Oral administration of (±)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques

Abstract

Rationale-Emergency Department visits and fatalities in which (±)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of "Ecstasy" is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition.Objective-To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly.Methods-Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (±)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system.Results-Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route or administration.Conclusions-The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.

High ambient temperature facilitates the acquisition of 3,4-methylenedioxymethamphetamine (MDMA) self-administration

“…The threshold for thermoregulatory effect of acute MDMA appears to be 5 mg/kg [40] and it is unknown if various intravenous self-administration patterns [0.5–1.0 mg/kg/inf is typical, resulting, e.g., in 4–7 mg/kg over 2 hrs [27], 30 mg/kg over 6 hrs [32] and 30 mg/kg over 2 hrs [33]] alter body temperature. A minimally invasive implanted radiotelemetry system, previously shown sensitive to the temperature disrupting effects of non-contingent administration of Δ9-tetrahydrocannabinol, mephedrone (4-methylmethcathinone), 3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP) and MDMA [47–50] as well as the intravenous self-administration of 4-methylmethcathinone [51] in rats, and similar to that found sensitive to effects of MDMA, methamphetamine and THC in monkeys [52–55], was used to minimize behavioral disruption during the self-administration sessions. Finally, the effect of high and low ambient temperature on the effects of MDMA on intracranial self-stimulation reward was determined to test the hypothesis that high ambient interferes with the ability of MDMA to reduce brain reward thresholds.…”

“…Since this was a rodent model featuring intravenous administration rather than the bolus oral consumption typical of human use, extrapolation must be cautious. Nevertheless, the similarity of effect of oral and injected MDMA on thermoregulatory disruption in one animal model [52, 53] suggests route of administration may not be qualitatively different for MDMA. Furthermore, this study emphasizes that the ongoing experience of higher versus lower levels of self-administration have lasting consequences on individual propensity to self-administer under future conditions.…”

In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats

“…A Kaplan-Meier survival analysis was used to compare acquisition of alpha-PVP and MDPV under the 0.05 mg/kg/inf dose (non-acquiring rats right censored at 20 sessions; group differences determined by Mantel-Cox Logrank test). The posthoc tests of the temperature and activity data included all possible comparisons but the reporting of results focuses on logical comparisons of interpretive interest as in prior studies of the effects of THC, MDMA, methamphetamine, MDPV and mephedrone (Aarde et al 2013f; Miller et al 2013a; Miller et al 2013f; Taffe et al 2015; Wright et al 2012) in rats as well as studies of MDMA, methamphetamine and THC in monkeys (Crean et al 2007; Crean et al 2006; Taffe 2011; 2012; Taffe et al 2006; Von Huben et al 2007). The first set of comparisons evaluated change from the pre-injection baseline within treatment conditions and the second set compared drug effects with the vehicle condition at corresponding time-points post-injection.…”

Δ9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys

“…Prior work has shown that 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) increases the body temperature of freely moving rhesus macaques following either intravenous or oral administration (Taffe et al, 2006, Crean et al, 2007) of doses (0.5–5.0 mg/kg) which overlap with those consumed by most human recreational users. These effects are present across a range of ambient temperatures (Von Huben et al, 2007) across which rat (Malberg and Seiden, 1998), but not human (Freedman et al, 2005), temperature responses change from hypo thermia to hyper thermia.…”