Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics

Luethi, Dino; Liechti, Matthias E.

doi:10.1093/ijnp/pyy047

Cited by 58 publications

(56 citation statements)

References 48 publications

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“…1) and potency ( Fig. 2) at the different transporters result in different pharmacological effects, different clinical potencies (i.e., the dose that is necessary to induce a psychoactive effect), and different abuse liabilities (Aarde and Taffe 2017;Gannon et al 2018;Javadi-Paydar et al 2018;Kuhar et al 1991;Luethi and Liechti 2018;Ritz et al 1987;Vandewater et al 2015;Wee et al 2005;Wee and Woolverton 2006). In rats, substances that are selective for DAT vs. SERT facilitate dose-dependent and abuse-related intracranial self-stimulation, indicating high abuse potential.…”

Section: Stimulantsmentioning

confidence: 99%

“…In some cases, the users reported to be unaware that they took 5-IT, because the products were mislabeled as 6-APB (Bäckberg et al 2014;Kronstrand et al 2013;Seetohul and Pounder 2013). Although the reported doses of 5-IT and 6-APB are similar, they differ in their selectivity for the dopaminergic vs. serotonergic system (Luethi et al 2018c;Luethi and Liechti 2018;Rickli et al 2015b). The extent to which mislabeling played a role in 5-IT intoxication remains unclear.…”

Section: Adverse Effects Of Benzofuran and Indole Derivativesmentioning

confidence: 99%

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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: Stimulantsmentioning

confidence: 99%

Section: Adverse Effects Of Benzofuran and Indole Derivativesmentioning

confidence: 99%

Designer drugs: mechanism of action and adverse effects

2020

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“…Nevertheless, SCs also have distinctive pharmacokinetic profiles, such as long half‐lives and distinctive neuromolecular effects . Furthermore, some SCs interact with targets other than monoamine transporters . These properties may also contribute to the psychological and behavioral effects of SCs.…”

Section: Introductionmentioning

confidence: 99%

“…18 Furthermore, some SCs interact with targets other than monoamine transporters. 19,20 These properties may also contribute to the psychological and behavioral effects of SCs. Reports show that certain SCs have appreciable affinity at 7-transmembrane, G proteincoupled receptors, [21][22][23][24] and one publication reports that 2,3dimethylmethcathinone is a 5-HT 2A receptor (5-HT 2A R) agonist.…”

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confidence: 99%

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT_2A receptors: In vitro and in vivo evidence

Chen

Blough

Murnane

et al. 2019

Drug Testing and Analysis

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Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT2A receptors (5‐HT2AR) and muscarinic M1 receptors (M1R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M1R (minimal displacement of [~Kd] [3H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM Ki values at 5‐HT2AR. In 5‐HT2AR–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT2AR functional activity of α‐PPP, and observed it competitively antagonized 5‐HT2AR signaling stimulated by the 5‐HT2R agonist (±)‐2,5‐dimethoxy‐4‐iodoamphetamine (DOI; Kb = 851 nM). To assess in vivo 5‐HT2AR activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppression at 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT2AR mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT2AR Kis > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT2AR in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT2AR antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.

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“…As a further example, activation of the serotonin (5-HT) receptor 5-HT 2A has been shown to mediate effects of hallucinogens with a strong correlation between hallucinogenic potencies in humans and receptor affinity in vitro. 10,[14][15][16] The NBOMes (2,5-dimethoxy-N-benzylphenethylamines) are serotonin 5-HT 2A receptor agonists similar to other hallucinogenic compounds, but present a higher receptor affinity compared to phenethylamine analogues without an N-benzyl moiety, 10,11 thus leading to stronger effects and responses, including fatal intoxications. [17][18][19][20] The route of consumption also varies depending on the type of NPS.…”

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confidence: 99%

Clinical value of analytical testing in patients presenting with new psychoactive substances intoxication

Grafinger

Liechti

Liakoni

2019

Brit J Clinical Pharma

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New psychoactive substances (NPS) have emerged worldwide in recent years, posing a threat to public health and a challenge to drug policy. NPS are usually derivatives or analogues of classical recreational drugs designed to imitate their effects while circumventing regulations. This article provides an overview of benefits and limitations of analytical screening in managing patients presenting with acute NPS toxicity. NPS typically cannot be analytically identified with the usual immunoassay tests. To detect NPS using an immunoassay, antibodies specifically binding to the new structures would have to be developed, which is complicated by the rapid change of the NPS market. Activity‐based assays could circumvent this problem since no prior knowledge on the substance structure is necessary. However, classical recreational drugs activating the same receptors could lead to false positive results. Liquid or gas chromatography coupled with mass spectrometry is a valuable NPS analysis tool, but its costs (e.g. equipment), run time (results usually within hours vs minutes in case of immunoasssays) and the need for specialized personnel hinder its use in clinical setting, while factors such as lack of reference standards can pose further limitations. Although supportive measures are sufficient in most cases for adequate patient management, the detection and identification of NPS can contribute significantly to public health and safety in cases of e.g. cluster intoxications and outbreaks, and to the investigation of these novel compounds' properties. However, this requires not only availability of the necessary equipment and personnel, but also collaboration between clinicians, authorities and laboratories.

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Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics

Cited by 58 publications

References 48 publications

Designer drugs: mechanism of action and adverse effects

Designer drugs: mechanism of action and adverse effects

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT_2A receptors: In vitro and in vivo evidence

Clinical value of analytical testing in patients presenting with new psychoactive substances intoxication

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Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics

Cited by 58 publications

References 48 publications

Designer drugs: mechanism of action and adverse effects

Designer drugs: mechanism of action and adverse effects

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

Clinical value of analytical testing in patients presenting with new psychoactive substances intoxication

Contact Info

Product

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The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT_2A receptors: In vitro and in vivo evidence