Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder : From Bench Research to Confirmation in Human Trials, Rafael M. Bitencourt and Reinaldo N. Takahashi, 2018

Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder : From Bench Research to
Confirmation in Human Trials

Rafael M. Bitencourt and Reinaldo N. Takahashi

Frontiers in Neuroscience, 2018, 12, 502, 1-10.

Doi : 10.3389/fnins.2018.00502


Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects. Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD. Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of 19-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system. These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well. Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD. The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.

Keywords : post-traumatic stress disorder, endocannabinoid system, cannabidiol, aversive memories, fear conditioning paradigm



Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition that may develop after experiencing a potentially traumatic event. The disorder manifests itself at different levels, through symptoms such as sleep disturbances; changes in cognition (e.g., repeated recall of the event), mood (e.g., depression, anxiety), and emotion (e.g., psychological instability); and reduced social skills. Through the fourth edition of the DSM-IV, post-traumatic stress was classified as an anxiety disorder; however, the latest edition, DSM-V, includes PTSD in a new category called “traumaand stress-related disorders.”. In this brand-new category, we consider disorders with poor adaptation to a traumatic experience. Maladaptive responses to trauma may trigger, among others, PTSD (Passie et al., 2012; Berardi et al., 2016).

At some point in their lives, approximately 10% of people will be affected by PTSD, resulting in an enormous economic and social impact. This impact is aggravated by the scarcity of psychological and, above all, pharmacological approaches to PTSD treatment (Hidalgo and Davidson, 2000; Yule, 2001; Jurkus et al., 2016). At present, approved treatments for PTSD involve anxiolytics and antidepressants, which are inefficient and have considerable side effects (Berger et al., 2009; Shin et al., 2014; Bernardy and Friedman, 2015).

The eCB system can provide more efficient and better tolerated alternatives to the standard treatments for PTSD. The eCB system plays an important role in the regulation of emotional behavior and is essential for synaptic processes that determine learning and emotional responses, especially those related to potentially traumatic experiences (Castillo et al., 2012; Riebe et al., 2012). Among the possible alternative approaches, the use of components from Cannabis sativa such as CBD is particularly promising. Recent reviews have reported promising results of CBD treatment of several neuropsychiatric disorders, including PTSD (Mechoulam, 2005; Izzo et al., 2009; Passie et al., 2012). What began as a possibility discovered in a study of an animal model of aversive conditioning (Bitencourt et al., 2008) gained strength through results obtained in humans (Das et al., 2013) (see Figure 1 for a brief history of CBD in PTSD). Because the compound has been proved to be well tolerated by humans, both in overall safety and possible side effects (Bergamaschi et al., 2011), CBD is now considered a new therapeutic possibility for treating PTSD.

This paper reviews the therapeutic potential of CBD in the treatment of PTSD. It starts from the first evidence obtained in animal studies (“bench research”) and proceeds to knowledge gathered in human trials (“confirmation in human trials”).


Cannabis sativa contains over 100 compounds called phytocannabinoids. Two of them demonstrate considerable therapeutic potential: 19-tetrahydrocannabinol (19-THC), considered the main component responsible for the psychoactive effects of the plant, and CBD, the main non-psychotomimetic constituent of Cannabis (Adams et al., 1940; Mechoulam and Shvo, 1963; Gaoni and Mechoulam, 1964). CBD constitutes about 40% of the active substances of the plant (Crippa et al., 2009). However, its pharmacological effects are different from, and often even opposite to, those of 19-THC, and are
not related to the development of tolerance and withdrawal syndrome (Mechoulam et al., 2007; Bergamaschi et al., 2011).