The endocannabinoid system is a promising area of treatment for PTSD, according to a new review of cannabis studies.

Published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, the review shows that CBD may be the most promising cannabinoid to lead future treatments, but further research is needed before any pharmacological agent can be made and distributed.

Post-traumatic stress disorder, or PTSD, is a type of anxiety disorder that may be developed following exposure to a stressful or frightening event. It is a chronic condition that can result in significant emotional distress and functional impairment due to the nature of the disorder’s symptoms. These include, but are not limited to, re-experiencing the trauma in the form of flashbacks or nightmares, hyperarousal, difficulty sleeping and concentrating, and a heightened risk of developing other mental health problems or engaging in self-destructive behaviors.

The researchers explain in their review that PTSD symptomology is believed to arise as a result of a “combination of dysregulated biological stress responding and maladaptive memory processes,” and that these can be attributed to the excessive release of stress hormones directly following the traumatic event. The hormonal response in turn affects emotion, which can lead to the over-consolidation of traumatic memories. This over-consolidation is what gives rise to the intrusive memories and flashbacks that characterize PTSD.

Cannabis and the cannabinoids have been identified as a potential therapeutic to assist in the treatment of PTSD due to their action on the endocannabinoid system, which has been recognized as an important factor in the body’s response to stress, processing of emotional memories, and in the lessening of the fear response, also known as fear extinction learning.

Preclinical models have demonstrated that fear extinction is facilitated by enhanced endocannabinoid signaling and reduced by endocannabinoid inhibition, implying that the endocannabinoid system could be a key part of the human trauma response.

However, despite being widely accepted by PTSD researchers, the endocannabinoid-fear extinction link is supported by few randomized studies, which would give a clear indication of how cannabis and cannabinoid medicines affect PTSD symptomology. While this can be partially attributed to the legality of cannabis and unknown health risks with long-term use, there is also a certain level of indecision in the field as to what pharmacological avenue is the best option for further study.





Different possibilities for endocannabinoid modulation

There are four main pharmacological avenues identified in the review: tetrahydrocannabinol (THC), synthetic cannabinoid receptor agonists, catabolic enzyme inhibitors, and cannabidiol (CBD). Each comes with its own pros and cons, and a wealth of pre-existing study.

Tetrahydrocannabinol

THC is a partial agonist with a high affinity to both the CB1 and CB2 cannabinoid receptors, and so it can affect the endocannabinoid system through direct agonism. In their review, the researchers found evidence of THC being linked to improved fear extinction, a reduced stress response, and reduced anxiety behavior when given at mild or moderate dosages. Marketed versions of THC were also found to improve PTSD symptoms such as nightmares, hyperarousal, and poor sleep quality. Animal studies have also affirmed a link between THC and reduced fearful behavior when exposed to a conditioned stimulus, with THC thought to disrupt memory reconsolidating through the CB1 receptor, thus reducing fear learning.

However, they also uncovered findings that linked THC with an increase in false recollection of memories when ingested prior to being asked to recall an experience. This kind of distortion is would be an unwanted side-effect of THC treatment alongside therapy. There is also the slightly more obvious side-effect of unwanted intoxication, and the potential for misuse which might arise because of this.

Synthetic cannabinoid receptor agonists

Given the stigmatization of THC that comes with the prohibition of cannabis, endocannabinoid research also gave rise to synthetic cannabinoids which, like THC, have an affinity with the CB1 and CB2 cannabinoid receptors. However, these synthetic cannabinoids are often much more potent than THC.

While the synthetic cannabinoids have also shown promise in reducing fear memories and anxiety behavior in animal studies, the researchers note that since the synthetic cannabinoids are more potent than THC, this can make calculating dosage very tricky when conducting human trials. Anecdotal evidence concerning the recreational use of synthetic cannabinoids such as “spice” indicate that the substances might have much stronger physiological and psychological effects than THC.

The sort of long-term use that might be required for PTSD treatment raises significant concerns over the adverse health effects or substance abuse relationships that trial participants could experience if these synthetic cannabinoids were improperly dosed during a study.

Catabolic enzyme inhibitors

Unlike THC and the synthetic cannabinoids, which affect the endocannabinoid system through direct interaction with cannabinoid receptors, catabolic inhibitors enhance cannabinoid signaling by inhibiting select enzymes that would normally breakdown endogenous cannabinoid ligands in the body.

The review includes evidence that the inhibition of the catabolic enzyme FAAH can lead to a favorable effect on fear extinction and on other processes relevant to PTSD symptomology. However, it was also noted that one FAAH inhibitor only resulted in a reduction in stress response in those who had experienced early life trauma, and that there appears to be inconsistencies in the literature describing the effect of FAAH inhibition on memory consolidation. Still, it is thought that further research efforts could help to clarify these observations.

Unfortunately, a recent Phase I clinical trial saw numerous previously-healthy participants experience serious adverse events — including one death — while taking an oral FAAH inhibitor. It is thought that this health risk is only associated with the specific FAAH inhibitor used in this trial, but the review authors note that because of these adverse events further trials of enzyme inhibitors “have been slowed.”

Cannabidiol

CBD is the primary non-intoxicant phytocannabinoid that is found in the cannabis plant; THC is the primary intoxicant. CBD is thought to affect the endocannabinoid system indirectly, as it has a very low affinity for the CB1 and CB2 receptors, but has a moderate effect on several other targets in the central and peripheral nervous systems.

It was observed in clinical trials that CBD could have a positive effect on fear extinction and on the consolidation of emotional memories, as well as being beneficial following both acute and chronic stress. One distinct advantage the CBD has over the other potential therapeutics is a more robust safety profile; the World Health Organization have previously asserted that there is no evidence that CBD could present a possible public health risk, nor is there a potential for abuse or misuse.

This isn’t to say that CBD appears to be a perfect solution, it has its disadvantages. For example, very little is known about the exact mechanisms through which CBD causes these effects. CBD also a low bioavailability, meaning that courses of treatment may use large dosages that result in large costs for patients if the treatment were to become commonplace.





Recommendations for the future

Given the studies reviewed here, the researchers concluded that while the endocannabinoid system is clearly a promising target for improving PTSD outcomes, it is still inconclusive exactly which pharmacological agents may be best suited to do the job.

Considering the current state of research into the negative effects of long-term sustained THC exposure, it was concluded that catabolic enzyme inhibition or cannabidiol treatments may be the most promising avenues at present on account of the minimal safety risks that the methods pose. Further research into safety and biological mechanisms could enable both agents to one day become successful add-ons to PTSD treatment.