Скачать или смотреть Psychedelic Mechanisms of Action: Subjective Experiences vs. Neuroplasticity (Atiq et al., 2025)

This video explores an ongoing question in psychedelic science: do psychedelics' Acute Subjective Experiences ("their trips") or their Neuroplastic ("psychoplastigenic") effects mediate therapeutic outcomes?

We will use Atiq et al's 2025 publication as our guide.

I. The Core Debate
Classic psychedelics act primarily as agonists or partial agonists (activators) of serotonin's 5-HT2A receptor.

II. The Clinical Model of Psychedelic-Assisted Therapy
Posits that profound alterations in consciousness (including mystical experiences and ego dissolution) mediate therapeutic outcomes.

III. The Pharmacological Model of Psychopalstogens
Endorses neural plasticity as the active mechanism in psychedelic therapies (suggesting subjective experiences may be secondary "side effects").

IV. Clinical Support (Humans)
Most human clinical trials suggest strong associations between the intensity of a psychedelic experience and positive outcomes, though recent data is mixed.

V. Depression
Early feasibility studies and Phase 2 trials for Psilocybin use in Treatment-Resistant Depression (TRD) finds components of altered states of consciousness (oceanic boundlessness & mystical-type experiences) predict symptom reduction at 5 weeks. However, placebo-controlled trials have not found a significant correlation between ASE scores and therapeutic benefits, suggesting the experience itself may not be the sole driver of efficacy.

VI. Alcohol Use Disorder
Strong correlations exist between mystical experience intensity and abstinence from alcohol in Alcohol Use Disorder (AUD).

VII. Eating Disorders
Patients with Anorexia Nervosa often display dysregulated 5-HT2A signaling, which may blung subjective effects. This allows researchers to test whether therapeutic benefits persist without ASEs. Findiings remain inconclusive.

VIII. Preclinical Findings
Animal models allow researchers to measure neuroplasticity directly. "Psychoplastogens" are small molecules capable of producing measurable changes in plasticity within short periods (24–72 hours) following a single administration. Non-hallucinogenic psychedelics demonstrate therapeutic efficacy in rodents without inducing the "head-twitch response" (a proxy for hallucinations). Examples of engineered non-hallucinogenic psychedelics (plastinogens) include:
Tabernanthalog (TBG): Iobogaine analog.
AAZ-A-154: Non-Hallucinogenic Psychoplastogen.
2-Br-LSD: LSD analog.
Ariadne: Mescaline analog.

IX. Mechanisms of Action
1. Neural Plasticity
Both hallucinogenic and non-hallucinogenic compounds activate 5-HT2A receptors to trigger intracellular signaling (involving beta-arrestin and G-proteins) that reshapes neural circuitry.

2. Mechanisms of Action II: Critical Periods
Recent studies suggest psychedelics reopen "critical periods" for social reward learning. The duration of the ASE appears proportional to the duration this learning window remains open—ranging from days with ketamine to weeks with ibogaine. This suggests the subjective state may mark a unique period of metaplasticity required for deep behavioral change.

XI. Future Directives
1. Anesthesia Studies
Administering psychedelics to patients under general anesthesia to block subjective awareness while allowing neurobiological mechanisms to function.

2. Receptor Antagonism
Co-administering psychedelics with selective antagonists (like pimavanserin) to block the perceptual effects while potentially preserving therapeutic signaling.

3. Microdosing
Investigating if sub-threshold doses that do not produce ASE can still drive neuroplasticity and symptom relief over time.

Source: Atiq, M.A., Baker, M.R., Voort, J.L.V. et al. Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties. Psychopharmacology 242, 1481–1506 (2025). https://doi.org/10.1007/s00213-024-06....

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