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

There is considerable evidence from the literature that psychedelics, such as N,N-dimethyltryptamine (DMT), are safe and effective treatments for depression. However, clinical administration to induce psychedelic effects and expensive psychotherapy-assisted treatments likely limit accessibility to t...

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Bibliographic Details
Published in:	European journal of pharmaceutical sciences Vol. 199; p. 106803
Main Authors:	Witowski, Christopher G., Hess, Mika R., Jones, Nate T., Pellitteri Hahn, Molly C., Razidlo, John, Bhavsar, Riya, Beer, Christina, Gonzalez-Velazquez, Natalie, Scarlett, Cameron O., Wenthur, Cody J., von Salm, Jacqueline L.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-08-2024
Subjects:	Administration, Cutaneous Animals Behavior, Animal - drug effects Brain - drug effects Brain - metabolism Delayed-Action Preparations - administration & dosage Delayed-Action Preparations - pharmacokinetics Dimethyltryptamine DMT Extended-release Female Hallucinogens - administration & dosage Hallucinogens - pharmacokinetics Male Mice N,N-Dimethyltryptamine - administration & dosage N,N-Dimethyltryptamine - pharmacokinetics Pharmacokinetics Psychedelics Skin Absorption - drug effects Transdermal Transdermal Patch Extended-release DMT Dimethyltryptamine Transdermal Psychedelics Pharmacokinetics
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Summary:	There is considerable evidence from the literature that psychedelics, such as N,N-dimethyltryptamine (DMT), are safe and effective treatments for depression. However, clinical administration to induce psychedelic effects and expensive psychotherapy-assisted treatments likely limit accessibility to the average patient. There is emerging evidence that DMT promotes positive behavioral changes in vivo at sub-hallucinogenic dosages, and depending on the target indication, subjecting patients to high, bolus dosages may not be necessary. Due to rapid metabolic degradation, achieving target levels of DMT in subjects is difficult, requiring IV administration, which poses risks to patients during the intense hallucinogenic and subjective drug effects. The chemical and physical properties of DMT make it an excellent candidate for non-invasive, transdermal delivery platforms. This paper outlines the formulation development, in vitro, and in vivo testing of transdermal drug-in-adhesive DMT patches using various adhesives and permeation enhancers. In vivo behavioral and pharmacokinetic studies were performed with lead patch formulation (F5) in male and female Swiss Webster mice, and resulting DMT levels in plasma and brain samples were quantified using LC/MS/MS. Notable differences were seen in female versus male mice during IV administration; however, transdermal administration provided consistent, extended drug release at a non-hallucinogenic dose. The IV half-life of DMT was extended by 20-fold with administration of the transdermal delivery system at sub-hallucinogenic plasma concentrations not exceeding 60 ng/mL. Results of a translational head twitch assay (a surrogate for hallucinogenic effects in non-human organisms) were consistent with absence of hallucinations at low plasma levels achieved with our TDDS. Despite the reported low bioavailability of DMT, the non-invasive transdermal DMT patch F5 afforded an impressive 77 % bioavailability compared to IV at two dosages. This unique transdermal delivery option has the potential to provide an out-patient treatment option for ailments not requiring higher, bolus doses and is especially intriguing for therapeutic indications requiring non-hallucinogenic alternatives. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0928-0987 1879-0720 1879-0720
DOI:	10.1016/j.ejps.2024.106803