A significant overlap has been demonstrated between PTSD and SUD [13] in several epidemiological studies which estimate that individuals with PTSD are 2–4 times more likely to have a SUD compared to non-PTSD subjects [43,44]. PTSD subjects with concomitant SUD reported being more likely to take substances to “self-medicate”, meant to mitigate distressing PTSD symptoms [45,46,47]. Particularly, expectations for anxiety and reduced tension represented the most commonly reported motivations for using cannabis and cannabinoid compounds amongst PTSD subjects [48], lifetime cannabis use being 3.3 times more likely in PTSD diagnosis [48]. Given the interactions between cannabinoids and specific neurotransmitters (e.g., GABA, serotonin, glutamate, and dopamine), it has been proposed that cannabis may potentially confer some degree of medical benefit to PTSD. In fact, PTSD subjects may use cannabis and cannabis-related compounds mainly due to their anxiolytic, sedative, hypnotic, dream recall suppressor, and antipsychotic activities [1,14,17,25,28,32,36,37,39]. Interestingly, military veterans are increasingly using cannabinoids for relief of PTSD-induced nightmares [14,28,33,40,42]. Nonetheless, nightmares associated with PTSD are often a residual symptom that remains difficult to treat despite improvements in other domains [9].

Preclinical research has shown promising findings for CBD as an enhancer of fear extinction and therapeutic consolidation of emotional memories [27,30,49]. Current evidence regarding the use of CBD for PTSD in humans and its relevance for intrusive memories and memory consolidation in PTSD is minimal and controversial [25]. A case-report reported that oral CBD administration (12–37 mg daily) was associated with reduced anxiety and sleep symptoms related to PTSD in a 10-year-old sexually-abused patient [50]. CBD has been shown to cause a decreased response to and increased extinction of aversive memories, improve performance on inhibitory avoidance tasks, as well as produce an anxiolytic effect in PTSD patients [25,51,52,53]. Preclinical and clinical studies on nabilone show promising findings, mainly in reducing nightmares and sleep disorders related to PTSD [27,28,33,42,53,54]. Conversely, no clinical evidence exists so far for dronabinol.

Despite improvements in PTSD symptomatology, there are demonstrable adverse health risks associated with cannabis use, as chronic recreational use is associated with dependence and THC-related cognition dysfunction and risk of psychosis [31,55]. Similarly, chronic use of marijuana is associated with global cortical downregulation of CB₁ receptor availability, as well as across regions such as the temporal lobe, nucleus accumbens, and cingulate cortex, resulting in reduced endogenous cannabinoid functioning, reflecting tolerance and dependence effects [27]. Moreover, the anxiolytic effects of cannabis depend upon the neurobiological interplay or ratio metric relationship between the two major phyto-cannabinoids found in the cannabis plant, THC and CBD [11,56]. Apart from beneficial effects on anxiety, hyperarousal, and trauma-related symptoms described, synthetic cannabinoids have been reported to induce anxiety in healthy subjects and increase symptom severity in PTSD patients [38,41], effects which have been attributed to a downregulation of the eCB signaling system, resulting in tolerance to the drug’s anti-anxiety effects and, in some cases, an unmasking of pro-anxiety properties [3]. Moreover, some toxic effects, including respiratory depression, hyperthermia, acute cerebral ischemia, and seizures have been related to synthetic cannabinoids [32]. Finally, abrupt discontinuation of daily synthetic cannabinoids use can precipitate withdrawal syndrome three or four days after stoppage characterized by waxing and waning behavioral, mood, and physical symptoms such weakness, sweating, restlessness, dysphoria, sleeping problems, anxiety, craving, and diaphoresis [32].

Furthermore, several limitations should be considered when interpreting the findings coming from the present systematic review. First, studies examined here show an extreme heterogeneity of methodological strategies (in terms of sample features, sample size, pretreatment cannabis users or not, concomitant other substances abused, type of cannabinoid taken, variable and/or unspecified dosages and route of administration of cannabinoids used by PTSD patients, etc.). Second, there are, so far, no randomized, controlled, clinical trials with active marijuana use. Furthermore, for ethical reasons it is not possible to carry out a clinical trial using medical cannabis in all countries, hence, most findings presented here come only from countries in which medical cannabis is allowed and/or performing trials using THC and/or other synthetic cannabinoids is permitted.

Increasing our understanding of appropriate cannabinoids dosing levels must be further established before definitive clinical trials can begin, and this may increasingly reflect a move away from whole plant products due to difficulty in regulating levels of the active compounds in this form of the product. Furthermore, the eCS acts in different ways even in the same disease states, meaning that for many conditions the direction in which the system should be modulated is unclear and upstream options for treatment should also be researched [27]. These limitations notwithstanding, our findings highlight the importance of carrying out further research, more specifically focusing on the role of the eCS in other systems relevant to PTSD, such as the dopaminergic and serotonergic pathways.