By Yoel H. Sitbon, PhD
Post-traumatic stress disorder (PTSD) is defined as an anxiety problem that develops after extremely traumatic events, such as combat, crime, an accident or natural disaster. While current therapies have shown some relief, there is an increasing need to shift our attention towards novel avenues to reduce side effects associated with commonly used medications. Recently, the use of medicinal cannabis (e.g., THC, CBD) and psychedelics (e.g., MDMA, LSD, ketamine, psilocybin) have been of great interest and several clinical trials are in place as potential therapies for patients with PTSD and 28 states have approved medical marijuana for the treatment of PTSD. While encouraging, there remains a wide array of experimental research that needs to be addressed to outweigh the benefits vs. the short and long-term risks.
Post-traumatic stress disorder (PTSD) is defined as an anxiety problem that develops after extremely traumatic events, such as combat, crime, an accident or natural disaster.1 This results in frequent flashbacks, nightmares, and increased anxiety, leading to decreased sleep time and quality, with women having a higher lifetime prevalence of PSTD than men.2-4 While current therapies such as cognitive behavior therapy (CBT) or pharmacological treatments (e.g., selective serotonin reuptake inhibitors [SSRIs], paroxetine, sertraline) have shown some relief, there is an increasing need to shift our attention towards novel therapeutic avenues, in part due the limited efficacy and adverse side effects of above interventions.5,6
As such, the endocannabinoid system has been of great interest notably due to the location of cannabinoid receptors (CB1) in brain regions known to be affected in PTSD, specifically the amygdala, hippocampus and cerebral cortex.7 Considering that different cannabis plants contain more than 500 constituents (delta-9-tetrahydrocannabinol (THC) and cannabinoids (CBD) being the best-known compounds) in various concentrations, studying their specific effects represent a challenge.8 A survey carried out in 2016 by Care by Design showed that cannabis was the most likely to improve PTSD symptoms including anger, anxiety, depression, pain and sleep problems compared to other medications prescribed (e.g., SSRIs, anti-anxiety medications).9 Administration of nabilone, a synthetic CB1 cannabinoid agonist, reduced nightmares, significant improvement in sleep and in reduction in nightmare severity/frequency relieving nightmares in the first double-blind, placebo-controlled trial in patients with PTSD.10 Currently, there are several clinical trials attempting to use either THC, CBD, or derivative agents such as Dronabinol as therapeutic agents to treat PTSD and 28 states have approved medical marijuana for the treatment of PTSD.11-13
Another area of novel and exciting research is the use of psychedelics (e.g., MDMA, ketamine, LSD, psilocybin) as emerging medicines for the treatment of psychological conditions including PTSD. The administration of MDMA results in measurable changes in brain activity and pronounced psychological alterations; in combination with psychotherapy, it was shown to decrease PTSD-associated symptoms via attenuating amygdala activity and activating the prefrontal cortex.14,15 Currently, there are seven clinical trials testing the effects of MDMA in PTSD, including one phase 3 trial being conducted in the United States, Canada, and Israel.16
In March 2019, the FDA approved esketamine (ketamine derivate) for treatment-resistant depression, suggesting it may be used as a potential therapeutic agent for PTSD patients and clinical studies have found that administration of a single or multiple dose of ketamine led to a rapid reduction of PTSD symptoms.17,18 Currently, there are eight clinical trials to determine the effects of ketamine to treat PTSD and associated depressive symptoms, including a placebo-controlled phase 2 study being conducted through the Minneapolis VA Health Care System evaluating the combination of ketamine with prolonged exposure (PE) therapy.19
At present, there are limited data available investigating the use of “classical psychedelics” (e.g., LSD, psilocybin, DMT) as a potential therapy in patients with PTSD, but animal studies have shown that both psilocybin and DMT facilitate fear extinction and decrease amygdala activity during emotion processing, which may indicate a therapeutic strategy for patients with PTSD.20-22
Overall, while more clinical studies are available to study the potential therapeutic effects of cannabis and psychedelics for the treatment of PTSD, there remains a wide array of experimental research that needs to be addressed to outweigh the benefits vs. the short and long-term risks.
- Post-traumatic Stress Disorder. Retrieved September 30, 2020, athttps://www.apa.org/topics/ptsd.)
- Olff M. Sex and gender differences in post-traumatic stress disorder: an update. Eur J Psychotraumatol 2017 8(sup4): 1351204.
- Giarratano P, Ford JD, Nochajski TH. Gender Differences in Complex Posttraumatic Stress Symptoms, and Their Relationship to Mental Health and Substance Abuse Outcomes in Incarcerated Adults. J Interpers Violence 2020;35:1133-57.
- Why Women Have Higher Rates of PTSD Than Men. Retrieved 2018. athttps://www.psychologytoday.com/us/blog/the-mindful-self-express/201809/why-women-have-higher-rates-ptsd-men.)
- Roberts NP, Roberts PA, Jones N, Bisson JI. Psychological interventions for post-traumatic stress disorder and comorbid substance use disorder: A systematic review and meta-analysis. Clin Psychol Rev 2015;38:25-38.
- Cipriani A, Williams T, Nikolakopoulou A, et al. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med 2018;48:1975-84.
- Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend 1998;51:173-87.
- Mechoulam R, Hanus LO, Pertwee R, Howlett AC. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 2014;15:757-64.
- PTSD patient survey. 2016. athttps://www.projectcbd.org/sites/projectcbd/files/downloads/ptsd-patient-survey_2016_march.pdf)
- 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;51:585-8.
- Radhakrishnan R, Ranganathan M, D’Souza DC. Medical Marijuana: What Physicians Need to Know. J Clin Psychiatry 2019;80.
- Treating Nightmares in Posttraumatic Stress Disorder With Dronabinol. (Accessed March 8, 2021, athttps://www.clinicaltrials.gov/ct2/show/NCT04448808.)
- Use of CBD Oil in the Treatment of Posttraumatic Stress Disorder. (Accessed March 8, 2021, athttps://www.clinicaltrials.gov/ct2/show/NCT04197102.)
- Gamma A, Buck A, Berthold T, Liechti ME, Vollenweider FX. 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy humans. Neuropsychopharmacology 2000;23:388-95.
- Ot’alora GM, Grigsby J, Poulter B, et al. 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial. J Psychopharmacol 2018;32:1295-307.
- A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD. (Accessed March 8, 2021, athttps://www.clinicaltrials.gov/ct2/show/NCT04077437.)
- Carhart-Harris RL, Murphy K, Leech R, et al. The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity. Biol Psychiatry 2015;78:554-62.
- Albott CS, Lim KO, Forbes MK, et al. Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin Psychiatry 2018;79.
- Ketamine-enhanced Prolonged Exposure Therapy in PTSD at (Accessed March 8, 2021,https://www.clinicaltrials.gov/ct2/show/NCT04560660.)
- Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res 2013;228:481-91.
- Cameron LP, Benson CJ, Dunlap LE, Olson DE. Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression. ACS Chem Neurosci 2018;9:1582-90.
- Kraehenmann R, Preller KH, Scheidegger M, et al. Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biol Psychiatry 2015;78:572-81.