Post-traumatic stress disorder (PTSD) has historically been difficult to effectively treat. However, there is tremendous promise with the renewed study of psychedelic (e.g., MDMA)-assisted therapy. Phase 2 and 3 trials have shown a significant improvement in PTSD symptoms with MDMA-assisted psychotherapy compared to placebo-assisted psychotherapy. Furthermore, previous studies have highly indicated that dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis may be heavily involved in the development of PTSD (as well as later life-associated psychiatric consequences of early life neglect/abuse) (Figure 1). We have also seen that stress/trauma-induced dysregulation in the HPA axis may be a consequence of aberrant expression in genes (and consequently proteins/receptors) involved in HPA axis functioning.
Figure 1. The Hypothalamic-Pituitary-Adrenal (HPA) Axis When an acute stressor is encountered: 1) the hypothalamus releases CRF onto the pituitary; 2) the anterior pituitary then releases ACTH, which travels to the adrenal glands; 3) the adrenals release cortisol in response to ACTH; 4) cortisol travels to the brain, where it interacts with glucocorticoid receptors in the hypothalamus and hippocampus; and 5) the interaction of cortisol with glucocorticoid receptors provides a negative feedback signal so that the stress response is terminated and the HPA axis, in essence, calms down. The experience of severe or chronic trauma may alter DNA methylation, thus causing impaired expression of glucocorticoid genes/receptors. With fewer glucocorticoid receptors available to receive negative feedback control from cortisol, the HPA axis may stay in a heightened state of activity -potentially leading to psychiatric illnesses such as PTSD or anxiety disorders.
Specifically, there are 3 such genes being thoroughly investigated: NR3C1 (encoding for the glucocorticoid receptor that is an integral part of healthy HPA functioning in response to stress); FKBP5 (which plays a role in the interaction and downstream consequences of cortisol/glucocorticoid receptor interaction); and CRHR1 (which codes for corticotropin-releasing hormone receptor 1). Aberrant methylation of these genes (and thus altered expression of these genes/proteins) may impact functioning of the HPA axis and lead to PTSD symptoms/psychiatric illness (Figure 2A). Thus, we potentially understand that certain life events/experiences can alter our “epigenome” -including DNA methylation, expression of important genes/proteins involved in HPA axis functioning, and development of a serious mental illness. Can we also intervene at the epigenetic level (Figure 2B)?
Figure 2. Shutting Off and On Expression of the NR3C1/Glucocorticoid Receptor Gene
A) The experience of trauma may alter DNA methylation to the extent that expression of genes important to the function of the HPA axis is dysregulated. B) Psychedelic-assisted psychotherapy (e.g., involving MDMA) may also be able to have epigenetic effects that ultimately allow for the healthy expression of genes and normal functioning of the HPA axis.
In this small (but mighty) study, Lewis and colleagues investigated the impact of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (vs. placebo-assisted therapy) on methylation of genes involved in the functioning of the HPA axis. Ultimately, 16 patients with severe PTSD were treated with MDMA-assisted psychotherapy while 7 similar patients were treated with placebo-assisted psychotherapy. Saliva swabs to obtain DNA methylation data were obtained at baseline and after the conclusion of treatment. While placebo-assisted therapy alone did have some effect on PTSD symptoms (using the Clinician-Administered PTSD Scale; CAPS-5) as well as methylation of HPA axis-related genes, the inclusion of MDMA into therapy vastly improved outcomes. These improvements over placebo in the MDMA group were significantly associated with methylation changes at specific sites in the NRC31 and CRHR1 genes.
Future studies may help to elucidate whether MDMA exerts its effects on DNA methyltransferase (the enzyme that adds methyl groups to genes -potentially silencing those genes) or a demethylase (enzymes that remove methyl groups, thus perhaps allowing genes to be expressed) or some combination of mechanisms. Additionally, the authors point out that there is still much to learn regarding the effects of methylation on gene silencing or expression (depending on the specific location surrounding or within a gene where methylation occurs); previous studies have had some contradictory data in that regard. However, we have a plethora of data from the past few decades that PTSD (as well as early life abuse and neglect) is associated with changes in methylation and expression of HPA axis-related genes (notably NR3C1) and aberrant function of the critical HPA-axis circuit. These preliminary data indicating that we may be able to “correct” aberrant methylation using therapy (significantly boosted by concomitant psychedelic/MDMA treatment) and ultimately witness drastic improvements in PTSD symptoms (or potentially alter the psychiatric trajectory of abused/neglected youth) is very exciting and encouraging.
Lewis CR et al. Front Psychiatry 2023;14:959590. Abstract
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