although this was an epidemiological rather than a clinical study, Lake says the findings are important because they’re generalizable to the population as a whole.

Aside from the three studies just highlighted, a number of other studies have also suggested that cannabinoids have a beneficial impact on PTSD symptoms. Two studies on nabilone—one an open-label clinical trial and the other a retrospective chart review—found that nabilone treatment was associated with improvement in PTSD symptoms, specifically a reduction in nightmares and improvements in sleep.21,22 An open-label clinical trial focused on THC in particular found that intake of this cannabinoid resulted in significant improvement in severity of global symptoms, sleep quality, frequency of nightmares, and hyperarousal among soldiers with combat-related PTSD.23 Finally, several studies have examined whole-plant cannabis and have found its use is associated with an improvement in scores on the Clinician Administered PTSD Scale.24-26 All of these studies suffer from significant weaknesses, such as small sample size, lack of a placebo or control group, reliance on patient report, or lack of peer review. However, all tentatively suggest the utility of cannabis for treating PTSD and underscore the need for future, more rigorous trials.

Red Flags: Could Cannabis Use Worsen Outcomes in PTSD Treatment?
While an array of studies suggests the potential for cannabis or cannabinoids to improve PTSD symptoms, some research suggests the opposite—that cannabis could potentially worsen outcomes in PTSD treatment.

One prospective longitudinal study evaluated cannabis use on PTSD symptoms among 260 male combat veterans, all of whom were admitted to a residential rehabilitation program for PTSD after not seeing improvement in outpatient treatment. The researchers wanted to know whether individuals diagnosed with cannabis use disorder would experience statistically different outcomes in their PTSD rehabilitation program. The answer was yes: Subjects with a diagnosis of cannabis use disorder showed less improvement in PTSD symptoms during the course of their treatment program than did individuals without cannabis use disorder. An obvious weakness of the study is that it looked at only cannabis use disorder rather than moderate cannabis usage, but the findings nonetheless serve to encourage caution.27

A second study, this one a retrospective longitudinal observational study, evaluated long-term cannabis use on PTSD symptoms among more than 2,000 veterans with severe PTSD who were admitted to an intensive PTSD treatment center.28 The participants were divided into four groups based on their patterns of marijuana use before and after discharge: never users, stoppers, continuing users, and starters. The study found that starting use of marijuana during the treatment program was associated with worsened PTSD symptoms from the time of admission to the time of discharge (the effect size was moderate). Meanwhile, stopping cannabis use was associated with improvement in PTSD symptoms (although the effect size was small). Thus, there’s some evidence to suggest that cannabis use could result in worse outcomes in treatment for PTSD.

In Sum
According to Lake, the evidence so far is inconclusive about the potential benefits of cannabis for PTSD. “There are some studies that do show improvement in certain symptoms associated with PTSD among people who use cannabis,” Lake says, adding that “there are also studies that show that people who use cannabis do not experience improvements. So it’s kind of all over the place.” Although studies that rely on patient reporting have generally found that cannabis use improves PTSD symptoms, Lake underscores the fact that “the quality of those types of studies is considered not as high as a clinical study.”

Several new studies are slated to appear in the coming months, including at least two large, high-quality clinical trials that have recently been completed in both the United States and Canada. “We are awaiting those with bated breath,” Hindocha says. But even these trials may not provide sufficient evidence to recommend cannabis in clinical practice. “Unfortunately, medicinal uses of cannabis have historically been difficult to study due to legal restrictions, so it could take a long time before there is enough evidence to support clinical recommendations,” Hindocha says.

At present, Hindocha’s best advice for clinicians is to tread carefully when prescribing cannabinoids or whole-plant cannabis. “Medical cannabis may help with some symptoms of PTSD, but expectations of patients who think it’s a cure-all should be managed,” she says. “PTSD does not often occur in isolation, [and] other psychiatric disorders should be taken into consideration before thinking about prescribing cannabinoids.”

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

Veterans Push for Better Cannabis Access

Cannabis remains a Schedule I substance according to the Controlled Substances Act, and the VA still warns against its use for medicinal purposes, including treatment of PTSD.

“Controlled studies have not been conducted to evaluate the safety or effectiveness of medical marijuana for PTSD. Thus, there is no evidence at this time that marijuana is an effective treatment for PTSD,” according to the department’s website.

Because of the VA’s stance, veterans are not able to obtain cannabis from VA doctors, even in states where medical marijuana is legal. But veterans are increasingly pushing to change that.

The 2019 member survey of Iraq and Afghanistan Veterans of America, a US veteran service organization with more than 400,000 members, found that 90% believed the VA should allow for research into cannabis as a treatment option. Just 20% of respondents
reported using cannabis for medicinal purposes, but 84% said they would be either “interested” or “very interested” in using medical cannabis if it were available to them. Accordingly, the organization lists medical cannabis access as one of its “Big Six” advocacy priorities.

Other organizations are joining the fight as well: In 2017, former Navy SEAL Nick Etten launched the Veterans Cannabis Project, a nonprofit advocacy organization that seeks to educate both lawmakers and veterans about the perceived health benefits of medical cannabis. “We believe medical cannabis saves lives and that veterans deserve full, legal access,” states the organization’s website.

— JSC

References

1. Legal medical marijuana states and DC. ProCon.org website. https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/. Updated July 24, 2019. Accessed January 7, 2020.

2. Karam EG, Friedman MJ, Hill ED, et al. Cumulative traumas and risk thresholds: 12- month PTSD in the World Mental Health (WMH) surveys. Depress Anxiety. 2014;31(2):130-142.

3. American Psychiatric Association. Trauma- and stressor-related disorders: posttraumatic stress disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, D.C.: American Psychiatric Association Publishing; 2013:271-280.

4. Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ. National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 2013;26(5):537-547.

5. Hoge CW, Riviere LA, Wilk JE, Herrell RK, Weathers FW. The prevalence of post-traumatic stress disorder (PTSD) in US combat soldiers: a head-to-head comparison of DSM-5 versus DSM-IV-TR symptom criteria with the PTSD checklist. Lancet Psychiatry. 2014;1(4):269-277.

6. Ravindran LN, Stein MB. Pharmacotherapy of PTSD: premises, principles, and priorities. Brain Res. 2009;1293:24-39.

7. Steenkamp MM, Blessing EM, Galatzer-Levy IR, Hollahan LC, Anderson WT. Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: a literature review. Depress Anxiety. 2017;34(3):207-216.

8. Shishko I, Oliveira R, Moore TA, Almeida K. A review of medical marijuana for the treatment of posttraumatic stress disorder: real symptom re-leaf or just high hopes? Ment Health Clin. 2018;8(2):86-94.

9. Jonas DE, Cusack K, Forneris CA, et al. Psychological and pharmacological treatments for adults with posttraumatic stress disorder (PTSD). Rockville, MD: Agency for Healthcare Research and Quality; 2013.

10. Bonn-Miller MO, Babson KA, Vandrey R. Using cannabis to help you sleep: heightened frequency of medical cannabis use among those with PTSD. Drug Alcohol Depend. 2014;136:162-165.

11. Hindocha C, Cousijn J, Rall M, Bloomfield MAP. The effectiveness of cannabinoids in the treatment of posttraumatic stress disorder (PTSD): a systematic review. J Dual Diagn. 2020;16(1):120-139.

12. Ganon-Elazar E, Akirav I. Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology. 2012;37(2):456-466.

13. Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418(6897):530-534.

14. Niyuhire F, Varvel SA, Martin BR, Lichtman AH. Exposure to marijuana smoke impairs memory retrieval in mice. J Pharmacol Exp Ther. 2007;322(3):1067-1075.

15. Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013;226(4):781-792.

16. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122-128.

17. O’Neil ME, Nugent SM, Morasco BJ, et al. Benefits and harms of plant-based cannabis for posttraumatic stress disorder: a systematic review. Ann Intern Med. 2017;167(5):332-340.

18. Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology. 2015;51:585-588.

19. 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.

20. Lake S, Kerr T, Buxton J, et al. Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians. J Psychopharmacol. 2020;34(2):181-188.

21. Fraser GA. The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD). CNS Neurosci Ther. 2009;15(1):84-88.

22. Cameron C, Watson D, Robinson J. Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J Clin Psychopharmacol. 2014;34(5):559-564.

23. Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A. Preliminary, open-label, pilot study of add-on oral Δ9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig. 2014;34(8):587-591.

24. Greer GR, Grob CS, Halberstadt AL. PTSD symptom reports of patients evaluated for the New Mexico Medical Cannabis Program. J Psychoactive Drugs. 2014;46(1):73-77.

25. Mashiah M. Medical cannabis as treatment for chronic combat PTSD: promising results in an open pilot study. Paper presented at: Patients Out of Time Conference; April 28, 2012; Tucson, AZ.

26. Reznik I. Post-traumatic stress disorder and medical cannabis use: a naturalistic observational study. Eur Neuropsychopharmacol. 2012;22(Suppl 2):S363-S364.

27. Bonn-Miller MO, Boden MT, Vujanovic AA, Drescher KD. Prospective investigation of the impact of cannabis use disorders on posttraumatic stress disorder symptoms among veterans in residential treatment. Psychol Trauma. 2013;5(2):193-200.

28. Wilkinson ST, Stefanovics E, Rosenheck RA. Marijuana use is associated with worse outcomes in symptom severity and violent behavior in patients with posttraumatic stress disorder. J Clin Psychiatry. 2015;76(9):1174-1180.

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