Hypothesis

Twice‑weekly microdosing of psilocybin (0.1–0.3 g dried) combined with daily 10‑minute heart‑rate‑variability (HRV) biofeedback will increase salivary BDNF concentrations and reduce PTSD symptom severity more than microdosing alone.

Rationale

• Psilocybin’s 5‑HT2A agonism triggers rapid calcium influx, activating the mTOR pathway and up‑regulating plasticity genes such as BDNF and c‑Fos within hours【2】.
• Microdosing produces sub‑psychedelic levels of this signal, priming synaptic machinery without triggering full‑scale hallucinatory states【1】.
• HRV biofeedback enhances vagal tone, raising acetylcholine release in the hippocampus and prefrontal cortex, which potentiates CREB‑dependent BDNF transcription【4】.
• The convergence of serotonergic priming and cholinergic amplification should produce a synergistic boost in neuroplastic biomarkers that is detectable in peripheral saliva.

Testable Predictions

1. Biomarker – After four weeks, the combined group will show a ≥20 % rise in salivary BDNF relative to baseline, whereas the microdose‑only group will show <5 % change.
2. Clinical – The combined group will achieve a ≥10‑point drop on the CAPS‑5 scale, exceeding the ≤5‑point change expected from microdosing alone.
3. Specificity – Salivary cortisol and HRV indices will shift in opposite directions (↓ cortisol, ↑ HF‑HRV) only in the combined condition, indicating a stress‑reducing neuroplastic state.

Falsifiability

If, after the intervention, salivary BDNF does not increase significantly in the combined group or PTSD symptom scores do not improve beyond the microdose‑only condition, the hypothesis is falsified. Likewise, a lack of correlated HRV changes would undermine the proposed cholinergic‑serotonergic synergy.

Methodological Sketch

• Recruit 60 participants with clinically confirmed PTSD (CAPS‑5 ≥ 30). Randomize to three arms: (A) microdose + HRV biofeedback, (B) microdose + sham biofeedback, (C) placebo + HRV biofeedback.
• Administer microdose twice weekly (Monday, Thursday) for four weeks; HRV biofeedback daily for 10 min (morning).
• Collect saliva upon waking on days 0, 7, 14, 21, 28 for BDNF ELISA; assess CAPS‑5 and PCL‑5 weekly.
• Record HRV (RMSSD, HF power) during each biofeedback session.

Expected Impact

Demonstrating a feasible at‑home biomarker‑guided protocol would close the gap noted in the literature—no validated neuroplasticity markers exist for psychedelic microdosing【2】—and provide a low‑cost, scalable adjunct to existing PTSD therapies.