Overcoming Pharmacokinetic and Peripheral Safety Challenges in Psychedelic Therapies: The Promise of Advanced Drug Delivery Systems.
Tianshu Zhang, Cong Lin, Xiaohui Wang
ACS Pharmacology & Translational Science June 12, 2026 DOI: 10.1021/acsptsci.6c00146 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Psychedelic-assisted therapy |
| Keywords | Drug delivery systems Intranasal administration Microneedle arrays Pharmacokinetics Psychedelics Transdermal patches |
| Key findings | Advanced delivery systems and molecular strategies can bypass hepatic metabolism, provide precise pharmacokinetic control, and reduce peripheral side effects, thereby improving the therapeutic potential of classic serotonergic psychedelics. |
Abstract
Classic serotonergic psychedelics-such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT)-hold remarkable promise for treating neuropsychiatric disorders, yet their clinical translation is severely constrained by first-pass metabolism, erratic pharmacokinetics, unsuitable action profiles, and off-target peripheral serotonin effects. To overcome these barriers, advanced delivery systemssuch as transdermal and microneedle patches, intranasal sprays, sublingual films, and injectable formulationshave been developed, alongside molecular strategies including prodrugs, "off-switch" 5-HT receptor antagonists for session control, selective receptor bias, and adjunctive pharmacological approaches. These innovations help bypass hepatic metabolism, enable precise control over onset and duration of action, and minimize peripheral receptor activation. Preclinical and early clinical evidence shows gains in bioavailability, half-life extension, and conversion of fleeting psychedelic effects into manageable windows. These platforms offer a path to safer, patient-centered therapies. Despite regulatory and trial-design challenges, delivery innovations provide the essential pharmacokinetic toolkit to advance the field and clinical adoption.