Editorial: Psychedelic substances and neurological diseases: from basics to clinical application

Summary

Psychedelics have shown potential in treating various psychiatric and neurological disorders, including depression and anxiety. They can induce neuroplasticity, which may alleviate symptoms of conditions like Alzheimer's and Parkinson's diseases. However, the review also highlights the neurotoxicity associated with commonly abused substances and emphasizes the need for new therapeutic approaches. Additionally, social hierarchy impacts drug reinforcement and addiction vulnerability, while trace amine receptors present new targets for treatment.

Study at a glance

Abstract

psychiatric disorders, beta-carbolines, trace amine, phosphoproteomics, social hierarchy. Scientific interest in psychedelic substances has re-emerged, offering new perspectives on the treatment of neuropsychiatric and neurological disorders.Historically, psychedelics have been associated with a wide spectrum of positive and negative effects, encompassing ritualistic and spiritual use, recreation and expansion of consciousness (Aicher et al., 2024). Importantly, psychedelics have been shown to induce neuroplasticity and alleviate symptoms associated with various neurological and psychiatric disorders (Lashgari et al., 2025). Clinical trials and basic research have demonstrated promising results in the use of these substances to treat conditions such as depression, anxiety, post-traumatic stress disorder, and even neurodegenerative diseases such as Alzheimer's disease, tauopathies and Parkinson's disease (Davis et al., 2021;Bradley et al. 2025;Cury et al., 2025, Vrechi et al., 2025). This collection aims to provide insights on the fundamental mechanisms of psychedelic action, its historical and contemporary uses, and emerging evidence supporting its effectiveness in clinical settings, with a primary focus on psychoactive substances from the perspective of toxicity and therapeutic potential.Regarding the mechanisms involved in neurotoxicity and its clinical implications, Wang et al. (2025) presented a review of six commonly abused recreational drugsmethamphetamine, cocaine, synthetic cathinones, ketamine, nitrous oxide, and heroin (morphine derivative)-and the neurotoxicity associated with these substances. Although acute morphine withdrawal promotes anxiety-like behavior in mice (Masukawa et al., 2000), Wang et al. highlight that, despite their distinct pharmacokinetic and pharmacodynamic profiles, these substances share convergent neurotoxic mechanism involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. This review is particularly relevant because it discusses the relationship between dissociative effects and neuroplasticity in the context of oxidative stress at the cellular level. Similarly, psychedelics such as ketamine and ethanol promote oxidative stress and induce apoptosis in neuronal cell models (Castelhano et al., 2025).Therefore, this review addresses the limitations of current pharmacotherapy, and highlights the need for new therapeutic approaches in cases of intoxication and abuse, including potential targets involved in neuroinflammation and antioxidant agents.Expanding the discussion beyond molecular toxicity, Xu et al. ( 2025) introduce a critical social dimension to drug reinforcement and vulnerability to addiction. Their original research demonstrates that social hierarchy modulates methamphetamine reinforcement in rats and is associated with distinct phosphoproteomic signatures in the nucleus accumbens. The authors reported higher levels of Histone Deacetylase 4 (HDAC4) phosphorylation in dominant rats, a protein previously described as playing critical roles in drug addiction. Notably, after behavioral training that altered the animals' social hierarchy between dominant and subordinate rats, the differences in HDAC4 phosphorylation levels were abolished; similarly, methamphetamine reinforcement was reversed. Collectively, these findings demonstrate the critical role of protein phosphorylation in regulating social hierarchy and its impact on drug reinforcement, offering a new pharmacological perspective on the social context of addiction.Focusing on the neuromodulation of anxiety and depression, the mini-review by Li et al. (2025) discusses the emerging role of trace amine-associated receptors (TAARs), particularly TAAR1, as potential therapeutic targets. Preclinical evidence that TAAR1 agonists exert antidepressant and anxiolytic effects in animal models, whereas TAAR5 antagonism reduces anxiety-related behaviors. Previously considered minor neurochemical components due to their low cerebral concentrations, trace amines are now increasingly recognized as key modulators of dopaminergic and serotonergic neurotransmission and stress-related responses. Thus, by contextualizing the role of TAARs in stress-related psychiatric disorders and depression, this mini-review substantially expands the pharmacological landscape of psychedelic science and suggests alternative or complementary targets for future therapeutic strategies. Moreover, pathways linked to neuroplasticity may also contribute to neurotoxicity depending on dose and context, underscoring the need for careful interpretation. Progress in this field will require rigorous controlled trials, standardized protocols, long-term follow-up, and mechanistic studies capable of distinguishing true therapeutic effects from nonspecific or expectancy-driven responses. Therefore, the collection "Psychedelic Substances and Neurological Diseases: From Basics to Clinical Application" offers a multidisciplinary perspective on how psychoactive substances can modulate neurological disorders such as depression and anxiety, as well as induce experiences that can promote complete physical, mental, and social well-being.

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