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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\u2010related disorders is extinction\u2010based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear\u2010related 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\u2010imbued 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\u2010related stimuli, effectively mitigating one of the hallmarks of fear\u2010related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear\u2010related 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\u2010line treatments. We highlight 3,4\u2010methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear\u2010related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen\u2010assisted psychotherapy.<\/jats:p>","DOI":"10.1002\/jnr.25017","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T03:28:09Z","timestamp":1644895689000},"page":"947-969","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Hallucinogenic drugs and their potential for treating fear\u2010related disorders: Through the lens of fear extinction"],"prefix":"10.1002","volume":"100","author":[{"given":"Emilija","family":"Glavonic","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, \u201cVIN\u010cA\u201d Institute of Nuclear Sciences\u2010National Institute of th\u0435 Republic of Serbia University of Belgrade  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Mitic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, \u201cVIN\u010cA\u201d Institute of Nuclear Sciences\u2010National Institute of th\u0435 Republic of Serbia University of Belgrade  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslav","family":"Adzic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, \u201cVIN\u010cA\u201d Institute of Nuclear Sciences\u2010National Institute of th\u0435 Republic of Serbia University of Belgrade  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-013-3304-5"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)01224-X"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881119897615"},{"issue":"6","key":"e_1_2_12_5_1","first-page":"605","article-title":"Anxiolytic effects of harmine injection on elevated plus\u2010maze behavior in male Wistar rats","volume":"15","author":"Ahlem M.","year":"2015","journal-title":"Global Veterinaria"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00017.2008"},{"issue":"3","key":"e_1_2_12_7_1","first-page":"17m11634","article-title":"Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment\u2010resistant depression","volume":"79","author":"Albott C. 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