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Tolerance to Lysergic Acid Diethylamide: Overview, Correlates, and Clinical Implications

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Abstract

The first reports on tolerance to the serotonergic hallucinogen lysergic acid diethylamide (LSD) were published half a century ago, yet hitherto, a systematic review on this topic is not available. In this chapter, we discuss tolerance to LSD with regard to its psychedelic and somatic effects in humans, as well as selected behaviors in animals. In humans, mental tolerance to LSD substantially manifests 24 h after its first administration and reaches a maximum by around the fourth day. Once established, tolerance cannot be overcome even if the initial dose is quadrupled. Mental tolerance to LSD generalizes to psilocybin and mescaline but not to tetrahydrocannabinol or amphetamine. As to LSD’s somatic effects, mental tolerance most reliably is accompanied by tolerance to mydriasis. Five days of abstinence is sufficient for tolerance to be reversed; symptoms of withdrawal are not encountered. In animals, LSD-induced shaking behavior, limb flicking, and hallucinogenic pausing are undermined by tolerance, too; the first-mentioned behaviors, for instance, are subject to tachyphylaxis. Mechanistically, pharmacodynamic adaptations of serotonin 5-HT2A and/or (downstream) glutamate receptors are likely to account for tolerance; a learning-related precipitation, however, has also been described. The rapid onset of mental tolerance probably is a main reason LSD generally is not taken on an everyday basis by humans. Given its rapid reversal, on the other hand, a once-per-week abuse cannot be excluded.

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... In the current work, we address the tolerance phenomenon characteristic for repeated hallucinogen application [for a review see 5,33,34]. Tolerance to hallucinogen induced shaking behaviour has often been associated with a downregulation of frontocortical 5-HT 2(A) receptors [35][36][37][38][39]. However, mathematical correlations for this receptor-behaviour association, apart from one study on antagonist related upregulation of both parameters [40], have not been presented. ...
... In humans, tolerance to the psychedelic effect of LSDgiven once a dayoccurs in as little as three days [33,34]. Although described anecdotally only, similar might hold true for DOB, too [51]. ...
... Although described anecdotally only, similar might hold true for DOB, too [51]. In animals, tolerance to hallucinogens inconsistently manifests varying across different behaviours, species, and regimens [for an overview see 33,34]. As to shaking 14 behaviour in SD rats, a once-per-day regimen is not sufficient for tolerance to manifest (data not shown [see 34]) [compare for DOI 52]. ...
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Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25mg/kg, i.p.) induce a ketanserin-sensitive (0.5mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7x in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. Copyright © 2014. Published by Elsevier B.V.
... [morning] and 3.0 mg/kg, i.p. [evening of days 1-3]) per day and HTRs were counted for 20 min after each morning application. The twice-perday regimen, with the increased dose (i.e., 3.0 mg/kg) in the evening, was chosen based on findings for LSD, which indicate that tolerance development is slightly facilitated by a higher frequency of application, but more strongly facilitated by a higher frequency of application with increased dosing every other application (Buchborn et al., 2016). ...
... interval and found a rapid loss of responsiveness to the second injection (compare for LSD and DOI: Darmani and Gerdes, 1995;Buchborn et al., 2016). To test the hypothesis that the observed tachyphylaxis was due to substance accumulation (i.e., two single 1.5 mg/kg doses accumulating to a less active 3.0mg/kg dose), we repeated the experiment injecting a 0.75mg/kg dose (which after thorough animal habituation induced significant HTRs; see Figure 1A) twice at a 1.5-h interval. ...
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The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
... There is also likely to be an optimal dose spacing. Repeated administration of LSD and/or psilocybin leads to rapid tolerance, or tachyphylaxis, of mental effects from 24 h which peaks after just four consecutive daily doses, cannot be overcome even with substantial dose increases or switching to the other substance (cross-tolerance) and is completely reversed by 5 days of abstinence (Buchborn et al., 2016). In rats, high doses of LSD (0.16 mg/kg) given every 2 days for 90 days resulted in hyperactive and asocial symptoms (Martin et al., 2014). ...
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Currently, there are no disease-modifying treatments for Alzheimer’s disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.
... There is also likely to be an optimal dose spacing. Repeated administration of LSD and/or psilocybin leads to rapid tolerance, or tachyphylaxis, of mental effects from 24 h which peaks after just four consecutive daily doses, cannot be overcome even with substantial dose increases or switching to the other substance (cross-tolerance) and is completely reversed by 5 days of abstinence (Buchborn et al., 2016). In rats, high doses of LSD (0.16 mg/kg) given every 2 days for 90 days resulted in hyperactive and asocial symptoms (Martin et al., 2014). ...
Article
Full-text available
Currently, there are no disease-modifying treatments for Alzheimer’s disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.
... These proteins and others might be altered by repeated intake of, e.g. LSD, even in very low doses (Buchborn et al., 2016). Even if this is somewhat speculative, it seems probable. ...
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Psychedelic substances are currently experiencing a renaissance in interest for both therapeutic as well as recreational applications. It has been proposed that microdosing, i.e., ingesting sub-perceptual doses of a psychedelic, could confer some of the benefits of these substances to users while minimizing the risks associated with full-dose use. This review aimed to summarize and examine the extant literature on psychedelic microdosing. Exploratory evidence published to date indicates a variety of benefits reported by microdosers including improvements in mood, focus, and creativity, with some null reports, and a minority of people reporting selective negative consequences such as increased anxiety and physiological discomfort. Methodological limitations of current evidence, however, make definitive conclusions hard to draw. Recommendations for future research are given.
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1. The reactions caused by intramuscular administration of 0.75 mcg/ kg and 1.5 meg/kg of LSD-25 have been compared in the same 10 subjects with those induced by 2.5 mg/kg and 5.0 mg/kg of mescaline. 2. Both LSD and mescaline caused dilatation of the pupils, increase in body temperature, elevation of pulse rate and increase in systolic blood pressure. Both drugs decreased the threshold for elicitation of the kneejerk. 3. After both drugs, similar abnormal mental states characterized by anxiety, difficulty in thinking, alteration in mood (generally euphoric), altered sensory perception (particularly visual), elementary and true visual hallucinations and alterations of body image were reported by the subjects. 4. The effects of mescaline appeared more slowly and persisted somewhat longer than did the effects of LSD. 5. LSD tartrate is 2400–4900 times as potent as mescaline hydrochloride. On a molecular basis, LSD is 4500 to 9275 times as potent as mescaline. 6. Patients receiving LSD daily developed direct tolerance to LSD; such patients were also cross tolerant to mescaline. Likewise patients receiving mescaline daily became tolerant to mescaline and cross tolerant to LSD. 7. It was inferred that LSD, psilocybin and mescaline probably share common mechanisms of action or some common final pathway.
Article
Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.
Article
Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT(2A)-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT(2A)-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT(2A) receptor as measured by a decrease in DOI-elicited head bobs. Acute parenteral or intrahippocampal LSD elicited a 5-HT(2A) but not a 5-HT(2C)-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).
Article
The effect of the following serotoninmimetics: L-5-hydroxytryptophan, LSD, quipazine, fluoxetine, paroxetine and fenfluramine on the duration of immobility in the so-called behavioral despair test in rats was studied. Only fenfluramine, like imipramine, reduced the immobility but this effect was antagonized by pretreatment with haloperidol. All the other drugs examined had either no effect or prolonged the immobility. These data suggest that the effect regarded as typical of antidepressants cannot be induced by serotoninmimetics.
Article
Repeated administration of LSD to rats (100 μg/kg every 6 hours for 4 days) resulted in significant decreases in both the KD (−17 & −23%) and Bmax (−25 %& −30%) for [3H]—5HT binding in forebrain and brainstem plus spinal cord. [3H] — LSD binding showed significant changes in Bmax values (−19%) in forebrain and brainstem plus spinal cord, while KD values were not significantly changed. Neither a single injection of LSD (100 μg/kg) nor repeated administration of brom-LSD (100 μg/kg every 6 hours for 4 days) produced any significant changes in binding. In addition, repeated LSD administration produced no significant changes in [3H] — spiroperidol binding.
Article
MDA (2.0 and 2.2 mg/kg) was compared to LSD (10 microgram/kg) and d-amphetamine (3.2 mg/kg) in single dose, antagonism, cross tolerance and appetite suppression studies. In single doses MDA specifically resembled d-amphetamine by producing marked mydriasis, nictitating membrane retraction, stereotypy and darting eye movements and LSD by markedly facilitating the flex or reflex, producing continuous stepping, whining and eye tracking movements. LSD and MDA increased respiration, body temperature and the latency of the skin twitch reflex and produced behavioral arousal. Cyproheptadine antagonized the effects of LSD but was ineffective against MDA. Phenoxybenzamine antagonized the respiratory, pupillary and hyperthermic effects of MDA and the respiratory effect of LSD. Chlorpromazine antagonized many of the effects of LSD and MDA. Spinal dogs were made tolerant to the behavioral and physiologic effects of LSD. Cross tolerance developed to some but not all of the effects of MDA. In intact dogs MDA was 1/10 as potent as d-amphetamine in suppressing appetite. It is concluded that MDA has properties resembling both LSD and amphetamine.
Article
LSD elicits a number of emergent behaviors in the cat, including limb flicking, abortive grooming, investigatory and hallucinatory-like behaviors, which we have proposed as an animal behavior model for studying the actions of LSD and related hallucinogens. These emergent behaviors were used in the present study to investigate the duration of action of LSD, as well as the onset and duration of tolerance. A dose of 10 microgram/kg of LSD produced significant behavioral changes for up to 4h, while a dose or 50 microgram/kg produced changes lasting for at least 8 h. Tolerance to a test dose of 50 microgram/kg of LSD is virtually complete one day after a single 50 microgram/kg dose, and lasts for approximately 5 days. Tolerance to a test dose of 50 microgram/kh of LSD one day after a single dose of 10 microgram/kg is quite marked, and lasts for approximately 3 days. A significant tolerance to a test dose of 50 microgram/kg of LSD occurs within 2 h after a single injection of 10 microgram/kg. The limb flick was found to be the most sensitive index in all tests: it showed the longest time-course, as well as the most rapid and longest-lasting tolerance. These studies demonstrate that the LSD-induced behavioral syndrome in the cat parallels important parameters of the action of LSD in humans, and thus enhances the usefulness of the model.
Article
A fixed-ratio schedule of water reinforcement (FR-10) was used to examine the relative contributions of pharmacological and behavioral mechanisms in the development of tolerance to the disruptive effects of LSD and mescaline in the rat. Rats treated daily with LSD or mescaline before operant testing developed tolerance to the impairement of responding, while rats treated daily after each session did not display tolerance when the drugs were administered before testing. These results indicate that behavioral compensatory mechanisms may be involved in the development of tolerance to the disruptive effects of LSD and mescaline on fixed-ratio (FR-10) performance.
Article
Lysergic acid diethylamide=25 (LSD) and N,N-dimethyltryptamine (DMT) abolish food-rewarded, fixed-ratio bar pressing by rats in a dose-related fashion. Adult male Holtzman rats trained to press a bar (respond) for milk reward on a 4-response fixed-ratio schedule were given i.p. injections of 3.2 or 10 mg/kg of DMT every 2 hours for 21 days. Every 24 hours the animals were placed in operant chambers for 30 minutes before a scheduled injection and were left in the chambers for 30 to 80 minutes after. During the first week of chronic treatment, daily bar pressing worsened progressively until the 6th day of the series, at which time rats in the 10 mg/kg group did not bar press at all. As the chronic injections continued, rates of bar pressing gradually increased until responding was not disrupted at all by an injection of DMT. Rats in the 3.2 mg/kg group showed cross-tolerance to an injection of LSD (0.1 mg/kg). Another group of rats was made partially tolerant to the disruptive effects of LSD (0.1 mg/kg i.p.) on bar pressing with a series of injections given once per day for 21 days and then three times per day for the next 4 days. Cross tolerance was not demonstrated to a challenge injection of 10 mg/kg of DMT. The LSD injections were continued for another 3 to 5 days until the animals were completely tolerant to the LSD. They then displayed cross-tolerance to 3.2 mg/kg of DMT.
Evidence has been presented that d-amphetamine interacts with various types of behavior in the context of a conditioning paradigm. Rats exposed simultaneously to a locomotor activity measurement and three dose levels of d-amphetamine on repeated occasions gradually developed dose-related enhancement of drug-stimulated activity, which persisted after discontinuation of the drug. Rats trained in FR-operant chambers with food reinforcement showed a decrease in the rate of lever pressing after administration of d-amphetamine. Tolerance to this effect required varying numbers of daily drug injections, according to the subject's degree of prior drug experience. In both situations the drug administrations were coupled with the behavioral measure to allow for conditioning effects. In a continuous avoidance procedure the initial dose of d-amphetamine did not enhance response rate, although subsequent doses did produce significant stimulation. Even when the initial doses were administered out of temporal phase with the avoidance measurement, the simultaneous administration of the drug and the behavioral procedure on a subsequent day resulted in a significant drug-induced stimulation of response rate. Thus, in this particular instance, the conditioning influence of the earlier doses was apparent whether or not the drug effect occurred in contiguity with the avoidance measurement. Other reports in the literature (16) suggest that hallucinogenic drug action may be characterized by the peculiar "pause" in an FR pattern of responding for food reinforcement. This proposal was substantiated and extended to a number of representative hallucinogenic agents. d-Amphetamine or chlorpormazine reduced the rate of FR responding without provoking an obvious pause. Examination of tolerance and cross-tolerance to the hallucinogenic pause in the FR pattern after LSD, mescaline, psilocybin, DOM, and DMT generally indicated interactions between the drugs, although this was not entirely consistent. It follows that the mechanisms of action of these drugs probably have elements in common, though they are not necessarily identical. In doses as small as 10 mg/kg, cinanserin, a serotonergic receptor-blocking agent, completely reversed the pause in FR pattern induced by the various hallucinogenic drugs.
Article
A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.
Article
The regulation of the 5-HT2 receptor-mediated head twitch response and of 5-HT2 receptor binding in the frontal cortex was studied in rats treated repeatedly with the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) (2.5 mg/kg, s.c.). Four injections in 24 h produced a near maximal reduction in the behaviour (-70%) and in the Bmax for [3H]ketanserin binding (-41%). The KD values tended to increase slightly. 5-HT2 receptors reappeared, with half-lives of 5.5 to 3 days. In view of the reported anomalous 5-HT2 receptor regulation by antagonists and the regular regulation by agonists, we propose a refinement in the receptor regulation theory.
Article
Daily administration of D-lysergic acid diethylamide (LSD) was previously shown to decrease serotonin2 (5-HT2) receptor binding in rat brain. Recently, 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropane, the substitution being with either iodine (DOI) or bromine (DOB), have been suggested to be relatively selective 5-HT2 agonists. These compounds share common behavioral and neurophysiological effects with LSD, suggested to be 5-HT2 receptor mediated, and the purpose of the present study was to determine whether they also affect 5-HT2 receptor binding after systemic administration in a similar way to LSD. Administration of DOI (1.0 mg/kg) or DOB (0.5 mg/kg) for 7 days resulted in a decrease in 5-HT2 binding, as evaluated with [3H]ketanserin, similar to the decrease after LSD. In a further evaluation of the parallelism of LSD and 5-HT2 agonists, it was found that 24 hr after one administration of a low dose of LSD (130 ug/kg) or DOI (1.0 mg/kg), there was no change in binding, but there was a decrease 24 hr after a high dose (LSD, 650 micrograms/kg; DOI, 7.0 mg/kg). Four hours after the high dose of LSD or DOI there was also a decrease in 5-HT2 binding. Thus, results have shown that 5-HT2 agonists are capable of down-regulating 5-HT2 receptors and that LSD acts in a parallel fashion. This study has also demonstrated that 5-HT2 receptors can be modified within hours after drug administration.
Article
An animal model for studying the actions of hallucinogenic drugs using primate social colonies is presented. Although hallucinogens induce a number of behavioral changes in this paradigm, one emergent behavior, limb jerks, appears to be selectively induced by three classes of hallucinogens in doses which correlate with those reported to be hallucinogenic in humans. Several non-hallucinogenic congeners of hallucinogens failed to significantly elicit this response. Other behavioral changes induced by hallucinogens in monkeys such as ptosis and social withdrawal may be useful in studying aspects of hallucinogen intoxication other than hallucinations, or psychosis in general. Upon daily administration, tolerance developed to all hallucinogens tested except two, as is seen in humans. Moreover, cross-tolerance between hallucinogens could be demonstrated. Further experiments with the hallucinogen 5-methoxy N,N-dimethyltryptamine revealed that although certain individual behaviors could be antagonized by serotonin antagonists, dopamine antagonists, and physostigmine, no drug completely reversed the behavioral abnormalities induced by this hallucinogen. It is suggested that this paradigm, which offers an hallucinogen-induced behavior which correlates well with the human hallucinogen response and permits observation of a wide variety of other potentially relevant behaviors in primates, may be useful in developing and testing theories of hallucinogenic drug action. It may be especially valuable in view of the present difficulties of conducting hallucinogen research in humans.
Article
The effect of ten daily injections of saline or d-lysergic acid diethylamide (LSD) (260 micrograms/kg i.p.) on serotonin1 (5-hydroxytryptamine1, 5-HT1) and 5-HT2 receptor binding was determined in brain membranes from rats killed 24 h after the last injection. [3H]LSD (3.0 nM) was used with either 30.0 nM 5-HT or 70.0 nM cinanserin to estimate 5-HT1 and 5-HT2 receptors, respectively. LSD administration decreased 5-HT2 binding in cortex, striatum, hippocampus, and diencephalon/midbrain without altering 5-HT1 or total specific binding.
Article
Nearly complete tolerance to a test dose of 50 micrograms/kg of LSD occurred within 24 h following an initial dose of 50 micrograms/kg of the drug, using limb flicking and abortive grooming as as behavioral indices in the cat. No changes in serotonin receptor binding were observed at this time. However, chronic administration of LSD (50 micrograms/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.
Article
The results on the Halstead-Reitan neuropsychological battery were compared for a group of 20 LSD users and a normal control group matched for age, sex, education, and intelligence. Only one of 20 variables was significantly different at the 5 per cent level and this was thought to be due to chance. Thus, it was concluded that there was no difference between the two groups. A further comparison between LSD users and university students yielded no significant difference in the Halstead-Wepman Aphasia Test.
Article
In the past decade there has been rising concern among physicians, lawmakers, clergy and others about the extra-medical use of LSD. Descriptions of heightened creativity due to frequent LSD use at one extreme contrast with warnings of personality deterioration at the other. A multitude of publications have dealt with LSD metabolism, physiology, mechanism of action, behavioral effects, uses in psychotherapy and, more and more, with its adverse effects.1–11 Most of the evidence so far has been from acute studies or from patients with clinical illness related to LSD. We were interested in studying the long-term effects on behavior and mental function in a population that has not had a frank psychiatric disturbance related to LSD. We also wanted to learn more about the actual characteristics of the users themselves, and about the sociological matrix in which this LSD use takes place. We were interested, then, in filling in some of the gaps.
Article
Twenty-one paid volunteers who were chronic users of LSD were interviewed and participated in a series of cognitive and perceptual tests and EEG studies. Among other observations derived from both interviews and testing, the authors noted that the group shared a set of magical-mystical beliefs and profound nonaggressive attitudes, as well as a unique sensitivity to certain types of sensory stimulation. The authors suggest that the beliefs and attitudes of the group may have arisen as learned consequences of frequent, intense LSD experiences in susceptible individuals.
Article
The hypothesis that the action of hallucinogenic drugs is mediated by a depression of the activity of brain serotonergic (raphe) neurons was tested by examining the behavioral effects of several hallucinogenic drugs while concurrently monitoring the activity of raphe neurons in freely moving cats. LSD produced a dose-dependent decrease in raphe unit activity and a dose-dependent increase in certain behaviors (e.g. limb flick and abortive groom), and the peak of the behavioral and unit changes were temporally correlated. However, there were three important dissociations between the behavioral and electrophysiological effects of LSD. Firstly, low doses of LSD produced only small decreases in raphe unit activity but significant behavioral changes. Secondly, the duration of LSD-induced behavioral changes significantly outlasted the depression of raphe unit activity. And thirdly, raphe neurons were at least as responsive to LSD during tolerance as they were in the nontolerant condition. Psilocin produced a dose-dependent decrease in raphe unit activity, while the behavioral changes were not dose-related. However, the peak behavioral changes corresponded to the maximal depression of raphe unit activity. The phenylethylamine hallucinogens, DOM and mescaline, both produced large behavioral changes but no overall effect on raphe neurons. Following administration of DOM or mescaline, some raphe units showed a significant increase, while some showed a significant decrease, and others showed no change in activity. Therefore, the phenylethylamine hallucinogens may exert a depressant effect upon a subset of serotonin-containing neurons, and an amphetamine-like excitatory effect upon another subset of these neurons. Consistent with previous studies, all hallucinogens produced a high concentration of slow waves in the cortical EEG. Following administration of LSD or psilocin, the appearance of slow waves in the EEG was often associated with a transitory decrease in unit activity, while this was not observed for the phenylethylamine hallucinogens. The present data, in conjunction with recent data from other laboratories, suggest that the serotonin hypothesis of hallucinogenic drug action should be re-evaluated.
Article
Tolerance to a test dose of 50 mg/kg of LSD occurred within 0.5-1.0 h following an initial dose of 10 mg/kg of the drug, using limb flicking and abortive grooming as behavioral indices in the cat. These findings represent an example of very rapidly developing drug tolerance using a behavioral index. These data are discussed within the context of hypotheses concerning the neurochemical bases of tolerance to LSD.
Article
Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.0 mg/kg) of the serotonin receptor antagonists mianserin, ketanserin or metergoline effectively blocked behavior, as measured by the cat limb flick response, elicited by either LSD (50 micrograms/kg) or DOM (250 micrograms/kg) but not that resulting either from lisuride (50 micrograms/kg) or a high dose of apomorphine (4 mg/kg). Pretreatment with 1.0 mg/kg of mianserin, which completely attenuated LSD's behavioral effect, failed to alter LSD-induced depression of mesencephalic serotonergic neuron discharge. These results demonstrate that at least some of the behavioral effects of LSD can be blocked by pharmacological antagonism of postsynaptic serotonin receptors which leaves LSD's presynaptic effect unaffected. Thus, the behavioral, and possibly psychoactive, effects of hallucinogens appear to be attributable to an action at 5HT2 receptors, presumably located postsynaptically.
Article
The characteristic behavioral effects of d-lysergic acid diethylamide (LSD) in cats first appeared at approximately 25 days of age and increased rapidly in magnitude over the next 10 days. However, 25 day old kittens showed no tolerance to the repeated administration of the drug. While the behavioral response to the initial dose of LSD remained relatively constant between 35 and 112 days of age, the tolerance gradually became more pronounced throughout this time period, reaching an adult level of virtually complete tolerance at 112 days. These findings provide new insight into the nature of the relationship between the primary drug action and the development of tolerance, and suggest a new strategy for investigating the neural bases of tolerance, i.e., examining the neurochemical effects of repeated LSD administration in kittens during various stages of tolerance development.
Food-deprived male rats were trained to press a bar on a fixed ratio-40 operant schedule for food reinforcement. Administration of 100 μg/kg LSD immediately before the start of the operant session resulted in cessation of responding for some portion of the 40-min test session ('hallucinatory pause'). Four successive days of LSD administration prior to the start of the behavioral session decreased the response to LSD on each succeeding day (tolerance). However, when 100 μg/kg LSD was given to these same animals on three successive days immediately after completion of the operant session, no tolerance was observed on day 4 when LSD was given before the start of the session. These data suggest that, with this particular dosing regimen and behavioral test, a large portion of the tolerance observed following repeated LSD administration results from behavioral adaptation to the drug.
Article
It is well established that repeated administration of both 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists and antagonists decreases the density of 5-HT(2A) and 5-HT(2C) receptors. However, the regulation of these two receptors has not been studied in the same tissue. Therefore, we examined the effects of repeated daily injections of the 5-HT(2) receptor agonists (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and D-lysergic acid diethylamide (LSD) and the antagonists d-2-bromolysergic acid diethylamide hydrogen tartrate (BOL) and alpha-phenyl-2-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939) on rabbit cortical 5-HT(2A) and 5-HT(2C) receptors. Repeated administration of DOI, LSD, or BOL decreased cortical 5-HT(2A) receptor density but had no effect on the density of cortical 5-HT(2C) receptors. Repeated administration of the selective 5-HT(2A) receptor antagonist MDL 11,939 significantly increased 5-HT(2A) receptor density. This unexpected outcome also occurred without any change in cortical 5-HT(2C) receptor density. The down-regulation of 5-HT(2A) receptors produced by chronic administration of BOL was associated with a decrease in DOI-elicited head bobs, whereas 5-HT(2A) receptor up-regulation produced by MDL 11,939 was associated with an increase in DOI-elicited head bobs compared with controls. These studies demonstrate that 5-HT(2A) receptor antagonists can both down- and up-regulate the density of cortical 5-HT(2A) receptors and these changes in receptor density have functional consequences for 5-HT(2A) receptor-mediated behaviors. Furthermore, because DOI, LSD, and BOL have approximately equal affinities for the 5-HT(2A) and 5-HT(2C) receptors, these results suggest that different mechanisms regulate 5-HT(2A) and 5-HT(2C) receptor density, in that chronic occupation of 5-HT(2C) receptors does not modulate their density in rabbit frontal cortex.
Article
1. In two experiments, using a cross-over design, the development of direct tolerance to LSD and psilocybin was measured after 10 (Experiment I) or 9 (Experiment II) volunteers had taken LSD in doses increasing to 1.5 meg/kg over the course of 6–7 days (Experiment I) or 13 days (Experiment II). On another occasion, the same patients received psilocybin in doses increasing to 150 mcg/kg over the course of 6–7 days (Experiment I) or 210 mcg/kg over the course of 13 days (Experiment II). 2. The development of cross tolerance to psilocybin in patients directly tolerant to LSD was measured by challenging the patients, after they had received LSD chronically, with 150 mcg/kg (Experiment I) or 210 mcg/kg (Experiment II) of psilocybin. Cross tolerance to LSD was evaluated by challenging the patients, after they had received psilocybin chronically, with 1.5 meg/kg of LSD. 3. A high degree of direct tolerance to LSD developed in both experiments, as manifested by statistically significant reductions in six of the seven parameters of response. Patients directly tolerant to LSD were also cross tolerant to psilocybin on five (Experiment I) or four (Experiment II) parameters. 4. Definite direct tolerance also developed after chronic administration of psilocybin in both experiments, but statistically significant reductions occurred in fewer parameters of response (four in Experiment I and three in Experiment II) than was the case with LSD. Patients chronically treated with psilocybin were also cross tolerant to LSD on four (Experiment I) or three (Experiment II) measurements. The degree of direct tolerance to psilocybin was less than the degree of direct tolerance to LSD. 5. The development of cross tolerance between LSD and psilocybin reinforces the idea that these two drugs cause psychic disturbances by acting on some common mechanism, or on mechanisms acting through a common final pathway.