Novel extended-release transdermal formulations of the psychedelic N,N-dimethyltryptamine (DMT)

Psychedelic tryptamines such as N,N-dimethyltryptamine (DMT) are being reconsidered as therapeutic agents for psychiatric and neurological disorders, but their clinical use is constrained by delivery challenges. DMT produces rapid and intense psychedelic effects via 5-HT2A receptor agonism and is rapidly degraded by monoamine oxidases, making oral dosing ineffective; consequently most clinical and research administrations rely on intravenous, intramuscular, inhalation, or insufflation routes that produce high, transient peak concentrations and require supervised settings. Preclinical work suggests that sub-hallucinogenic exposures of DMT may still drive neuroplastic changes relevant to therapeutic outcomes, and the head-twitch response (HTR) in rodents has been used as a proxy to define hallucinogenic versus sub-hallucinogenic plasma levels. This study aimed to design, formulate, and evaluate single-layer drug-in-adhesive (DIA) transdermal patches delivering DMT freebase, with the objective of producing sustained peripheral exposure while keeping peak plasma concentrations below a proposed 60 ng/mL threshold for psychedelic subjective effects. Witowski and colleagues report in vitro screening (Franz cell diffusion) of six formulations varying adhesives, solvents and permeation enhancers, followed by GLP manufacture of a lead formulation (F5) and in vivo pharmacokinetic and HTR testing in male and female Swiss-Webster mice to assess pharmacokinetics, brain exposure, and hallucinogenic-like activity.

Formulation development screened six DIA patch formulations (F1–F6) using DMT freebase dissolved in ethanol or ethyl acetate, combined with three common transdermal adhesives (acrylate, silicone, polyisobutylene) and, in one formulation, the permeation enhancer isopropyl myristate. Non-GLP material was used for initial screening; GLP-grade DMT (98.5% purity) was used to manufacture patches for in vivo testing. Coating and drying procedures are described (150–250 μm coat thickness, oven drying at 70 °C for 2 h), and GLP patches were produced at a university facility. Some procedural parameters in the extraction text (e.g. specific stirrer rpm) are not clearly reported in the extracted material. In vitro release was assessed using Franz diffusion cells fitted with Strat-M membranes and a 10% ethanol/water receiver to aid solubility at 37 °C with stirring. Single-replicate Franz cell experiments sampled multiple timepoints to calculate flux and cumulative release; the methods state linear regression of concentration versus time was used to compute flux. Patch content and recovery were evaluated via solvent extraction, sonication, evaporation and HPLC quantification; recovery from the DIA matrix was reported as 92% and the HPLC method had a lower limit of quantification (LLOQ) of 20 ng/mL. In vivo work used male and female Swiss-Webster mice (6–8 weeks, 30–40 g). Hair was removed from the dorsal neck area and patches were applied under brief isoflurane anaesthesia and secured with jackets. Animals received either intravenous (IV) DMT or an active patch, with the other manipulation being vehicle to control handling. Doses tested were nominally 1 mg/kg and 5 mg/kg (extraction truncates some numeric labels but these doses are consistently described in the results). Blood sampling for IV cohorts occurred as early as 5 min and up to 240 min or more; sampling for transdermal cohorts began at 60 min and included later timepoints up to 1440 min. Brain tissue was collected at specified early timepoints and flash-frozen for LC-MS/MS analysis. The extracted text contains some truncated timing details for brain collections. Plasma and brain DMT concentrations were quantified by LC/MS/MS using validated calibration ranges and triplicate injections; assay performance criteria (calibration R ≥ 0.995, QC within ±15%, triplicate %RSD ≤ 15%) are reported. Pharmacokinetic parameters were computed from log-linear elimination slopes; AUCs were calculated using appropriate t = 0 values for IV and TD plots, and relative bioavailability (F) was computed as the dose-normalised AUC ratio. HTR was measured in magnet-implanted mice using automated magnetometer cages; mice were habituated, given treatments, and head-twitch counts were recorded and analysed relative to saline-treated controls. Statistical testing used GraphPad Prism with p < 0.05 as the significance threshold.

Formulation screening showed acrylate adhesive (Duro-Tak 4098) provided the highest DMT loading and flux among the adhesives tested; ethanol was the preferred solvent for DMT solubilisation. Six formulations (F1–F6) were characterised for coat weight, thickness and DMT content; F5 (acrylate adhesive, ethanol, 10.5% w/w DMT) was selected as the lead non-enhanced formulation and F6 (with isopropyl myristate, 16.1% w/w DMT) gave higher loading. Franz cell diffusion demonstrated largely linear, zero-order release over 72 h (R2 > 0.98) for all formulations except F4 (polyisobutylene), and cumulative delivery over 72 h was 520 μg/cm2 for F5 and 775 μg/cm2 for F6. F5 flux was stable at 1 week, 1 month and 2 months post-manufacture (flux range reported in the extracted text: 6.54 ± 2.73 μg/(cm2·hr)). In vivo pharmacokinetics revealed stark differences between IV and transdermal administration. For 5 mg/kg IV dosing, peak plasma concentrations (Cmax) occurred at the 5-min timepoint and averaged 597 ng/mL in males and 1437 ng/mL in females. At 1 mg/kg IV, Cmax averaged 372 ng/mL (males) and 528 ng/mL (females). The F5 transdermal patch produced much lower peak plasma levels and delayed Tmax: at 5 mg/kg, male Cmax = 37.0 ng/mL (1 h) and female Cmax = 54.8 ng/mL (4 h); at 1 mg/kg, male Cmax = 8.0 ng/mL (1 h) and female Cmax = 15.7 ng/mL (1 h). Apparent elimination half-lives were markedly prolonged with the patch: IV t1/2 ≈ 10.8 ± 2.5 min (males) and 10.0 ± 0.1 min (females), versus TD t1/2 ≈ 273 ± 10.5 min (males) and 210 ± 14.6 min (females). Relative plasma bioavailability following transdermal delivery was reported as approximately 77% compared to IV; the precise SD for the value in the results text was not clearly extracted but a value of 77 ± 10% is reported elsewhere in the manuscript. Brain concentrations mirrored peripheral exposure patterns. After 5 mg/kg IV, brain Cmax at 15 min averaged 4503 ng/g (males) and 8080 ng/g (females). At 1 mg/kg IV, brain Cmax were substantially lower (353 ng/g males, 250 ng/g females). For transdermal dosing, brain DMT was detectable above the LLOQ only at the 1-hour timepoint for the 5 mg/kg dose and those concentrations were significantly lower than after 5 mg/kg IV (Two-Way ANOVA: F Route [1,20] = 18.03, p = 0.0004). Brain concentrations were below the LLOQ at all timepoints after 1 mg/kg transdermal dosing. In the HTR assay, IV DMT produced a transient but robust increase in head-twitch counts, with an 18-fold elevation relative to IV saline during the 0–10 min bin (Sidak's test p = 0.0214) and time-dependent variation overall (Two-Way RM ANOVA: Route×Time F(11,99) = 3.69, p = 0.0002). The transdermal cohort did not show significant HTR changes compared with TD vehicle up to 1 h post-administration (Two-Way RM ANOVA: Route×Time F(11,242) = 0.66, p = 0.77). The investigators also observed sex-dependent differences in systemic exposure, with females generally achieving higher Cmax and AUC values than males across routes and doses. Finally, the authors note a discrepancy between in vitro 72-h sustained release and in vivo detectability of DMT, which in mice extended only to about 8 h, likely reflecting species-specific cutaneous and systemic metabolism.

Witowski and colleagues interpret these findings as the first demonstration that DMT can be delivered effectively via a non-invasive single-layer DIA transdermal patch, achieving prolonged systemic exposure, substantial relative bioavailability, and greatly reduced peak concentrations compared with IV dosing. The lead formulation (F5) produced a roughly 20-fold apparent extension in plasma half-life and maintained peripheral concentrations that, at the doses tested, did not exceed the authors' target threshold of 60 ng/mL thought to associate with subjective psychedelic effects. As a consequence, the patch did not induce significant HTR in mice, whereas IV DMT produced a rapid, transient increase in HTR consistent with hallucinogenic-like activity in this preclinical model. The discussion situates these results against earlier work suggesting that sub-hallucinogenic DMT exposures can still engage neuroplastic pathways; the researchers emphasise that transdermal delivery could enable outpatient, lower-risk regimens that avoid intense subjective effects and the need for continuous clinical supervision. They also highlight practical formulation insights: acrylate adhesives and ethanol solvent supported higher DMT loading and flux, and the addition of an enhancer (isopropyl myristate) further increased loading and permeation. Limitations acknowledged by the authors include species differences in metabolism and skin permeability, the faster drug clearance typical of rodents relative to larger mammals and humans, and discrepancies between in vitro Franz cell persistence and in vivo duration of exposure. Sex differences in PK were noted and the authors recommend that future clinical work monitor male–female differences. They also recognise that the current study does not establish whether the achieved exposure profiles will produce therapeutic efficacy or whether subjective psychedelic experiences are necessary for clinical benefit. The investigators call for further studies in larger animals and humans to determine translatability, to explore higher or enhancer-containing formulations that might elicit HTR via transdermal routes, and to evaluate neural and behavioural endpoints relevant to therapeutic indications.

The authors conclude that a low-dose transdermal DMT product is feasible and that their optimized DIA patch (F5) provides sustained systemic exposure with high relative bioavailability, a greatly extended apparent half-life, and peak plasma concentrations below the authors' proposed hallucinogenic threshold, thereby avoiding the HTR in mice. They state this approach could enable non-hallucinogenic, take-home dosing paradigms for psychiatric or neurological indications, while recommending additional PK/PD studies in larger species and humans to establish therapeutic potential and translatability.