Pyretogenic effect of lysergic acid diethylamide

Earlier work on ergot alkaloids established many peripheral autonomic and oxytocic effects, yet lysergic acid diethylamide (LSD) differs markedly in producing prominent hallucinogenic activity rather than those classical peripheral actions. While studying LSD in intact, normal rabbits, the investigators observed pronounced hyperpnea, which prompted them to examine whether LSD also raises body temperature. Previous reports of thermoregulatory and autonomic effects of LSD in animals and humans had been inconsistent, so clarifying any pyretogenic (fever-producing) action was of interest. This study set out to characterise the pyretogenic effect of LSD across several species (rabbits, dogs, cats), to document its time course and route-dependence, and to probe mechanisms by testing a range of pharmacologic interventions. The authors also explored peripheral temperature changes (skin and ear) to assess whether altered heat loss could explain any rise in core temperature, and they evaluated whether various drugs could antagonise the response.

The experimental work was performed primarily in unanesthetised animals, with the rabbit used for detailed studies because it showed the most marked temperature response. LSD was supplied in ampoules at 0.1 mg/ml and administered either subcutaneously or intravenously without dilution. A commonly reported dose in the extracted text is 50 µg/kg given subcutaneously; the intravenous route was also used and appeared to shorten the time of onset and duration of effect without changing the magnitude of the fever. Core temperature was monitored by rectal measurement. Surface temperatures were measured on a shaved area of the rabbit's back (approximately 4 in.2) and on the ear, using a McKesson model 205 Dermalor instrument. To test whether vasoconstriction of the ear accounted for any rise in core temperature, the investigators clamped rabbit ears with hemostats and monitored rectal temperature for up to 6 hr. Several pharmacologic agents were tested for their ability to reduce the LSD-induced fever: antipyrine, dihydroergotamine, Hydergine, dibenamine, and sodium pentobarbital (anesthetic doses). Pentobarbital was used intravenously at 30 mg/kg in experiments examining antagonism of the pyretogenic response. The extracted text does not clearly report sample sizes, randomisation, blinding, or formal statistical methods. Timing observations reported in the prose include onset, peak, and total duration of the temperature response, but no inferential statistics or variability estimates are provided in the available extraction.

Administration of LSD produced a rise in rectal (core) temperature in rabbits, dogs, and cats, with the rabbit showing the most pronounced effect. After subcutaneous injection of 50 µg/kg in the rabbit, core temperature began to increase within 10–20 minutes, reached a peak after 2–4 hours, and the total duration of the pyretogenic action lasted about 7–9 hours. Use of the intravenous route shortened the latency to onset and the duration of the response, but the magnitude of the fever was reported as not significantly different between routes. Surface temperature over a shaved area of back skin did not change significantly in LSD-treated rabbits, whereas ear temperature fell markedly and remained depressed well beyond the period of elevated rectal temperature. Clamping the ears with hemostats in a normal rabbit produced no change in rectal temperature over 6 hours, suggesting that reduced heat loss via the ears was unlikely to be the primary cause of the LSD-induced rise in core temperature. Several pharmacologic attempts to attenuate the fever were unsuccessful: antipyrine, dihydroergotamine, Hydergine, and dibenamine did not reduce the LSD-induced temperature rise. In contrast, intravenous sodium pentobarbital at 30 mg/kg markedly antagonised the pyretogenic effect. When pentobarbital was administered before LSD, the pyretogenic response was prevented for as long as the animal remained anaesthetised; administration of pentobarbital at the height of the temperature increase reduced the fever and restored temperature to approximately normal. The extraction also notes the initial observation of marked hyperpnea in intact rabbits treated with LSD, which motivated the thermoregulatory measurements. The extracted text does not provide numerical sample sizes, measures of variance, or statistical test results.

The investigators regard the pyretogenic effect of LSD as reproducible and dependable in their animal studies, contrasting with prior inconsistent reports in humans and other intact animals. They propose that the fever could either be a component of LSD's central nervous system action or a separate side effect unrelated to its primary hallucinogenic properties. The persistent fall in ear temperature alongside an elevated rectal temperature argues against a simple peripheral vasoconstriction-mediated reduction of heat loss as the sole mechanism; this interpretation was supported by the ear-clamping experiment, which did not alter rectal temperature. Pharmacologically, the authors note that the LSD-induced fever was not antagonised by antipyrine or by several agents tested, but was markedly suppressed by an anaesthetic dose of pentobarbital. This observation suggests a central mechanism sensitive to general anaesthesia, although the precise pathways remain undefined. The authors acknowledge ongoing work to determine the mechanism of the pyretogenic response and to evaluate whether this reliably measurable effect could serve as a useful end-point in further pharmacological studies of LSD. The extracted text does not report formal limitations such as sample size, statistical power, or potential species-specific generalisability, although the authors emphasise that the rabbit was preferentially used because of the pronounced response seen in that species.

Lysergic acid diethylamide produces a rise in body temperature in normal rabbits, cats, and dogs. This pyretogenic effect is antagonised by intravenous sodium pentobarbital but is not reduced by antipyrine or by the other agents tested in these experiments. The investigators suggest the effect could be exploited as a pharmacologic end-point while further studies investigate its mechanism.