Doses Of Lysergic Acid Diethylamide Research Articles

Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity

BackgroundThe practice of “microdosing,” or the use of repeated, very low doses of lysergic acid diethylamide (LSD) to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. MethodsThe present study was designed to examine the effects of a single low dose of LSD (13 μg) versus placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, 18 to 35 years old, participated in 2 functional magnetic resonance imaging scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state blood oxygen level–dependent and arterial spin labeling scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. ResultsLSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala–middle frontal gyrus connectivity strength. ConclusionsThese preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug’s purported antidepressant effect.

Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and d-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and d-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), d-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than d-amphetamine, and d-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and d-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and d-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and d-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with d-amphetamine. d-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or d-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and d-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

The Effects of Low Doses of Lysergic Acid Diethylamide in Healthy Humans: Demystifying the Microdosing of Psychedelics

SEE CORRESPONDING ARTICLE ON PAGE 792 Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human VolunteersBiological PsychiatryVol. 86Issue 10PreviewNumerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100–200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0–26 μg) on mood and behavior in healthy volunteers under double-blind conditions. Full-Text PDF

Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers

BackgroundNumerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100–200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0–26 μg) on mood and behavior in healthy volunteers under double-blind conditions. MethodsHealthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed. ResultsLSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. ConclusionsSingle microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.

Cessation and reduction in alcohol consumption and misuse after psychedelic use.

Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders. To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use. An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non-clinical settings. 343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress. Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects.

Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes.Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study.Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo.Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.

Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

Background:The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice.Methods:We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects.Results:Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4ng/mL) were reached (median, range) 1.5 (0.5–4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance.Conclusions:These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide.

Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials

Assessments of lysergic acid diethylamide (LSD) in the treatment of alcoholism have not been based on quantitative meta-analysis. Hence, we performed a meta-analysis of randomized controlled trials in order to evaluate the clinical efficacy of LSD in the treatment of alcoholism. Two reviewers independently extracted the data, pooling the effects using odds ratios (ORs) by a generic inverse variance, random effects model. We identified six eligible trials, including 536 participants. There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36-2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I² = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.

Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration

Lysergic acid diethylamide (LSD) is a psychoactive drug that transiently alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia. Characterizing gene expression profiles after LSD will be important for understanding how it alters behavior, and will lead to novel insights into disorders, such as schizophrenia, whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs. We previously identified a small collection of genes within the rat prefrontal cortex that respond to LSD. Many of the products of these genes are involved in the process of synaptic plasticity. In the current report, we present a detailed analysis of the expression of these genes within the brain using RNase protection analysis. We find that the gene response to LSD is quite dynamic. The expression of some genes increases rapidly and decreases rapidly, while other genes change more gradually. Dose–response studies show two classes of expression; gene expression maximally stimulated at lower doses, versus gene expression that continues to rise at the higher doses. The role of the 5-HT 1A and 5-HT 2A receptor in mediating the increases in gene expression was examined in a series of experiments using receptor specific antagonists. Most expression increases were due to activation of the 5-HT 2A receptor, however expression of two genes had neither a 5-HT 1A nor a 5-HT 2A receptor component.

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including hallucinations and detachment from reality. These remarkable behavioral effects have many similarities to the debilitating symptoms of neuropsychiatric disorders such as schizophrenia. The effects of hallucinogens are thought to be mediated by serotonin receptor activation; however, how these drugs elicit the unusual behavioral effects remains largely a mystery, despite much research. We have undertaken the first comprehensive analysis of gene expression influenced by acute LSD administration in the mammalian brain. These studies represent a novel approach to elucidate the mechanism of action of this class of drugs. We have identified a number of genes that are predicted to be involved in the processes of synaptic plasticity, glutamatergic signaling and cytoskeletal architecture. Understanding these molecular events will lead to new insights into the etiology of disorders whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs, and also may ultimately result in new therapies.

Poisonous Plants: When They Are a Threat to Children

Poisonous Plants: When They Are a Threat to Children

LSD produces place preference and flavor avoidance but does not produce flavor aversion in rats.

The hedonic properties of lysergic acid diethylamide (LSD) were assessed using the place conditioning, taste reactivity, and taste avoidance tests. LSD produced a conditioned place preference, but only at the highest dose tested (0.2 mg/kg). A single preexposure to the conditioning chamber (latent inhibition) prevented the establishment of a place preference. When paired with sucrose, doses of 0.05 to 0.2 mg/kg of LSD produced taste avoidance, but no dose of LSD produced an aversion to the taste as assessed by the taste reactivity test. These results suggest that LSD, like other rewarding drugs, produces taste avoidance by a mechanism other than that produced by emetic drugs.

Electrophysiological assessment of putative antagonists of 5-hydroxytryptamine receptors: a single-cell study in the rat dorsal raphe nucleus

The intravenous administration of low doses of lysergic acid diethylamide (LSD) or of the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) depresses the firing activity of dorsal raphe 5-HT-containing neurons, presumably via the activation of 5-HT1A receptors. The present studies were undertaken to determine the effect of different types of 5-HT receptor antagonists on this effect of LSD and 8-OH-DPAT. (-)-Propranolol (2 mg/kg i.v.), methiothepin (2 mg/kg i.p., twice daily for 4 days followed by an additional dose of 2 mg/kg i.p., prior to the experiment), pelanserine (0.5 mg/kg i.v.), and indorenate (125 micrograms/kg i.v.) failed to block the effects of either LSD or 8-OH-DPAT on the firing activity of 5-HT neurons of the dorsal raphe nucleus. However, spiperone (1 mg/kg i.v.) significantly reduced the effect of both LSD and 8-OH-DPAT. These results indicate that, among the five putative 5-HT receptor antagonists tested, only spiperone can antagonize the suppressant effect of 5-HT receptor agonists on the firing of dorsal raphe 5-HT neurons.

Evidence for antiserotonergic properties of yohimbine

Yohimbine (YOH) is a widely used pharmacological tool employed to produce a selective blockade of alpha 2-adrenergic receptors. In the present study operant behavior was used as a biobehavioral assay to determine the activity of YOH at serotonergic receptors, as indicated by its ability to antagonize the behavioral effects of a serotonergic agonist, lysergic acid diethylamide (LSD). Rats were trained to respond on a Fixed Ratio 15 schedule for food reinforcement. YOH (0.5–5.0 mg/kg) or vehicle and LSD (50 μg/kg) were administered (IP) 30 min and immediately prior, respectively, to the 30-min operant session. In a separate study, the ability of YOH (0.5–2.5 mg/kg) to antagonize a higher dose of LSD (100 μg/kg) was examined. Relatively low doses of YOH (0.5–1.0 mg/kg) were able to partially, but significantly antagonize the LSD-induced suppression and typical hallucinogen-induced disruption of schedule-controlled responding. These results suggest that YOH, even at moderate doses, may act nonselectively as an antagonist at 5-HT receptors, in addition to its antagonist action at alpha 2-adrenergic receptors. This study demonstrates the utility of operant behavior as a biobehavioral assay to study the receptor mediated action of drugs.

The effects of intracranial administration of hallucinogens on operant behavior in the rat I. lysergic acid diethylamide

Lysergic acid diethylamide (LSD) was infused in one μl volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted with stainless steel cannulae aimed at the brain area to be examined. Bilateral cannulae were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surbery, LSD (8.6 to 86 μg) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 μg for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 μg. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion. The time-course of effects of equivalent doses of LSD was shorter than the 40-min operant session for IP, ICV, dorsal raphe, lateral habenula, and dorsal hippocampus administrations. However, median raphe and prefrontal cortex infusions of comparable doses increased pausing throughout the 40-min session. The dose-response curve for IP administration of LSD was shifted to the left in animals with cannulae in dorsal raphe or prefrontal cortex, whereas no changes were seen in the response to IP administration of LSD in animals cannulated in the other sites. These data suggest that the disruption of operant behavior by LSD may have important components of activity in the dorsal raphe, median raphe and the prefrontal cortex. Nevertheless, it seems likely that LSD acts at multiple brain sites simultaneously in order to induce these behavioral effects.

Behavioral effects of intracerebroventricular administration of LSD, DOM, mescaline or lisuride

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 μg) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 μg. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 μg). DOM (40 to 120 μg) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 μg ICV vs. 153 μg IP). Mescaline was much more potent in disrupting c intervals was 74 μg, in contrast to an ED50 following systemic administration of 2551 μg, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 μg ICV and 4 μg IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals. The highest dose produced a peak effect early after ICV administration while IP administration produced a peak effect late in the session. These data suggest differences in the sites of action of these drugs. Alternatively, the differences in the relative efficacies of ICV administration of LSD, DOM, mescaline and lisuride may reflect differences in rates of distribution and/or metabolism of these drugs.

Morphologic alterations in the Purkinje neuron of the rat induced by lysergic acid diethylamide and fixation

The effect of lysergic acid diethylamide (LSD) on the morphology of the cerebellar cortex of the rat was studied with electron microscopy. Hippocampal electrical activity was used as an objective measure of drug efficacy. At a dose of 1700 μg/kg, the amplitude from the hippocampus was diminished (in 2 to 5 min) and this effect lasted for about 65 to 165 min. A morphologic alteration consisting of cisternal stacks occurred in the dendrites of Purkinje neurons of rats treated with this dose of LSD, with the perfusion carried out correctly. These stacks of smooth endoplasmic reticulum were seen 2 h after injection and persisted for at least 8 h. A reduction in the volume of perfused fluid to less than 500 ml caused similar changes in the dendrites of the Purkinje neuron of untreated rats; this was one way to experimentally induce a faulty perfusion. With LSD and faulty perfusion (reduced volume) more severe changes occurred in the dendrites and small stacks of smooth endoplasmic reticulum were seen in the Purkinje soma; similar changes were also seen when the perfusion of a control animal was mismanaged during the initial 3 min. The Purkinje neuron seems to manifest morphologic alterations, generally of two types, with exposure to a variety of noxious agents. The LSD caused some perturbation of this neuron, and this was found under properly controlled conditions of fixation. The results are interpreted as indicating that LSD is causing a metabolic alteration which could disrupt the synaptic activity over several hours.

Progesterone Enhancement of Lysergic Acid Diethylamide and Levo-5-Hydroxytryptophan Stimulation of the Copulatory Response in the Female Rat

Copulatory behavior in the ovariectomized rat, i.e. the lordosis response (LR) on being mounted by a male, can be induced by administration of either estrogen alone or estrogen followed by progesterone. LR has been shown to be inhibited by lysergic acid diethylamide (LSD) in certain doses (greater than or equal to 50 micrograms/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (greater than or equal to 2.5 mg/kg). This effect was recently found to be enhanced by increasing doses of progesterone. In contrast, small doses of LSD (5-30 micrograms/kg) have been shown to increase LR activated by estrogen alone. The effects of various hormone treatments on the stimulatory action of LSD were tested in the present study. When the lordosis behavior was activated by estradiol benzoate (EB) alone (25 or 7 X 2 micrograms/kg), LR increased 10 min after injection of LSD in a dose of 10 micrograms/kg. There were no detectable effects in animals treated with estrogen alone when the dose of LSD was lowered to 1 microgram/kg. LSD in the latter dose gave an increased response, however, when LR was activated by EB (5 micrograms/kg) in combination with progesterone (4.0 mg/rat). An analogous study was conducted with L-5-HTP, after pretreatment with pargyline and R04-4602. Small doses of L-5-HTP (0.25 and 0.05 mg/kg) stimulated the LR and the influence of progesterone was the same as for small doses of LSD. Possible mechanisms underlying the observed influence of progesterone on serotonergic mechanisms involved in the lordosis behavior are discussed.

Modification of apomorphine hypothermia by drugs affecting brain 5-hydroxytryptamine function

Intraperitoneal administration of apomorphine caused hypothermia in mice. Pretreatment with the serotonin (5-HT) receptor antagonists methysergide (3 mg/kg), cinanserin (10 mg/kg) or brom-LSD (3 mg/kg) potentiated this response of apomorphine. Brain 5-HT depletion by p-chlorophenylalanine caused similar modification. On the contrary, the 5-HT receptor agonists quipazine (3 mg/kg) and MK-212 (3 mg/kg), significantly blocked apomorphine hypothermia. It was concluded that 5-HT modulates the dopamine (DA)-mediated body temperature changes and that drug-induced alterations in the brain 5-HT function modify apomorphine-induced hypothermia in a predictable manner. One mg/kg dose of lysergic acid diethylamide (LSD) blocked apmorphine hypothermia. The apomorphine-blocking effect of both quipazine and LSD developed tolerance. Morever, LSD showed cross tolerance with quipazine. It was concluded that the hypothermia-blocking property of LSD resides on its ability to activate the hypothalamic 5-HT receptors.

A possible role of the serotonergic system in thermoregulation in the rabbit.

Abstract In order to examine the possible role of the serotonergic system in the brain stem on thermoregulation, lysergic acid diethylamide (LSD) was administered intravenously or locally into the nucleus raphe dorsalis (NRD) or the nucleus raphe magnus (NRM) of rabbits at various ambient temperatures. Intravenously administered LSD (12–17 μg/kg) caused hyperthermic responses in the ambient temperatures of 15, 25 and 35°C. The magnitude of these responses was greater between 15 and 25°C than it was at 35°C. Injected locally, LSD also caused an increase in the rectal temperature and a fall in the ear skin temperature. These changes were dependent on the dose of LSD administered in both the NRD and the NRM groups. With local administration of LSD into the NRD, heat production increased slightly even at the ambient temperature of 29°C. On the other hand, no changes occured over the 180 min period following administration of the drug into the NRM. From these results it could be concluded that the afferent input through cold fibers makes a synapse with 5-HT inhibitory receptors on the warm-responsive neurons in the midbrain and also connects with an excitatory synapse in the heat production system. It could also be concluded that LSD acts on these receptors as an agonist or an antagonist, consequently inducing a hyperthermic reaction.