Post-traumatic stress disorder (PTSD) affects millions worldwide, with 40–70% of patients experiencing refractory disease despite available treatments. MDMA, like classic psychedelics such as psilocybin, has been used to enhance psychotherapy since its discovery, but research into its mechanisms has been limited due to its Schedule 1 classification. The pro-social effects of MDMA are thought to improve therapeutic alliance and facilitate trauma processing, but this may not fully explain its efficacy. A more nuanced explanation combines MDMA's pro-social effects with molecular mechanisms, such as increased brain-derived neurotrophic factor (BDNF) availability in fear memory learning pathways, potentially accounting for its therapeutic actions in PTSD.
Psilocybin, a naturally occurring psychedelic compound, may relieve depression by promoting neuronal plasticity and altering brain network connectivity. Recent clinical trials suggest it effectively reduces symptoms in major depressive disorder and treatment-resistant depression. Cellular experiments in mice demonstrate psilocybin promotes neuritogenesis, potentially addressing the cellular root of depression. Human brain imaging shows psilocybin therapy enhances functional connectivity in intrinsic networks, leading to durable improvements in depressive symptoms. This review highlights psilocybin's promise as a psychotherapeutic that targets neuronal atrophy, a model supplanting the neurotransmitter deficit hypothesis.