Discussion
bad drug, anxiety
The present study characterized pharmacokinetics and pharmacodynamics of DMT at low and high doses that were administered via 90-min continuous intravenous infusions with and without an initial loading bolus. The bolus dose was moderately well tolerated and typically described by the participants as a very intense and overwhelming experience that was perceived simultaneously as good, bad and anxiety-inducing. After the bolus administration of DMT at doses of 15 and 25 mg, plasma DMT concentrations peaked at 2.5 and 2.9 min and rapidly declined over 15 min. Subjective effects of DMT developed very rapidly during the 45-s bolus administration, reached a maximum within 2–3 min, and also decreased within approximately 15 min. In contrast, DMT administration as a continuous infusion at a stable rate of 0.6 or 1 mg/min over 90 min produced slowly rising plasma DMT concentrations, with maximal concentrations within 72 min. Subjective effects after DMT administration as an infusion increased slowly and gradually over 20–30 min when a plateau was reached until the infusion was ended at 90 min. The bolus administrations produced significantly greater subjective effects than the infusions. This was also the case for the low bolus dose compared with the high infusion. Thus, although the high infusion resulted in higher plasma DMT concentrations than the low bolus dose, the subjective effects of the low bolus were more intense. This is likely attributable to the more rapid rate of increase in DMT concentrations and more rapid onset of subjective effects during a DMT bolus vs. infusion. Thus, the participants considered the effects of DMT less intense when plasma levels of DMT rose more slowly compared with a rapid increase that was produced by the bolus administration. Possibly, the bolus doses produced high initial brain concentrations by rapid uptake of DMT at the blood-brain barrier followed by a slower washout and gradual distribution to other compartments. The bolus administrations were associated with significantly greater “bad drug effects”, anxiety, and cardiovascular stimulant effects at the onset compared with infusions of DMT. Similarly, different doses of 7–20 mg DMT that were administered in 13 participants produced high subjective peak effects within 1–3 min, which disappeared within 20 min [The present study also validly determined pharmacokinetic parameters of DMT using concentration measurements after stopping the infusion. A few previous studies measured DMT concentrations after bolus administrations not allowing to distinguish between DMT distribution and elimination [DMT showed no consistent effects on neuroendocrine markers such as oxytocin and BDNF. Only the high infusion of DMT increased circulating oxytocin compared with placebo. However, sampling at 60 min may have been too late to detect oxytocin changes after the bolus dose. Plasma BDNF levels were not altered by DMT. Some previous studies found increases in plasma or serum BDNF levels in response to psychedelics [The present study has several strengths. We used a relatively large study sample (