Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

Halberstadt, Adam L.; Chatha, Muhammad; Klein, Adam K.; Wallach, Jason; Brandt, Simon D.

doi:10.1016/j.neuropharm.2019.107933

Cited by 157 publications

(198 citation statements)

References 129 publications

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“…At 5-HT 2C receptors, 2C derivatives were shown to be partial or full agonists (Eshleman et al 2014;Moya et al 2007), and NBOMe derivatives were shown to be full agonists (Eshleman et al 2018;Jensen et al 2017). Consistent with the in vitro findings, psychedelic phenethylamines were shown to induce 5-HT 2A -dependent behaviors in vivo, such as wet dog shakes, back muscle contractions, and a head twitch response (Elmore et al 2018;Fantegrossi et al 2005;Halberstadt et al 2020;Halberstadt and Geyer 2014). In addition to interactions with serotonergic receptors, phenethylamine psychedelics have been shown to interact with other monoaminergic targets, including adrenergic, dopaminergic, and histaminergic receptors, monoamine transporters, and MAOs (Eshleman et al 2018;Kolaczynska et al 2019;Luethi et al 2018d;Noble et al 2018;Rickli et al 2015c;Wagmann et al 2019a).…”

Section: Mechanism Of Action Of Phenethylaminesmentioning

confidence: 64%

Designer drugs: mechanism of action and adverse effects

2020

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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at l-opioid receptors and c-aminobutyric acid-A (GABA A) or GABA B receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB 1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT 2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

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Section: Mechanism Of Action Of Phenethylaminesmentioning

confidence: 64%

Designer drugs: mechanism of action and adverse effects

2020

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“…Besides motor activity, we examined the effects of LSD on head twitch, grooming, retrograde walking, and nose-poking behaviors. LSD and other psychedelics are well-known to stimulate head-twitch responses in mice [18, 45,48] and this response has been proposed as a proxy for hallucinations in humans [13]. Compared to the vehicle, LSD stimulated head-twitch responses to similar extents in WT and βArr1-KO mice.…”

Section: Discussionmentioning

confidence: 99%

LSD’s effects are differentially modulated in arrestin knockout mice

Nadkarni

et al. 2021

Preprint

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Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, the hallucinogenic side effects of psychedelics often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5HT2A serotonin receptor (5HT2AR). 5HT2AR activation stimulates Gq and arrestin (Arr) mediated signaling. To separate effects of these signaling modes, we have used Arr1 and Arr2 mice. We find that LSD stimulates motor activities to similar extents in WT and Arr1 KO mice, with non-significant effects in Arr2 KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and Arr1 KO animals. In contrast, LSD only slightly stimulates head twitches in Arr2 KO mice, without effects on retrograde walking or nose poking. The 5HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and Arr1 KOs. PPI is unaffected in Arr2 KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in Arr1 KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in Arr1 KOs, and is without effect in Arr2 mutants. Both MDL and the 5HT1AR antagonist, WAY100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in Arr1 KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through Arr1 and Arr2, and that the psychedelic drug-like actions of LSD appear to require Arr2.

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“…Clinical research with newer lysergamides has yet to be carried out in detail but serotonergic hallucinogens such as LSD induce the head‐twitch response (HTR) in mice and rats, which reflects 5‐HT 2A receptor activation (the primary target of hallucinogens in the CNS) 25,26 . In addition to having the ability to differentiate between hallucinogenic and non‐hallucinogenic 5‐HT 2A receptor agonists, 27,28 the HTR assay also allows in vivo potencies to be compared in a manner that has cross‐species translational relevance to humans 24,29 . ALD‐52, 1P‐LSD, and 1B‐LSD have been shown to elicit the HTR and it appears that this is the result of LSD formation in vivo 18,24 .…”

Section: Introductionmentioning

confidence: 99%

Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD)

Brandt

Kavanagh

Westphal³

et al. 2020

Drug Testing and Analysis

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Lysergic acid diethylamide (LSD) is a prototypical serotonergic psychedelic drug and the subject of many clinical investigations. In recent years, a range of lysergamides has emerged with the production of some being inspired by the existing scientific literature. Others, for example various 1‐acyl substituted lysergamides, did not exist before their appearance as research chemicals. 1‐Cylopropanoyl‐LSD (1CP‐LSD) has recently emerged as a new addition to the group of lysergamide‐based designer drugs and is believed to be psychoactive in humans. In this investigation, 1CP‐LSD was subjected to detailed analytical characterizations including various mass spectrometry (MS) platforms, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, solid phase and GC condensed phase infrared spectroscopy. Analysis by GC–MS also revealed the detection of artificially induced degradation products. Incubation of 1CP‐LSD with human serum led to the formation of LSD, indicating that it may act as a prodrug for LSD in vivo, similar to other 1‐acyl substituted lysergamides. The analysis of blotters and pellets is also included. 1CP‐LSD also induces the head‐twitch response (HTR) in C57BL/6 J mice, indicating that it produces an LSD‐like behavioural profile. 1CP‐LSD induced the HTR with an ED50 = 430.0 nmol/kg which was comparable to 1P‐LSD (ED50 = 349.6 nmol/kg) investigated previously. Clinical studies are required to determine the potency and profile of the effects produced by 1CP‐LSD in humans.

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Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

Cited by 157 publications

References 129 publications

Designer drugs: mechanism of action and adverse effects

Designer drugs: mechanism of action and adverse effects

LSD’s effects are differentially modulated in arrestin knockout mice

Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD)

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