The Top 7 Atypical Psychedelics: A Brief Clinical Guide

The field of psychedelics as mental health treatments has seen a marked increase in interest within psychiatry. In the current “psychedelic renaissance,” or third wave of psychedelic research, findings from numerous clinical trials have demonstrated efficacy for psychedelics in the management of depression, anxiety, posttraumatic stress disorder (PTSD), substance use disorders, and other psychiatric conditions. Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT) have reemerged in clinical research and may soon receive approval from the US Food and Drug Administration (FDA). Their clinical effects are primarily mediated through serotonin 5-hydroxytryptamine receptor 2A (5-HT2A) receptor agonism.^1,2

In parallel, researchers have increasingly investigated psychedelics that do not share this classical serotonergic mechanism. For the purposes of this article, these compounds are referred to as atypical psychedelics, defined as substances that produce psychedelic or psychedelic-like effects without primary 5-HT2A receptor agonism.

1. Ketamine/Esketamine

Ketamine, synthesized in 1962 as a structural derivative of phencyclidine, is commonly classified as a dissociative psychedelic and is among the most extensively studied psychedelic-like agents in psychiatry. It acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and has attracted significant attention due to its rapid antidepressant effects. Ketamine is widely used off-label for treatment-resistant depression and suicidal ideation,³ whereas its (S)- enantiomer, esketamine, has received FDA approval for treatment-resistant depression. Results from a study published in the New England Journal of Medicine found ketamine to be noninferior to electroconvulsive therapy.⁴ Findings from more recent studies suggest that esketamine may also be effective as a monotherapy for depression, beyond its traditional use as an adjunctive treatment.⁵

2. Dextromethorphan

Like ketamine, dextromethorphan acts as an NMDA receptor antagonist in addition to functioning as a serotonin and norepinephrine reuptake inhibitor. At high doses, it can produce psychedelic-like effects. Although it did not demonstrate efficacy as a monotherapy for depression, a combination formulation with bupropion was later found to be effective and subsequently approved by the FDA for depressive disorders.⁶

3. MDMA

Unlike classical psychedelics, 3,4-methylenedioxymethamphetamine (MDMA) primarily acts as a monoamine releaser and reuptake inhibitor, with additional downstream effects on oxytocin signaling. These mechanisms contribute to enhanced empathy and emotional openness without the pronounced perceptual distortions or ego dissolution typically associated with classical psychedelics. As a result, MDMA is classified as an entactogen or empathogen. MDMA-assisted psychotherapy has consistently demonstrated efficacy in the treatment of PTSD in clinical trials.⁷

4. 5-MeO-DMT

Mebufotenin (5-MeO-DMT) is a naturally occurring tryptamine found in several plant species and in the defensive secretion of the Colorado River toad (Incilius alvarius). A synthetic form is also used in research settings. It exhibits a mixed pharmacological profile, with strong 5-HT1A receptor affinity alongside 5-HT2A agonism. After decades of nonclinical and community use, findings from a recent phase 2b randomized controlled trial (n = 81) reported that 57.5% of patients with treatment-resistant depression achieved remission by day 8 following 3 escalating doses of inhaled 5-MeO-DMT.⁸

5. Ibogaine

Ibogaine, an alkaloid derived from African plant species, has attracted growing interest for its potential in treating substance use disorders, to the extent that it has been specifically highlighted in recent policy discussions aimed at accelerating psychedelic research. Like ketamine, ibogaine’s mechanism entails NMDA receptor antagonism. However, ibogaine and its active metabolite noribogaine interact with other systems, including opioid receptors (μ and κ) and nicotinic acetylcholine receptors. Its antiaddictive effects have also been linked to these broader neuropharmacological actions, especially nicotinic receptor antagonism. Although anecdotal reports and findings from open-label studies suggest therapeutic potential, evidence remains limited, with only a small pilot randomized controlled trial (n = 20) evaluating its effects in stimulant use disorder. Increasing numbers of individuals also seek treatment abroad, particularly in Mexico, a phenomenon sometimes referred to as ibogaine tourism.^9,10

6. Salvinorin A

Salvinorin A is the primary psychoactive compound in Salvia divinorum. It is a highly potent and selective opioid κ receptor agonist, producing extremely rapid-onset effects within seconds and having a short duration of approximately 8 minutes. Findings from early human studies at Johns Hopkins University, including work by Roland Griffiths and colleagues, characterized its acute subjective effects in healthy volunteers. However, its clinical applications remain largely unexplored. Proposed areas of interest include pain management, substance use disorders, and depression.^11,12

7. Muscimol

Muscimol is the principal psychoactive compound in Amanita muscaria, the iconic red-and-white mushroom. It acts as a potent γ-aminobutyric acid A receptor agonist, producing sedative, hypnotic, and dream-like or oneiric states. Although it has received limited attention in psychiatric research, it has been explored for potential applications in neurological conditions such as Parkinson disease, Huntington disease, essential tremor, and epilepsy.^13-16

Concluding Thoughts

Renewed scientific interest, increasing public engagement, and evolving policy frameworks have created an opportunity to systematically study these long-neglected compounds, many of which may hold significant clinical potential. Beyond classical serotonergic psychedelics centered on 5-HT2A receptor agonism, atypical psychedelics expand the pharmacological and phenomenological landscape of altered states of consciousness, opening new avenues for psychiatric research and therapeutic development.

Dr Forcen is a psychiatrist in the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Pennsylvania.

References

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