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Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT 2A ) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT 2A receptors.

[11C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test–retest variability of cerebral [11C]Cimbi-36 PET and compare [11C]Cimbi-36 and the 5-HT2A receptor antagonist [18F]altanserin. Sixteen healthy volunteers (mean age 23.9±6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [11C]Cimbi-36; eight were scanned twice to determine test–retest variability in [11C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [18F]altanserin. Regional differences in the brain distribution of [11C]Cimbi-36 and [18F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. Test–retest variability of [11C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [11C]Cimbi-36 and [18F]altanserin (mean Pearson's r: 0.95±0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [11C]Cimbi-36 as compared to [18F]altanserin was found in the choroid plexus and hippocampus in the human brain. Excellent test–retest reproducibility highlights the potential of [11C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [11C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors. •[11C]Cimbi-36 demonstrated excellent reproducibility as a 5-HT2A receptor agonist PET radioligand in healthy volunteers.•In vivo binding of [11C]Cimbi-36 and [18F]altanserin was highly correlated demonstrating that they both image 5-HT2A receptors in the human brain•In choroid plexus and hippocampus, [11C]Cimbi-36 binding exceeded [18F]altanserin binding suggesting high density of 5-HT2C receptors here.•[11C]Cimbi-36 may be used to detect both 5-HT2A and 5-HT2C receptor binding in the human brain

Abstract Background and Hypotheses Negative symptoms of schizophrenia (NSS) carry a substantial burden, and there are no treatments currently approved for NSS. The efficacy of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, in treating NSS was assessed. Study Design ADVANCE-2 was a phase 3, randomized, double-blind, placebo-controlled study of pimavanserin in patients with schizophrenia and predominantly negative symptoms. Patients were randomized (1:1) to receive pimavanserin (34 mg/day) or placebo alongside ongoing background antipsychotic medication. Eligible adults were aged 18–55 years and had access to a caregiver. The primary and key secondary endpoints were the change from baseline to week 26 in the Negative Symptom Assessment–16 (NSA-16) total score and Clinical Global Impression–Schizophrenia Scale-Severity (CGI-SCH-S) negative symptom score, respectively. Study Results Of the 454 randomized patients, 71 (39 placebo; 32 pimavanserin) discontinued and 383 (188 placebo; 195 pimavanserin) completed the study. The safety and full analysis sets comprised 453 and 446 patients, respectively. The NSA-16 change from baseline to week 26 was not significantly different between groups (least squares mean difference: −0.67; SE, 0.95; [95% CI: −2.54, 1.20]; P = .48; Cohen’s d effect size: 0.07). Treatment-emergent adverse events occurred in 30.4% with pimavanserin and 40.3% with placebo. Conclusions In this study, pimavanserin was well tolerated, and although it demonstrated a similar treatment effect as in the prior phase 2 study favoring pimavanserin, treatment with pimavanserin vs placebo did not result in significant differences for primary or other endpoints.

Rationale Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. Objectives This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. Results LSD, compared with placebo, significantly increased cognitive bizarreness ( p  < 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control ( p  < 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. Conclusions LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.

Background Preclinical data have suggested involvement of the endocannabinoid (eCB) system in MDMA-induced memory impairment. Clinical research has shown that blockade of the 5-HT 2 receptor nulls memory impairment during MDMA intoxication. Interestingly, studies have demonstrated that the eCB and the 5-HT system interact. It was hypothesized that MDMA would cause an increase in eCB concentrations together with a decrease in memory performance, and that combining MDMA with a 5-HT 2 receptor blocker ketanserin would lead to a counteraction of the MDMA effects on eCB concentrations and memory. Methods Twenty healthy recreational polydrug users entered a double-blind placebo-controlled within-subject study. Participants received a pre-treatment (ketanserin 40 mg, placebo) followed 30 min later by a treatment (MDMA 75 mg, placebo). Verbal memory was tested by means of a 30-word learning test. Endocannabinoid concentrations (anandamide (2-AG); N -arachidonylethanolamine (AEA)) were assessed in blood at baseline, before (90 min post-treatment) and after cognitive tests (150 min post-treatment). Results Findings showed that MDMA impaired memory 90 min post-treatment in the word learning task. This effect was a replication of previous studies using the same dose of MDMA (75 mg) and the same learning paradigm. Contrary to our hypothesis, MDMA did not affect eCB concentrations, nor did ketanserin block MDMA-induced memory impairment. Ketanserin caused an increase in AEA concentrations, 180 min after administration. Conclusion Current findings suggest that peripherally measured endocannabinoids are not associated with the verbal memory deficit during MDMA intoxication. Trial registration number: NTR3691.

The psychedelic drug LSD alters thinking and perception. Users can experience hallucinations, in which they, for example, see things that are not there. Colors, sounds and objects can appear distorted, and time can seem to speed up or slow down. These changes bear some resemblance to the changes in thinking and perception that occur in certain psychiatric disorders, such as schizophrenia. Studying how LSD affects the brain could thus offer insights into the mechanisms underlying these conditions. There is also evidence that LSD itself could help to reduce the symptoms of depression and anxiety disorders. Preller et al. have now used brain imaging to explore the effects of LSD on the brains of healthy volunteers. This revealed that LSD reduced communication among brain areas involved in planning and decision-making, but it increased communication between areas involved in sensation and movement. Volunteers whose brains showed the most communication between sensory and movement areas also reported the strongest effects of LSD on their thinking and perception. Preller et al. also found that another drug called Ketanserin prevented LSD from altering how different brain regions communicate. It also prevented LSD from inducing changes in thinking and perception. Ketanserin blocks a protein called the serotonin 2A receptor, which is activated by a brain chemical called serotonin that, amongst other roles, helps to regulate mood. By mapping the location of the gene that produces the serotonin 2A receptor, Preller et al. showed that the receptor is present in brain regions that show altered communication after LSD intake, therefore pinpointing the importance of this receptor in the effects of LSD. Psychiatric disorders that produce psychotic symptoms affect vast numbers of people worldwide. Further research into how LSD affects the brain could help us to better understand how such symptoms arise, and may also lead to the development of more effective treatments for a range of mental health conditions.

Purpose To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. Methods Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6–7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. Results Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. Conclusions There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Sleep paralysis is a state of involuntary immobility occurring at sleep onset or offset, often accompanied by uncanny “ghost-like” hallucinations and extreme fear reactions. I provide here a neuropharmacological account for these hallucinatory experiences by evoking the role of the serotonin 2A receptor (5-HT 2A R). Research has shown that 5-HT 2A R activation can induce visual hallucinations, “mystical” subjective states, and out-of-body experiences (OBEs), and modulate fear circuits. Hallucinatory experiences triggered by serotonin—serotonergic (“pseudo”) hallucinations, induced by hallucinogenic drugs—tend to be “dream-like” with the experiencer having insight (“meta-awareness”) that he is hallucinating, unlike dopaminergic (“psychotic” and “life-like”) hallucinations where such insight is lost. Indeed, hallucinatory experiences during sleep paralysis have the classic features of serotonergic hallucinations, and are strikingly similar to perceptual and subjective states induced by hallucinogenic drugs (e.g., lysergic acid diethylamide [LSD] and psilocybin), i.e., they entail visual hallucinations, mystical experiences, OBEs, and extreme fear reactions. I propose a possible mechanism whereby serotonin could be functionally implicated in generating sleep paralysis hallucinations and fear reactions through 5-HT 2A R activity. Moreover, I speculate on the role of 5-HT 2C receptors vis-à-vis anxiety and panic during sleep paralysis, and the orbitofrontal cortex—rich with 5-HT 2A receptors—in influencing visual pathways during sleep paralysis, and, in effect, hallucinations. Finally, I propose, for the first time, a drug to target sleep paralysis hallucinations and fear reactions, namely the selective 5-HT 2A R inverse agonist, pimavanserin. This account implicates gene HTR2A on chromosome 13q as the underlying cause of sleep paralysis hallucinations and could be explored using positron emission tomography.

The aim of this study was to prepare a nasal gel of risperidone and to investigate the pharmacokinetics and relative bioavailability of the drug in rats. Compared with oral dosing, the risperidone nasal gel exhibited very fast absorption and high bioavailability. Maximal plasma concentration (c ) and the time to reach c (t ) were 15.2 μg mL and 5 min for the nasal gel, 3.6 μg mL and 30 min for the oral drug suspension, respectively. Pharmacokinetic parameters such as t , c and AUC of oral and nasal routes were significantly different (p < 0.01). Relative bioavailability of the drug nasal preparation to the oral suspension was up to 1600.0 %. Further, the in vitro effect of the risperidone nasal gel on nasal mucociliary movement was also investigated using a toad palate model. The risperidone nasal formulation showed mild ciliotoxicity, but the adverse effect was temporary and reversible.