Post-traumatic stress disorder (PTSD) typically develops in response to an extremely threatening or distressing experience (or a series of experiences), with symptoms presenting as re-experiencing the trauma through dreams and vivid intrusive thoughts, avoidant behaviour, anxiety, and a persisting state of hypervigilance.1 People afflicted with PTSD have been shown to present with prolonged inflammation due to an increased level of pro-inflammatory molecules, such as interleukin-1 beta (IL-1β).2
In addition, the levels of reactive oxygen species (ROS), which are typically generated through normal cellular processes, are also found in excess.3 In this scenario, the ROS are implicated in premature cell ageing and induce mutagenesis, i.e., they can modify DNA.4 Sustained inflammation and ROS delays healing, resulting in altered cell behaviour or even cell death, and eventually leading to disease.5 The mechanisms underlying inflammation and ROS are interconnected, which makes them an attractive potential target for future PTSD therapies.
Dimethyltryptamine (DMT) is a compound capable of inducing potent psychedelic experiences that are typically much shorter than other “classical” psychedelics such as psilocybin or LSD.6 Despite its discovery in western medicine in the late 50’s by Dr. Stephen Szara7, indigenous tribes of the Amazon rainforest have been using DMT ritualistically for hundreds of years in the form of a brewed tea, commonly known as ayahuasca.8
Ayahuasca is a complex mixture containing DMT, the monoamine oxidase inhibitors harmine and harmaline (which prevent the body from breaking down DMT when ingested orally), as well as various other compounds that may have clinical relevance. However, these mixtures vary in their composition from batch to batch. To ensure treatments are replicable, the complexity of the mixture can be standardized and reduced to a combination of DMT and a monoamine oxidase inhibitor such as harmine or harmaline, known as “pharmahuasca”.9
Psychedelics have shown promising efficacy in treating mental health disorders, with potential mechanisms including the promotion of neural plasticity, reducing inflammation, or even stimulating positive emotional processes.10,11 Exposure to a single dose of a psychedelic is enough to sustainably ablate the fear response in animal models of anxiety12, however the potential of DMT (or ayahuasca) to treat PTSD has not been extensively investigated. In a recently published paper, Dr. Kelley and colleagues sought to bring new light to this matter by exploring the mechanisms through which DMT and pharmahuasca could help treat PTSD.13
Validation of the Rat PTSD Model
To study how DMT and pharmahuasca affect the expression of genes associated with PTSD, a previously developed PTSD model induced in rats (henceforth referred to as PTSD rats)14 was used. Although the behavioural and biochemical profiles of the PTSD rats were previously established14,15, it is unclear which genes are differentially expressed (DEGs) when compared to a control (i.e., rat models without PTSD) and to what extent they overlap with DEGs in humans affected by PTSD.
The researchers identified around 200 genes expressed in PTSD rats to be differently regulated in contrast to controls. This compares to around 400 DEGs in the brains of humans affected with PTSD relative to healthy individuals.16 When comparing the DEGs identified in both human and rat datasets, they found an overlap of 20 DEGs (henceforth referred to as ‘PTSD genes’) that are involved in processes including inflammation, cell growth, and cell signalling between neurons (GABA signalling – a pathway found to be affected in PTSD patients).17
Rescue of Differentially Expressed Genes
When PTSD rats were administered DMT, harmaline, or pharmahuasca, around 4000, 5000, and 3000 genes were found to be differently regulated, respectively, compared to controls. Out of the 20 overlapping ‘PTSD genes’ between PTSD rats and PTSD afflicted humans, the expression of 9, 12, and 14 genes was restored closer to that of the controls after DMT, harmaline, or pharmahuasca treatment, respectively. DMT treatment also downregulated genes involved in the production of ROS and upregulated those associated with neurotransmission and neural plasticity. Harmaline does not only inhibit the enzymes that prevent DMT from being degraded, but it also plays an active role in both reducing the levels of ROS products and promoting neuroplasticity.
Unlike harmaline or DMT alone, pharmahuasca did not rescue the expression of the gene encoding somatostatin, a molecule involved in neurotransmission and found to be downregulated in both this rat PTSD model and in PTSD sufferers.16 Nevertheless, pharmahuasca increased the expression of genes encoding the receptors to which somatostatin binds to. In addition, pharmahuasca was shown to downregulate the expression of a major factor (NFKB2) involved in regulating the inflammatory response and to upregulate the expression of genes implicated in pathways which allow neurons to form connections to other neurons (synaptogenesis). Interestingly, pharmahuasca reduced the expression of an enzyme involved in the production of endogenous DMT, which is expressed in the brains of both humans and rats.18
ROS Production Reversed
It was previously shown that PTSD rats have an increased level of ROS products in their brain and other tissues.15 The study conducted by Dr. Kelley and colleagues not only corroborated these findings, but also demonstrated that both DMT and pharmahuasca treatment can reduce the levels of ROS closer to those found in a non-PTSD control group.
Previous research has shown that a single treatment of a serotonin receptor binding psychedelic results in lasting synaptic structure changes.12 In this study, however, it is unclear whether the rescued expression of the ‘PTSD genes’ following the treatments is sustained in their absence and longer timepoints would be required to observe this. Although expression of ‘PTSD genes’ was restored to levels similar to the control groups after treatment, it is unclear whether the behaviour of the PTSD rats changed, an observation that could have strengthened their results.15
In addition, the neuroanatomy of the brains of PTSD affected individuals is known to be structured differently compared to non-affected individuals19, however, no histological examinations of the brains from PTSD rats that underwent the various treatments were performed. Consequently, it is unclear whether the neuroanatomy is altered in this PTSD model, although this is something that could be further explored in future research to strengthen the model. Lastly, this study was largely limited to gene expression analysis, which does not necessarily translate into the function of the cells. Nevertheless, they did show that actual ROS levels were reduced, complimenting some of their gene expression data.
Some of these limitations were discussed by the authors of this study, who emphasized that their aim was to expand the knowledge regarding transcriptional regulation following psychedelic treatment by building and analyzing a large gene expression dataset.
The results presented in the study carried out by Dr. Kelley and colleagues advanced our knowledge regarding the validation of an animal model of PTSD and the expression of genes after psychedelic exposure. They also showed a decrease in the actual levels of ROS following psychedelic treatment, emphasizing the validity of their gene expression data. This study expands our understanding of PTSD and opens an avenue of developing effective psychedelic based treatment regimens for this disorder.
Great article! Thanks for the write up
How far have you taken this treatment?
Volunteers while under the influence of administered pharmauasca to say someone who has experienced psychedelics enough to know when they were being given a type of hallucinogenic, do they have any rights? Compensation? Free will?
“Real world” “Full Disclosure”
Those are pretty real.
Curious about the success rate of the willing over the unwilling or unknowingly dosed ones.
From a dozen to less than a handful to one.
Can’t speak for that study but in general: yes of course all study participants have rights. They often are paid and they have a right to quit the study ANY time, as in all other types of research with human subjects. And you would never dose an unwilling person.