Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

Abstract

Fear‐related disorders, mainly phobias and post‐traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear‐related disorders is extinction‐based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear‐related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear‐imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat‐related stimuli, effectively mitigating one of the hallmarks of fear‐related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear‐related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first‐line treatments. We highlight 3,4‐methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear‐related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen‐assisted psychotherapy.

Neural Mechanisms and Psychology of Psychedelic Ego Dissolution

“…Its connectivity with the prefrontal cortex is also important to extinction learning (Quirk and Mueller, 2008;Herry et al, 2010;Milad and Quirk, 2012;Baldi et al, 2021), and dysfunction of this connectivity marks fear disorders such as PTSD (Rauch et al, 2006;Shin et al, 2006). Under psilocybin, the basolateral AMG demonstrates an elevated expression level of c-Fos (a marker of neural activity) (Davoudian et al, 2022) and is implicated in mice under nonclassic psychedelics such as 3,4-methylenedioxymethamphetamine (Glavonic et al, 2022). However, destruction of the basolateral AMG had a negligible effect on prefrontal 5-HT cortical excitation in preclinical research.…”

3,4-Methylenedioxy methamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs

“…However, the need of alternatives to clinical drugs and based on such previous evidence fueled efforts to re-take clinical studies with these scheduled substances, although most of them were denied regulatory approval. Thus, clinical trials with MDMA and several psychedelics such as LSD, psilocybin and DMT on depression, anxiety and PTSD have been carried out with promising results, even in treatment-resistant cases ( 15 , 16 ). Such studies demonstrate the psychotherapeutic utility of these compounds and encourage to carry on with these studies but, as it also happens with clinically approved medicines, these drugs may have side effects, contraindications and some non-optimal pharmaceutical properties that claim for the search of alternatives which, retaining the therapeutic activity, overcome these issues.…”