Administration Of LSD Research Articles

Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants

BackgroundLSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited.ObjectiveThis study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants.Methods and materialsData from 142 healthy subjects enrolled in six double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA, and d-amphetamine; 31 subjects received LSD and psilocybin; and 25 subjects received psilocybin and escitalopram. At the end-of-study visit (mean 39.8 days after last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6).ResultsThirteen out of 142 subjects reported reoccurring drug-like experiences (LSD: seven, psilocybin: two, both: four). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. Two subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD.ConclusionReoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.

Safety pharmacology of acute LSD administration in healthy subjects

RationaleLysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache.ObjectivesSafety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects.MethodsWe conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies.ResultsLSD dose-dependently increased subjective, physiologic, and adverse effects. The dose–response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena.ConclusionsThe single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.

Decreased directed functional connectivity in the psychedelic state

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.

Altered network hub connectivity after acute LSD administration.

LSD is an ambiguous substance, said to mimic psychosis and to improve mental health in people suffering from anxiety and depression. Little is known about the neuronal correlates of altered states of consciousness induced by this substance. Limited previous studies indicated profound changes in functional connectivity of resting state networks after the administration of LSD. The current investigation attempts to replicate and extend those findings in an independent sample. In a double-blind, randomized, cross-over study, 100 μg LSD and placebo were orally administered to 20 healthy participants. Resting state brain activity was assessed by functional magnetic resonance imaging. Within-network and between-network connectivity measures of ten established resting state networks were compared between drug conditions. Complementary analysis were conducted using resting state networks as sources in seed-to-voxel analyses. Acute LSD administration significantly decreased functional connectivity within visual, sensorimotor and auditory networks and the default mode network. While between-network connectivity was widely increased and all investigated networks were affected to some extent, seed-to-voxel analyses consistently indicated increased connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These latter observations are consistent with findings on the importance of hubs in psychopathological states, especially in psychosis, and could underlay therapeutic effects of hallucinogens as proposed by a recent model.

Antioxidant Effect of Sericin in Brain and Peripheral Tissues of Oxidative Stress Induced Hypercholesterolemic Rats.

This study evaluated the antioxidant effect of crude sericin extract (CSE) from Antheraea assamensis in high cholesterol fed rats. Investigation was conducted by administering graded oral dose of 0.25 and 0.5 gm/kg body weight (b.w.)/day of CSE for a period of 28 days. Experiments were conducted in 30 rats and were divided into five groups: normal control, high cholesterol fed (HCF), HCF + 0.065 gm/kg b.w./day fenofibrate (FF), HCF + sericin 0.25 gm/kg b.w./day (LSD), and HCF + sericin 0.5 gm/kg b.w./day (HSD). In brain, heart, liver, serum, and kidney homogenates nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), superoxide dismutase, reduced glutathione (GSH) was measured. LSD treatment prevented the alterations in GSH and PCC levels in hypercholesterolemic (HyC) brain tissue homogenates of rats. CSE lowers the serum total cholesterol level in HyC rats by promoting fecal cholesterol (FC) excretion. CSE increases FC level by promoting inhibition of cholesterol absorption in intestine. The endogenous antioxidant reduced significantly and the oxidative stress marker TBARS level increases significantly in the peripheral tissue of HCF rats. However, the administration of LSD and HSD exhibited a good antioxidant activity by reducing the TBARS level and increasing the endogenous antioxidant in peripheral tissue. In addition, a histological examination revealed loss of normal liver and kidney architecture in cholesterol fed rats which were retained in sericin treated groups. The findings of this study suggested that CSE improves hypercholesterolemia in rats fed a HyC diet. Clinical relevance of this effect of CSE seems worthy of further studies.

Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide.

This paper reports on the effects of LSD on mental time travel during spontaneous mentation. Twenty healthy volunteers participated in a placebo-controlled crossover study, incorporating intravenous administration of LSD (75 μg) and placebo (saline) prior to functional magnetic resonance imaging (fMRI). Six independent, blind judges analysed mentation reports acquired during structured interviews performed shortly after the functional magnetic resonance imaging (fMRI) scans (approximately 2.5 h post-administration). Within each report, specific linguistic references to mental spaces for the past, present and future were identified. Results revealed significantly fewer mental spaces for the past under LSD and this effect correlated with the general intensity of the drug's subjective effects. No differences in the number of mental spaces for the present or future were observed. Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past. These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one's past, likely mediated by DMN functioning, is symptomatic.

An animal model of schizophrenia based on chronic LSD administration: Old idea, new results

Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as “clearly a paranoid state.” We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.

Interaction between LSD and dopamine D2/3 binding sites in pig brain

The psychoactive properties of the hallucinogen LSD have frequently been attributed to high affinity interactions with serotonin 5HT2 receptors in brain. Possible effects of LSD on dopamine D2/3 receptor availability have not previously been investigated in living brain. Therefore, we used PET to map the binding potential (pB) of [11C]raclopride in brain of three pigs, first in a baseline condition, and again at 1 and 4 h after administration of LSD (2.5 microg/kg, i.v.). There was a progressive treatment effect in striatum, where the pB was significantly reduced by 19% at 4 h after LSD administration. Concomitant maps of cerebral blood flow did not reveal significant changes in perfusion during this interval. Subsequent in vitro studies showed that LSD displaced [3H]raclopride (2 nM) from pig brain cryostat sections with an IC50 of 275 nM according to a one-site model. Fitting of a two-site model to the data suggested the presence of a component of the displacement curves with a subnanomolar IC50, comprising 20% of the total [3H]raclopride binding. In microdialysis experiments, LSD at similar and higher doses did not evoke changes in the interstitial concentration of dopamine or its acidic metabolites in rat striatum. Together, these results are consistent with a direct interaction between LSD and a portion of dopamine D2/3 receptors in pig brain, possibly contributing to the psychopharmacology of LSD.

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

Assessment of the serotonin reuptake blocking property of YM992: electrophysiological studies in the rat hippocampus and dorsal raphe.

YM992 is a selective serotonin (5-HT) reuptake inhibitor and a 5-HT(2A) antagonist with potential antidepressant activity. As expected from a 5-HT reuptake inhibitor, which induces an accumulation of 5-HT in the dorsal raphe, YM992 inhibited the firing activity of these 5-HT neurons (ED50: 2.0+/-0.2 mg/kg, i.v.). This effect was reversed by the 5-HT(1A) antagonist WAY 100635. YM992 also dose-dependently prolonged the time for CA3 neurons to recover 50% of their firing rate following microiontophoretic applications of 5-HT, a reliable index of the function of the 5-HT reuptake carrier. In a second series of experiments, the adaptative properties of 5-HT neurons were examined during sustained administration of YM992 (20 mg/kg/day, s.c., delivered by osmotic minipumps) after 2 days of treatment. YM992 decreased by more than 60% the firing activity of the 5-HT neurons. There was a partial recovery of firing after 7 days and a complete one after 14 days of treatment in the presence of the minipump still delivering the drug. In a third series of experiments, the sensitivity of pre- and postsynaptic 5-HT(1A) receptors in the dorsal raphe and the dorsal hippocampus were assessed. The results showed that YM992 attenuated the inhibitory effect of intravenous administration of LSD and the 5-HT(1A) agonist 8-OH-DPAT on the firing activity of 5-HT neurons. As did the selective 5-HT reuptake inhibitor fluvoxamine, YM992 markedly increased the effectiveness of the electrical stimulation of ascending 5-HT fibres on firing activity of the postsynaptic hippocampus pyramidal neurons. This enhancement of 5-HT neurotransmission by YM992 was attributable to a desensitization of the terminal 5-HT(1B) autoreceptors since the postsynaptic 5-HT(1A) receptors in the hippocampus remained normosensitive.

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine—I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT 1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED 50 = 9.1 ± 1.1 μg/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA 3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT 1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT 1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT 1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT 1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT 1A receptors.

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonist d-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 and beta-adrenergic antagonist d,l-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 micrograms/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 micrograms/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. (ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intraocular mescaline and LSD on visual-evoked responses in the rat.

The effects of mescaline and LSD on the flash-evoked cortical potential (FEP) were determined in unrestrained rats with chronically-implanted electrodes. Systemic administration of mescaline or LSD significantly attenuated the primary component of the FEP at three stimulus intensities with the greatest effect observed 60-90 minutes following drug administration. The magnitude and specificity of the effects of these agents on the primary response suggest that they produce deficits in conduction through the retino-geniculato-cortical system. The serotonin receptor antagonists, cyproheptadine and methysergide, antagonized the mescaline-induced depression of the FEP in accordance with neurochemical and behavioral evidence that mescaline acts as a partial agonist on serotonin receptors. Topical or intraocular administration of atropine antagonized the actions of systemically-administered mescaline. In addition, intraocular administration of mescaline or LSD attenuated the FEP indicative of an action of these hallucinogens on visual processing in the retina which is modulated by muscarinic receptor activity.

Effects on in vitro brain protein synthesis of a translational inhibitor isolated from rabbit brain following intravenous administration of LSD.

Inhibition of brain protein synthesis following intravenous administration of d-lysergic acid diethylamide (LSD) is accompanied by generation of a translational inhibitor protein in the postribosomal supernatant of cerebral hemispheres. Addition of an enriched preparation of this factor to a brain cell-free translation system resulted in a selective reduction in the level of phosphorylation of proteins of molecular weight 55K, 41K, and 25K. A similar set of changes was also observed in a brain cell-free system prepared 1 hr subsequent to drug injection. The brain inhibitor reduced the translational capacity of a messenger RNA-dependent reticulocyte lysate programmed with brain polysomes isolated from saline-injected animals however little effect was apparent when polysomes were prepared from LSD-treated animals. The translational inhibitor did not affect the spectrum of translation products from either set of polysomes.

Changes in body temperature after administration of antipyretics, LSD, Δ 9-THC and related agents: II

Antipyretics, in particular acetaminophen, aspirin and ibuprofen, constitute the single most important class of drugs used therapeutically for an effect on body temperature. Hallucinogens exert prominent actions on the central nervous system, and it is not surprising that, like so many other centrally-acting agents, they too often affect temperature. This compilation primarily covers the considerable amount of data published from 1981 through 1985 on the interactions of these drugs and thermoregulation, but data from many earlier papers not included in a previous compilation are also tabulated. The effects of agents not classically considered as antipyretics on temperatures of febrile subjects are also covered. The information listed includes the species used, the route of administration and dose of drug, the environmental temperature at which experiments were performed, the number of tests, the direction and magnitude of change in body temperature and remarks on special conditions, such as age or brain lesions. Also indicated is the influence of other drugs, such as antagonists, on the response to the primary agent.

Involvement of the central serotoninergic system in the changes of leu-enkephalin level in discrete rat brain areas

The effects of acute and chronic treatment with LSD and acute treatment with mescaline, m-CPP, citalopram and fenfluramine on leu-enkephalin /LENK/ content in rat brain were examined. The acute LSD treatment was found to decrease and chronic treatment to increase the LENK content in the frontal cortex. In the thalamus with hypothalamus the LENK level fell after the administration of LSD, mescaline, citalopram and fenfluramine, while in the str̂iatum it increased significantly, except for fenfluramine treatment. Methergoline and methiothepin prevented the effects of acute and chronic LSD administration. The diminished LENK level was associated with a decrease of 5-HT or 5-HIAA content in the rat brain areas investigated. Therefore, it has been concluded that the serotoninergic system may modulate the LENK pathway.

Separation of tolerance to the behavioral effects of LSD from changes in serotonin receptor binding in rats

Nearly complete tolerance to a test dose of 50 μg/kg of LSD occurred within 24 h following an initial dose of 50 μg/kg of the drug, using limb flicking and abortive grooming as behavioral indices in the cat. No changes in serotonin receptor binding were observed at this time. However, chronic administration of LSD (50 μg/kg every 12 h for 6 days) produced a significant decrease in serotonin receptor binding in both the forebrain and brainstem plus spinal cord. These data suggest that the behavioral effects of LSD and tolerance to LSD as measured here are mediated predominantly by different sites.

Tolerance to the behavioral effects of bromocriptine in cats.

Repeated daily administration of LSD and related hallucinogens produces tolerance to their behavioral effects. The objective was to test whether repeated administration of bromocriptine (BC) produced behavioral tolerance. Experiments began after 4 weeks of habituation and baseline measurements. Cats were then injected daily with BC (10 mg/kg i.p.) for 7 days. The frequency of 40 different behaviors and neurological signs were scored for 60 min after one h post-injection. There was a rapid tolerance to the 'emergent' behavior induced by BC. In the case of hallucinatory-like behavior/escape, tolerance to a second dose of BC one day after a first dose was virtually complete. A substantial tolerance to BC effects such as abortive grooming, increased investigatory-play behavior and grooming occurred within one day. The decrease in sleep produced by BC was absent at the fourth day. Limb flicks and body shakes decreased but persisted until the seventh day. There was also tolerance to emotional behavior (irritability, rage, threat, flight) but motor effects (circling, ataxia, hypokinesia) remained throughout the week. Autonomic reactions were unaffected by BC. The results indicated that the psychotomimetic effects (but not the motor or autonomic) of BC showed rapid and long-lasting tolerance. These studies suggest that BC-induced alterations in cats parallel parameters of action of hallucinogens in humans.

Comparison of the effects of LSD and lisuride on A10 dopamine neurons in the rat

Extracellular single-unit recording techniques were used to compare the effects of d-lysergic acid diethylamide (LSD) and its non-hallucinogenic congener lisuride hydrogen maleate (LHM) on the activity of dopamine (DA) neurons in the A10 region of the rat ventral tegmental area. Lisuride hydrogen maleate potently suppressed the firing rates of A10 DA cells (ID 50 = 0.021 mg/kg). The DA antagonist haloperidol prevented, but did not reverse, the effect of lisuride. In addition, the DA agonist apomorphine was unable to suppress further the firing rates of A10 DA cells that had been partially suppressed by small doses of lisuride. These results suggest that lisuride acted as a non-competitive or irreversible DA agonist. In contrast to lisuride, LSD exerted mixed effects on A10 DA cells, partially depressing the firing rates of 54% of the cells tested, increasing the firing rates of 23% of the cells and exerting no effect on the other 23%. The response of a particular A10 DA cell to administration of LSD was dependent upon its baseline firing rate. Haloperidol readily reversed the LSD-induced partial suppression of the firing of A10 DA cells. Also, LSD effectively reversed apomorphine-induced suppression and increased the doses of apomorphine required to suppress firing of A10 DA neurons. These results suggest that, in addition to its weak DA agonist effects, LSD also exerted partial DA antagonist effects. Pharmacological and physiological manipulations of serotonergic neuronal systems failed to implicate a role for serotonin in the effects of LSD and lisuride on A10 DA neurons. These qualitative and quantitative differences between the effects of LSD and lisuride on A10 DA neurons suggest that the potent DA agonist actions of lisuride may contribute to its lack of hallucinogenic potential.

8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity

It was demonstrated that the simplified ergot congener 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, is able to elicit pronounced biochemical and behavioural alterations indicative of central serotoninomimetic activity. Since these effects are resistant to prior monoamine depletion and/or synthesis inhibition by means of reserpine andα-propyldopacetamide (H22/54), respectively, they are most likely to be attributable to direct serotonin-receptor agonism by 8-OH-DPAT. With regard to central 5-HT neurotransmission the effects of 8-OH-DPAT-increased 5-HT levels, decreased 5-HIAA levels, 5-HT-synthesis rate and 5-HT utilization and inhibited 5-HT neuronal firing-are virtually identical, and comparable in potency, to those reported to result from the administration of lisuride or LSD. In contrast, however, to lisuride and LSD (included for comparative purposes in this study) as well as to several differently N-substituted, 5,6-dihydroxy, 6,7-dihydroxy and 5-, 6- and 7-monohydroxy 2-aminotetralins, 8-OH-DPAT lacks appreciable effects on central catecholamine receptors. The compound may thus be regarded the most potent, selective centrally acting 5-HT agonist described to date. accordance with this it was shown that the full-blown 5-HT-like behaviour syndrome induced by 8-OH-DPAT cannot be antagonized by reserpin phenoxybenzamine, propranolol and haloperidol. In addition, of the truputative 5-HT-receptor blockers cyproheptadine, methergoline and methrothepin only the latter was able to counteract the 8-OH-DPAT-induce syndrome. The results are discussed in relation to the recent subclassification of central 5-HT receptor sites. A comparison between the chemical structures and biological activities for different fragments of the ergot nucleus was also made. The data suggest, in that while the role of the A ring in the ergot structure for dopaminer activity at present is unclear, this ring may be important for the 5-HT-receptor activity like in e.g. lisuride and LSD. Moreover, based on the present results and literature reports, it is speculated that a selective 5-HT-receptor agonist such as 8-OH-DPAT would be liable to induce hallucinations in man.