Fig 3 - uploaded by Mark Allen Geyer
Content may be subject to copyright.
Effects of lisuride (a) and LSD (b) on prepulse inhibition in rats. (a1) Effect of lisuride (0.0375, 0.075 and 0.15 mg/kg, s.c.) on average prepulse inhibition. (a2) Effects of the selective 5-HT 2A antagonist MDL 11,939 on the disruption of PPI induced by lisuride. (b1) Effect of LSD (0.05, 0.1 and 0.2 mg/kg, s.c.) on average prepulse inhibition. (b2) Effects of the selective 5-HT 2A antagonist MDL 11,939 on the disruption of PPI induced by LSD. Values represent mean±S.E.M. for each group. Drug doses are mg/kg. *p < 0.05, **p < 0.01, significantly different from vehicle control; ## p < 0.01, significantly different from LSD-treated animals. Male Sprague-Dawley rats (250-275 g) were placed in a stabilimeter chamber 30 min after treatment with MDL 11,939, 10 min after treatment with lisuride hydrogen maleate, or 5 min after treatment with LSD tartrate. After a 5 min acclimation period to 65 dB broadband background noise,%prepulse inhibition was assessed using a combination of startle trials (a 40 ms 120 dB pulse of broadband white noise) and prepulse trials (a 20 ms acoustic prepulse at either 68, 71 or 77 dB, an 80 ms delay, and then a 40 ms 120 dB startle pulse) presented in a pseudo-randomized order. Data from Halberstadt and Geyer, 2010.
Source publication
One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT2A receptor. These compounds produce a 'model psychosis' in normal individuals that resembles at least some of the positive symptoms of schizophr...
Context in source publication
Context 1
... recruited by lisuride. Interestingly, although both LSD and lisuride disrupt PPI in rats, they do so by different receptor mechanisms; the PPI disruption induced by lisuride was not blocked by MDL 11,939 or the selective 5-HT 1A antagonist WAY-100635, but was prevented by pretreatment with the selective DA D 2/3 receptor antagonist raclo- pride ( Fig. 3; Halberstadt and Geyer, ...
Similar publications
The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychoti...
The growing interest in the rapid and sustained antidepressant effects of the dissociative anesthetic ketamine and classic psychedelics, such as psilocybin, is remarkable. However, both ketamine and psychedelics are known to induce acute mystical experiences; ketamine can cause dissociative symptoms such as out-of-body experience, while psychedelic...
LSD and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized redu...
Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatr...
Background
Studies have shown evidence for long-term effects of psychedelics on personality, but comprehensive models of psychedelic-mediated personality changes have yet to be explored.
Aims
The present study aims to investigate (1) perceptions of personality change in the general population, (2) moderators of perceived personality change includi...
Citations
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. ...
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. Therefore, we tested whether repeated low doses of psilocybin altered PPI or startle habituation. ...
... High and repeated doses of serotonergic psychedelics are known to modulate pre-pulse inhibition of the acoustic startle reflex and have been used to model this schizophrenia endophenotype [29,31,43]. We found no effects of the psilocybin treatment regimen on pre-pulse inhibition or startle amplitude, and no effect on short-term habituation to the startle reflex. ...
Pharmacotherapy with psilocybin, a serotonergic psychedelic, shows promising benefits in a range of neuropsychiatric disorders. While its psychedelic effects last for a few hours, therapeutic effects of psilocybin can persist long after a single administration in clinical and preclinical studies. We tested the hypothesis that these therapeutic effects entail remodeling of biologically informed rat brain networks related to compulsions and anxiety. Specifically, the cortico-striato-thalamo-cortical (CSTC) network and the cortico-amygdalo-hippocampal-hypothalamus (CAHH) networks. We used serial positron emission tomography (PET) to assess the acute and persistent effects of a single psilocybin dose on glucose metabolism and metabolic connectivity in the CSTC and CAHH networks in rat brain, in relation to the in vivo occupancy at serotonin 5HT2A receptors after acute psilocybin challenge. Notably, we found metabolic changes in two of the main hubs in the CSTC network i.e. thalamus and dorsal striatum accompanied by a persistent change in metabolic connectivity between thalamus and medial prefrontal cortex which may indicate a shift in thalamocortical gating after acute administration of psilocybin. Within the CAHH network, we found an acute metabolic increase in insula after psilocybin administration and a persistent enhancement of metabolic connectivity between the insula and the medial prefrontal cortex, and the ventral hippocampus. Our findings of acute and persistent changes in metabolic activity and connectivity within these networks provide new insights towards understanding the mechanism of the therapeutic effects of psilocybin in a range of neuropsychiatric disorders.
... Mescaline, an alkaloid that occurs naturally, is classified within the phenylalkylamine family of molecules [1]. Mescaline is predominantly found in various cacti, with notable sources including the Peyote cactus (Lophophora williamsii), the San Pedro cactus (Echinopsis pachanoi), as well as the Peruvian torch (Echinopsis peruviana), Bolivian torch (Echinopsis lageniformis), and Pereskia aculeate [2,3]. ...
... In pharmacology, mescaline acts as an agonist for serotonin receptors, specifically 5-HT2A and 5-HT2C, as well as the α2A adrenergic receptor [16][17][18][19]. Notably, it exhibits a superior affinity for the 5-HT2A receptor (EC50 = 10 M), thereby serving as an agonist for serotonin 2A/C (5HT2A/C) receptors [1,20,21]. Nonetheless, the binding mode and molecular mechanism of mescaline as an agonist for the 5-HT2A receptor remain elusive. ...
... Mescaline can induce different cognitive states, often manifesting symptoms similar to those observed in schizophrenia [1]. The German psychiatrist Kurt Beringer was the pioneer in noting the parallels between the effects of mescaline and the symptoms of schizophrenia [22,23]. ...
... Moreover, a similar effect has been observed in mice after the administration of psilocin and 5-MeO-DMT and it was demonstrated that the mechanism responsible for it is the activation of 5HT 1A receptors . Also, it is important to highlight that one of the symptoms observed in the patient of the case we reported was catatonia, accordingly to previous investigations that have shown that hallucinogens, especially at high doses, can produce withdrawal and catatonia-like state (Halberstadt and Geyer 2013). ...
The 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT, known online as “Moxy”) is a new psychedelic tryptamine first identified on Italian national territory in 2014. Its hallucinogen effects are broadly well-known; however, only few information is available regarding its pharmaco-toxicological effects.
Following the seizure of this new psychoactive substances by the Arm of Carabinieri and the occurrence of a human intoxication case, in the current study we had the aim to characterize the in vivo acute effects of systemic administration of 5-MeO-MiPT (0.01–30 mg/kg i.p.) on sensorimotor (visual, acoustic, and overall tactile) responses, thermoregulation, and stimulated motor activity (drag and accelerod test) in CD-1 male mice. We also evaluated variation on sensory gating (PPI, prepulse inhibition; 0.01–10 mg/kg i.p.) and on cardiorespiratory parameters (MouseOx and BP-2000; 30 mg/kg i.p.). Lastly, we investigated the in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) profile of 5-MeO-MiPT compared to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) and N,N-dimethyltryptamine (DMT).
This study demonstrates that 5-MeO-MiPT dose-dependently inhibits sensorimotor and PPI responses and, at high doses, induces impairment of the stimulated motor activity and cardiorespiratory changes in mice. In silico prediction shows that the 5-MeO-MiPT toxicokinetic profile shares similarities with 5-MeO-DIPT and DMT and highlights a cytochrome risk associated with this compound.
Consumption of 5-MeO-MiPT can affect the ability to perform activities and pose a risk to human health status, as the correspondence between the effects induced in mice and the symptoms occurred in the intoxication case suggests. However, our findings suggest that 5-MeO-MiPT should not be excluded from research in the psychiatric therapy field.
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. ...
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. Therefore, we tested whether repeated low doses of psilocybin altered PPI or startle habituation. ...
... High and repeated doses of serotonergic psychedelics are known to modulate pre-pulse inhibition of the acoustic startle reflex and have been used to model this schizophrenia endophenotype [29,31,43]. We found no effects of the psilocybin treatment regimen on pre-pulse inhibition or startle amplitude, and no effect on short-term habituation to the startle reflex. ...
Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users frequently report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats with repeated low doses of psilocybin administration at a dose derived from occupancy at rat brain 5-HT2A receptors in vivo. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptors. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments probing the effects of repeated low doses of psilocybin. Results further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention, while pointing to a possible physiological mechanism.
... Another serious adverse event reported in literature is LSDinduced psychosis, transient and long-term (Table 3). LSD acts on the 5-HT2A serotonin receptor, can alter brain connectivity of resting state networks, and can affect gene expression for neuroplasticity, all of which could lead to the induction of psychotic symptoms (Halberstadt and Geyer 2013;Müller et al. 2018;Nichols and Sanders-Bush 2002). The risk factors of persisting psychotic symptoms induced by LSD use are not known. ...
There has been a resurgence of interest in the use of psychedelic therapies for several mental and substance use disorders. Psilocybin, a “classic” serotonergic psychedelic, has emerged as one of the primary compounds of interest in clinical research. While research on psilocybin’s potential mental health benefits has grown, data on the safety and efficacy of other serotonergic psychedelics remain limited. A comprehensive scoping review on the use of mescaline, ibogaine, ayahuasca, N,N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) in the treatment of mental and substance disorders was conducted. Independent reviewers screened titles, abstracts, and full texts and conducted data extraction. Seventy-seven studies met the inclusion criteria. There were 43 studies of LSD, 24 studies of ayahuasca, 5 studies of DMT, 5 studies of ibogaine, and 5 studies of mescaline. Commonly reported benefits included improved mood and anxiety symptoms, improved insight, reduced substance use, improved relationships, and decreased vegetative symptoms. Commonly reported adverse effects were psychological, neurological, physical, and gastrointestinal in nature. Serious adverse events (homicide and suicide) were reported in published studies of LSD. In conclusion, there is only low-level evidence to support the safety and efficacy of non-psilocybin serotonergic psychedelics in individuals with mental and substance use disorders.
... As with stimulant drugs, a common concern is that these drugs might worsen symptoms, especially because they can induce experiences that resemble symptoms of schizophrenia. 101 Nevertheless, it has been proposed that psychedelic drugs may have a role in schizophrenia treatment, and the potential benefits remain to be determined. 102 It is not known whether psychedelic drugs enhance social motivation in healthy adults, using tasks specifically designed to assess this construct (eg, social incentive delay task or willingness to exert effort to obtain a social reward). ...
Background and hypothesis:
Diminished social motivation is a negative symptom of schizophrenia and leads to severe functional consequences for many patients suffering from the illness. However, there are no effective medications available to treat this symptom. Despite the lack of approved treatments for patients, there is a growing body of literature on the effects of several classes of drugs on social motivation in healthy volunteers that may be relevant to patients. The aim of this review is to synthesize these results in an effort to identify novel directions for the development of medications to treat reduced social motivation in schizophrenia.
Study design:
In this article, we review pharmacologic challenge studies addressing the acute effects of psychoactive drugs on social motivation in healthy volunteers and consider how these findings may be applied to deficits in social motivation in schizophrenia. We include studies testing amphetamines and 3,4-methylenedioxymethamphetamine (MDMA), opioids, cannabis, serotonergic psychedelics, antidepressants, benzodiazepines, and neuropeptides.
Study results:
We report that amphetamines, MDMA, and some opioid medications enhance social motivation in healthy adults and may represent promising avenues of investigation in schizophrenia.
Conclusions:
Given the acute effects of these drugs on behavioral and performance-based measures of social motivation in healthy volunteers, they may be particularly beneficial as an adjunct to psychosocial training programs in patient populations. It remains to be determined how these medications affect patients with deficits in social motivation, and in which contexts they may be most effectively administered.
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. ...
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. Therefore, we tested whether repeated low doses of psilocybin altered PPI or startle habituation. ...
... High and repeated doses of serotonergic psychedelics are known to modulate pre-pulse inhibition of the acoustic startle reflex and have been used to model this schizophrenia endophenotype [29,31,43]. We found no effects of the psilocybin treatment regimen on pre-pulse inhibition or startle amplitude, and no effect on short-term habituation to the startle reflex. ...
Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users often report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats using repeated low doses of psilocybin. Dosing is based on in vivo occupancy at rat brain 5-HT2A receptors. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptor. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments into the effects of repeated low doses of psilocybin. They further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention while pointing to a possible physiological mechanism.
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. ...
... Exposure to high doses of psilocybin or other 5-HT 2A receptor agonizts induce deficits in pre-pulse inhibition (PPI) of the startle reflex [29][30][31], which is a widely accepted endophenotype of schizophrenia. Indeed, repeated psilocybin dosing (at high dose) has been used to model that aspect of schizophrenia [31]. Therefore, we tested whether repeated low doses of psilocybin altered PPI or startle habituation. ...
... High and repeated doses of serotonergic psychedelics are known to modulate pre-pulse inhibition of the acoustic startle reflex and have been used to model this schizophrenia endophenotype [29,31,43]. We found no effects of the psilocybin treatment regimen on pre-pulse inhibition or startle amplitude, and no effect on short-term habituation to the startle reflex. ...
The combination of neuroimaging and targeted neuromodulation is a crucial tool to gain a deeper understanding of neural networks at a circuit level. Infrared neurostimulation (INS) is a promising optical modality that allows to evoke neuronal activity with high spatial resolution without need for the introduction of exogenous substances in the brain. Here, we report the use of whole-brain functional [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging during INS in the dorsal striatum, performed using a multifunctional soft neural probe. We demonstrate the possibility to identify multi-circuit connection patterns in both cortical and subcortical brain regions within a single scan. By using a bolus plus infusion FDG-PET scanning protocol, we were able to observe the metabolic rate evolution in these regions during the experiments and correlate its variation with the onset of the INS stimulus. Due to the focality of INS and the large amount of viable molecular targets for PET, this novel approach to simultaneous imaging and stimulation is highly versatile. This pilot study can pave the way to further understand the brain connectivity on a global scale.
... Relatedly, there has been interest in the question of whether anti-psychotics tend to block psychedelics experiences, 7 similarities and differences between drug-induced and endogenous hallucinations (Leptourgos et al., 2020), and potential links between early psychotic and psychedelic experiences (Carhart-Harris, 2013;Hartogsohn, 2020;Langlitz, 2013). Psychedelics are also regularly used in animal research to model symptoms of psychosis, although several other options are available as well 8 (Halberstadt & Geyer, 2013). ...
... LSD was referred to as a "psychoticum" as far back as 1949 (Hartogsohn, 2020). Ketamine has been suggested by some to be the best model for schizophrenia because it produces both negative and positive symptoms (Halberstadt & Geyer, 2013;Vollenweider et al., 1997), although some have raised doubts about this , noting that the negative symptoms of schizophrenia are too non-specific to be useful in modeling and that the positive symptoms are better modeled by other psychedelics (Gouzoulis-Mayfrank et al., 1998). Others have suggested that tetrahydrocannabinol (THC, the primary psychoactive component of cannabis) is better at inducing the positive symptoms associated with schizophrenia (Morrison et al., 2009). ...
Experiences of psychedelics and psychosis were deeply entangled in scientific practices in the mid-20th century, from uses of psychedelic drugs that could model psychosis, to detailed phenomenological comparisons of endogenous and drug-induced madness. After the moral panic of the 1960s shut down psychedelic research, however, these two phenomena became disentangled. In the decades following, the science of psychosis transformed, shedding the language of psychoanalysis, and adopting the new scientific veneer of psychiatry. Today, as psychedelic science re-emerges, the research programs surrounding psychosis and psychedelics now stand in stark contrast. Here, I look closely at how these research programs respond to questions related to what is worth measuring, what is worth investigating, and how we ought to respond to these experiences. This comparison reveals radically different assumptions and values that guide each research paradigm and shape clinical practice. While psychedelic research often includes scales that seek to capture experiences of mysticism, meaningfulness, and ego dissolution, research related to psychosis focuses on the measurement of pathological symptoms and functioning. Research into psychosis primarily seeks universal and reductionist causal explanations and interventions, while psychedelic research embraces the importance of set and setting in shaping unique experiences. Responses to psychedelic crisis involve warmth, compassion, and support, while responses to psychotic experiences often involve restraint, seclusion, and weapons. I argue that these differences contain important lessons for psychiatry. However, as psychedelic research struggles to meet regulatory requirements and fit within the paradigm of evidence-based medicine, these differences may quickly dissolve.
... Psychedelic drugs as a model for schizophrenia In humans, as well as in translational animal models, serotonergic psychedelic drugs induce symptoms resembling the positive symptoms of schizophrenia [88,93,94], including deficits in prepulse inhibition (PPI) and altered acoustic startle response [95], whereas non-competitive NMDA receptor antagonists such as ketamine and PCP, especially when administered (sub) chronically, can also model the negative and cognitive symptoms that are characteristic of schizophrenia [96][97][98][99][100]. Psilocybin, LSD, and mescaline all model psychosis in non-schizophrenic humans, which closely resembles the early stage of schizophrenia [101,102] and also in laboratory animals [103,104]. Interestingly, although serotonergic psychedelic drugs evoke psychotic-like phenotypes, these symptoms are attenuated by serotonergic but not by dopaminergic antagonists such as haloperidol suggesting that psychedelic-induced psychosis is mediated via serotonergic rather than dopaminergic pathway [88], and also that imbalanced 5-HT2A signaling play a role in schizophrenia, and hence may serve as a target for treatment of the disease. ...
Schizophrenia is a widespread psychiatric disorder that affects 0.5–1.0% of the world’s population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.
