Translated from our German original by AI. The German text was researched, written, and edited by the Psychedelia Foundation team and remains the authoritative version.
Psychedelics, entactogens, and so-called psychoplastogens are among the approaches currently under intensive investigation for fast-acting treatments of depression and related mental disorders. That is the picture drawn by pharmacologist Daniel Hoyer in a recent review in the British Journal of Pharmacology.
The substances examined include classic psychedelics such as psilocybin, LSD, and DMT or ayahuasca, the non-psychedelic entactogen MDMA, and ketamine, esketamine, and ibogaine. Further compounds such as dextromethorphan/bupropion and esmethadone are also discussed as fast-acting pharmacological approaches.
Clinical research is most advanced for psychedelics and MDMA in depression, treatment-resistant depression, generalized anxiety disorders, and PTSD. Hoyer points to clinical studies suggesting a rapid onset of effect for certain substances. At the same time, most psychedelics remain in development and hold no approval for neuropsychiatric indications.
One focus of the review is the possible biological mechanisms. Classic psychedelics act above all as agonists at the serotonin 5-HT2A receptor. Beyond that, individual substances affect further serotonergic and dopaminergic systems. Changes in neuroplasticity and synaptogenesis are also discussed for psychedelics and other fast-acting substances, with BDNF and mTORC1 signaling pathways among the mechanisms involved.
The functional organization of the brain could matter as well. In depression, changes have been described in various neural networks, including the default mode network (DMN), the salience network, and cortico-thalamic networks. According to Hoyer, imaging studies show that psychedelic and entactogenic substances can alter this network activity. Such changes could potentially serve as biomarkers in future, helping to tailor treatments more closely to individual patients.
The term psychoplastogen refers to substances that can rapidly promote neuroplastic changes without necessarily producing a psychedelic experience. Hoyer himself notes that the precise boundaries of this still young term have not been conclusively settled.
Overall, the author sees clear signals for a biological basis of depression, generalized anxiety disorder, PTSD, and related conditions. He classifies these as complex disorders in which biochemical, neurological, and neuroimmunological processes could all be involved. Psychedelics, entactogens, and psychoplastogens could act on several of these processes at once. Which of these mechanisms are actually decisive for the therapeutic effects, and how safe and effective treatments can be developed from them, remains a subject for further research.
