Pharmacodynamic effects and plasma pharmacokinetics of N,N-dimethyltryptamine after intranasal versus subcutaneous administration in male rats

Abstract

Rationale
There is growing interest in the therapeutic utility of psychedelic compounds that act as serotonin-2 A receptor (5-HT2A) agonists. N,N-dimethyltryptamine (DMT) is a 5-HT2A agonist that produces intense and short-lived psychedelic subjective effects, but the compound requires non-oral routes of administration that bypass gastrointestinal metabolism.

Objectives
Intranasal (IN) delivery of DMT represents one potential non-oral route of administration, but the feasibility of using this route is not well studied. Here, we examined the pharmacodynamic effects and plasma pharmacokinetics of DMT after IN and subcutaneous (SC) administration in rats.

Methods
Male Sprague-Dawley rats fitted with intravenous (IV) catheters and SC temperature transponders received DMT fumarate (1, 3, or 10 mg/kg) or saline vehicle by IN or SC routes. Blood samples were withdrawn via catheters at various times after treatment, with behavioral scores and body temperatures measured prior to each blood draw. Plasma DMT and its N-oxide metabolite were quantified using liquid chromatography tandem quadrupole mass spectrometry (LC-QQQ-MS).

Results
DMT produced a similar spectrum of pharmacodynamic effects after both routes, including increases in flat body posture and decreases in core body temperature. DMT displayed more rapid pharmacokinetics after the IN route (t1/2 range = 11.9–14.3 min) when compared to the SC route (t1/2 range = 45.5–122.7 min), and peak drug concentrations were greater with IN delivery.

Conclusions
Our findings show the feasibility of using IN administration to deliver DMT in a reproducible and non-invasive manner. Importantly, the maximal DMT concentrations in rats given low IN doses (i.e., 30.2–55.6 ng/mL DMT) overlap with those reported in humans receiving psychoactive doses.