by Duncan Fisher

September 01, 2022 - 4 min read

Cannabis use by military personnel during and after the Vietnam War was unusually high. Anecdotal evidence from veterans questioned about it was that marijuana helped control nightmares and flashbacks. This dovetails with subsequent research into the endocannabinoid system, part of the body’s neural cell-signaling network, and the physiological reason for mammals’ sensitivity to natural cannabinoids. That system turns out to function in part as a regulatory buffer for emotional responses, short- and long-term, to stress. It should therefore be no surprise that post-traumatic stress syndrome (PTSD) often co-occurs with cannabis use. And in laboratory study, cannabis, or some constituent part of cannabis, does appear to alleviate some of the symptoms, probably by normalizing endocannabinoid function. It may possibly be that a phenotypical state of endocannabinoid deficiency could exist, representing a stress susceptibility in some people. This could explain some of the heavy cannabis use in some veterans rather than others. Interestingly, a 2018 animal study suggests that brief and repeated neonatal stress does induces phenotypical changes on neural cannabinoid receptors, and that they manifest differently between adolescents and adult brains, and male and female ones.

The etiology of PTSD is complex, involving distinct memory phases, that include acquisition, consolidation, retrieval, and extinction, and multiple cognitive tasks, emotional or aversive or non-emotional. There is consensus that these alterations, combined with changes in mood, anxiety, and arousal, comprise the complex and aberrant adaptation to traumatic stress that is PTSD. In the memory processes, several lines of evidence suggest that cannabinoids act differentially across each of them, in separate brain areas, though generally in the retrosplenial cortex. There, cannabidiol has been shown to disrupt the consolidation of specific and generalized fear memory, via the CB1 and CB2 receptors. Its effect overall is to undo, partly as prophylaxis and partly as therapy, long-lasting inappropriate behavioral consequences of threat stress. This is a learned fear paradigm, mediated by 5HT1A receptor gene expression. The therapeutic goal is to act principally in the two opposing processes of reconsolidation and extinction of the fear memory, in hopes of restoring suitably coping reaction to stressful events. 

It is chiefly at the CB1 receptor site, in distinct circuits of the extended amygdala, that fear responsiveness to unpredictable threat is modulated. Stimulation of those receptors on GABAergic nerve terminals increases dopamine release, which mitigates the effects of stress. There is downstream regulation, too, and feedback control, of hypothalamic-pituitary-adrenocortical axis activity. This may be the general target in translational medicine against PTSD. Human studies of fear extinction with cannabinoids are yet few, however, and results are not completely consistent.

Focal studies on possible mechanisms of action have shown that stress evokes bidirectional changes in the two endocannabinoid molecules anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels, reliably causing a downregulation or loss of CB1 receptors. The decline in AEA appears to contribute to stress response, and increased 2-AG signaling contributes to termination and adaptation of HPA axis arousal, and possibly contributes to changes in pain perception, memory, and synaptic plasticity.

WIN55,212-2, a synthetic cannabinoid, administered during late adolescence has prevented stress-induced impairments and reduced anxiety in rats. There, WIN normalized the up-regulation in PFC-GRs and CA1-CB1r in females, and in males, normalized the up-regulation in PFC-GR and down-regulation in BLA-CB1r. Chronic exposure to WIN55,212-2 prior to an emotional trauma may have deleterious effects on emotional function. If it does, direct CB1/2 receptor activation may not be the optimal way to manipulate the endocannabinoid system in stress-related syndromes. However, in other studies, WIN55,212-2, with and without the fatty acid hydrolase (FAAH) inhibitor URB597, have prevented trauma-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction, and startle response, and as well decrease in BDNF levels in the hippocampus and prefrontal cortex.  

FAAH is the primary degradation enzyme of AEA. Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety. Administration of URB597 shortly after exposure to trauma prevents the development of a PTSD-like phenotype. Another selective reversible FAAH inhibitor, SSR411298, seems also to restore the development of maladaptive behaviors to acute and chronic stress in rodents. This, too, appears a promising drug candidate, perhaps in concomitant therapy. Finally, the dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses stress-induced behavioral despair in rats, and modulates their HPA-axis response. 

A novel route to cannabinoid-focussed precision medicine for PTSD is stimulation of neurosteroidogenesis, in patients showing a downregulation of allopregnanolone biosynthesis. This can be done by acting on neurosteroidogenic targets or by mimicking allopregnanolone itself. Neuronal targets have been discovered, notably PPAR-a. This strategy centers on the crosstalk between neurosteroids and the endocannabinoid system. It may be that here will emerge unique bio-signatures for stress-induced disorders. 

Most promising of all is oral CBD. Combined with routine psychiatric care in a 2018 case study, there was a reduction of PTSD symptoms in adults, particularly in the subset who reported frequent nightmares.

DiolPure products contain PureForm CBD™ transformed from aromatic terpenes for pharmaceutical-grade purity. PureForm CBD™ is bioidentical to CBD extracted from hemp and cannabis, but free of any residual cannabinoids like THC or impurities or chemicals that can associate with traditional plant-derived production processes. 

The foregoing is a report on trends and developments in cannabinoid industry research. No product description herein is intended as a recommendation for diagnosis, treatment, cure or prevention of any disease or syndrome. 

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