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 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.

Spongian Diterpenoids Derived from the Antarctic Sponge Dendrilla antarctica Are Potent Inhibitors of the Leishmania Parasite.

From the CH2Cl2 extract of the Antarctic sponge Dendrilla antarctica we found spongian diterpenes, including previously reported aplysulphurin (1), tetrahydroaplysulphurin-1 (2), membranolide (3), and darwinolide (4), utilizing a CH2Cl2/MeOH extraction scheme. However, the extracts also yielded diterpenes bearing one or more methyl acetal functionalities (5-9), two of which are previously unreported, while others are revised here. Further investigation of diterpene reactivity led to additional new metabolites (10-12), which identified them as well as the methyl acetals as artifacts from methanolysis of aplysulphurin. The bioactivity of the methanolysis products, membranoids A-H (5-12), as well as natural products 1-4, were assessed for activity against Leishmania donovani-infected J774A.1 macrophages, revealing insights into their structure/activity relationships. Four diterpenes, tetrahydroaplysulphurin-1 (2) as well as membranoids B (6), D (8), and G (11), displayed low micromolar activity against L. donovani with no discernible cytotoxicity against uninfected J774A.1 cells. Leishmaniasis is a neglected tropical disease that affects one million people every year and can be fatal if left untreated.

Darwinolide, a New Diterpene Scaffold That Inhibits Methicillin-Resistant Staphylococcus aureus Biofilm from the Antarctic Sponge Dendrilla membranosa.

A new rearranged spongian diterpene, darwinolide, has been isolated from the Antarctic Dendroceratid sponge Dendrilla membranosa. Characterized on the basis of spectroscopic and crystallographic analysis, the central seven-membered ring is hypothesized to originate from a ring-expansion of a spongian precursor. Darwinolide displays 4-fold selectivity against the biofilm phase of methicillin-resistant Staphylococcus aureus compared to the planktonic phase and may provide a scaffold for the development of therapeutics for this difficult to treat infection.