Effects of serotonergic psychedelics on mitochondria: Transdiagnostic implications for mitochondria-related pathologies

Abstract

The use of serotonergic psychedelics has gained increasing attention in research, clinical practice and society. Growing evidence suggests fast-acting, transdiagnostic health benefits of these 5-hydroxytryptamine 2A receptor agonists. Here, we provide a brief overview of their benefits for psychological, cardiovascular, metabolic, neurodegenerative, and immunological pathologies. We then review their effect on mitochondria including mitochondrial biogenesis, functioning and transport. Mitochondrial dysregulation is a transdiagnostic mechanism that contributes to the aforementioned pathologies. Hence, we postulate that psychedelic-induced effects on mitochondria partially underlie their transdiagnostic benefits. Based on this assumption, we propose new treatment indications for psychedelics and that the health benefits induced by psychedelics depend on patient-specific mitochondrial dysregulation.

Psychotomimetic compensation versus sensitization

“…Indeed, psychotic symptoms (e.g., hallucinations) occur more frequently in contexts of chronic or high stress—for example, during fever, 25 sleep deprivation, 26 starvation, 27 low oxygen conditions 28 or socially stressful scenarios that elicit fear or shame. 29 Psychotomimetic compensation—mirroring the effects of psychotomimetic drugs—may help normalize metabolic function, 30 , 31 reduce inflammation, 32 prevent brain damage 33 and ameliorate signs and symptoms of injury and illness such as lethargy, behavioral inhibition, social withdrawal, pain, low motivation, sadness and shame (Figure 1 ).…”

“…One explanation for these phenomenological similarities is that stress‐induced 5‐HT2AR activation functions, in part, to increase access to energy (e.g., stored glucose) and increase ATP synthesis and metabolism 31 , 147 , 148 , 149 in demanding circumstances, as well as to help buffer the organism against the excitotoxic effects of excessive energy demands or compromised metabolic function. 31 , 150 , 151…”

“…Psychedelic activation of 5‐HT2ARs promotes mitochondrial biogenesis, 30 , 152 , 153 resulting in increased expression of antioxidant enzymes, decreased cellular reactive oxygen species, and enhanced neuroprotection against excitotoxic and oxidative stress 30 (also see Ref. [ 31 ] for review). Consistent with these effects, the psychedelic agent N,N‐dimethyltryptamine (DMT) reduces infarct size and improves functional recovery following experimentally‐induced cerebral ischemia in rodents and psychedelics more generally are under development for stroke, as well as neurodegenerative conditions such as Alzheimer's disease.…”