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Hallucinogens induce the head-twitch response (HTR), a rapid reciprocal head movement, in mice. Although head twitches are usually identified by direct observation, they can also be assessed using a head-mounted magnet and a magnetometer. Procedures have been developed to automate the analysis of magnetometer recordings by detecting events that match the frequency, duration, and amplitude of the HTR. However, there is considerable variability in the features of head twitches, and behaviors such as jumping have similar characteristics, reducing the reliability of these methods. We have developed an automated method that can detect head twitches unambiguously, without relying on features in the amplitude-time domain. To detect the behavior, events are transformed into a visual representation in the time-frequency domain (a scalogram), deep features are extracted using the pretrained convolutional neural network (CNN) ResNet-50, and then the images are classified using a Support Vector Machine (SVM) algorithm. These procedures were used to analyze recordings from 237 mice containing 11,312 HTR. After transformation to scalograms, the multistage CNN-SVM approach detected 11,244 (99.4%) of the HTR. The procedures were insensitive to other behaviors, including jumping and seizures. Deep learning based on scalograms can be used to automate HTR detection with robust sensitivity and reliability.

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT 2A -Gq but not 5-HT 2A -β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT 2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT 2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT 2A agonists. We also demonstrate that β-arrestin-biased 5-HT 2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT 2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics. Serotonin 5-HT 2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT 2A -selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT 2A -Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.

Abstract The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

RationaleThe lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.ObjectiveIn this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.MethodsCompetitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.ResultsECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.ConclusionsThese findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

Rationale Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle. Methods The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S -(+) and R -(−) isomers of ketamine, and N -allylnormetazocine (NANM; SKF-10,047). Results MXE disrupted PPI when administered at 3 and 10 mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S -(+)-ketamine > NANM > R -(−)-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10 mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75 mg/kg, SC) produced a similar profile of effects in the BPM. Conclusions These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine.

Although it is well established that hallucinogens act as 5-HT 2A and 5-HT 2C receptor agonists, little is known about the relative contributions of 5-HT 2A and 5-HT 2C receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT 2A and 5-HT 2C receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose–response function, with lower doses (0.625–5.0 mg/kg) increasing and higher doses (⩾10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT 2A receptor KO mice, suggesting the involvement of 5-HT 2A receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT 2A KO mice and attenuated by pretreatment with the selective 5-HT 2C/2B antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT 2C receptors, an interpretation that is supported by the finding that the selective 5-HT 2C agonist WAY 161,503 produces reductions in the locomotor activity that are potentiated in 5HT 2A KO mice. These results show for the first time that 5-HT 2A and 5-HT 2C receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT 2A and 5-HT 2C receptors exert opposing effects on locomotor activity.

Rationale The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT 2A agonists. The HTR is widely used as a behavioral assay for 5-HT 2A activation and to probe for interactions between the 5-HT 2A receptor and other transmitter systems. Objective High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response. Results Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR. Conclusions These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.

Rationale Metabotropic glutamate (mGlu) receptors have been suggested to play a role in neuropsychiatric disorders including schizophrenia, drug abuse, and depression. Because serotonergic hallucinogens increase glutamate release and mGlu receptors modulate the response to serotonin (5-HT) 2A activation, the interactions between serotonin 5-HT 2A receptors and mGlu receptors may prove to be important for our understanding of these diseases. Objective We tested the effects of the serotonergic hallucinogen and 5-HT 2A agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), and the selective 5-HT 2A antagonist, M100907, on locomotor activity in the mouse behavioral pattern monitor (BPM) in mGlu5 wild-type (WT) and knockout (KO) mice on a C57 background. Results Both male and female mGlu5 KO mice showed locomotor hyperactivity and diminished locomotor habituation compared with their WT counterparts. Similarly, the mGlu5-negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP) also increased locomotor hyperactivity, which was absent in mGlu5 KO mice. The locomotor hyperactivity in mGlu5 receptor KO mice was potentiated by DOM (0.5 mg/kg, subcutaneously (SC)) and attenuated by M100907 (1.0 mg/kg, SC). M100907 (0.1 mg/kg, SC) also blocked the hyperactivity induced by MPEP. Conclusions These studies demonstrated that loss of mGlu5 receptor activity either pharmacologically or through gene deletion leads to locomotor hyperactivity in mice. Additionally, the gene deletion of mGlu5 receptors increased the behavioral response to the 5-HT 2A agonist DOM, suggesting that mGlu5 receptors either mitigate the behavioral effects of 5-HT 2A hallucinogens or that mGlu5 KO mice show an increased sensitivity to 5-HT 2A agonists. Taken together, these studies indicate a functional interaction between mGlu5 and 5-HT 2A receptors.

Rationale 4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4- n -propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs. Objectives The present studies were conducted to examine the structure–activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT 2A receptor-mediated behavior induced by psychedelic drugs in mice. The HTR is commonly used as a behavioral proxy in rodents for human psychedelic effects and can be used to discriminate hallucinogenic and non-hallucinogenic 5-HT 2A agonists. Methods HTR dose–response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL/6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence. Results 2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT 2A receptor. Binding and functional studies confirmed that the compounds have nanomolar affinity for 5-HT 2 receptor subtypes and act as partial agonists at 5-HT 2A . Conclusions In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT 2A receptor. These findings further support the classification of 2C-T compounds as psychedelic drugs.