Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues
Jason Wallach, Heather Kang, Tristan Colestock, Hamilton Morris, Zuner A. Bortolotto, Graham L. Collingridge, David Lodge, Adam L. Halberstadt, Simon D. Brandt, Adeboye Adejare
PLoS One June 17, 2016 DOI: 10.1371/journal.pone.0157021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Diphenidine (DPH) 2-methoxy-diphenidine (2-MXP) 2-Cl-diphenidine (2-Cl-DPH) |
| Topics | Serotonin |
| Keywords | Pharmacology Dopamine Norepinephrine transporter Reuptake inhibitor Opioid Phencyclidine Nmda receptor Biochemistry |
| Citations | 73 |
| Key findings | 1,2-Diarylethylamines including DPH and 2-MXP are relatively selective NMDAR antagonists that reduce sensorimotor gating in rats, with DPH showing an ED50 of 9.5 mg/kg. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 32
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- New/emerging psychoactive substances and associated psychopathological consequences Psychological Medicine July 22, 2019
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- New psychoactive substances (NPS) and serotonin syndrome onset: A systematic review. Experimental Neurology May 1, 2021
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Cites 12
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Testing and Analysis 2014
- Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects Molecular Psychiatry October 15, 2013
- The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One June 14, 2016
- First Reported Fatalities Associated with the 'Research Chemical' 2-Methoxydiphenidine Journal of Analytical Toxicology February 19, 2015
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