Rewarding and reinforcing effects of two dissociative-based new psychoactive substances, deschloroketamine and diphenidine, in mice.
Jin Mook Kim, Boreum Han, Hyun Kyu Min, Jaesuk Yun, Young-Hoon Kim, Sun-Ok Choi, Mi Sun Kang
Pharmacology, Biochemistry, and Behavior February 1, 2022 DOI: 10.1016/j.pbb.2022.173333 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal behavioral study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | deschloroketamine diphenidine |
| Dose | 10 mg/kg deschloroketamine; 10-60 mg/kg diphenidine; 1 mg/kg/infusion deschloroketamine; 1, 2 mg/kg/infusion diphenidine |
| Topics | Ketamine |
| Keywords | Conditioned place preference Dependence liability Deschloroketamine Diphenidine New psychoactive substances Self-administration |
| Citations | 4 |
| Key points | Deschloroketamine showed both rewarding and reinforcing effects in mice, while diphenidine only induced rewarding effects. |
Abstract
Dissociative-based new psychoactive substances (NPSs) are increasingly available through the Internet, and public health problems related to the recreational use of these substances have been increasing globally. Two such NPSs are deschloroketamine and diphenidine, which are primarily used recreationally as ketamine substitutes. However, there is little scientific evidence to describe the dependence liability of NPSs. This study aimed to evaluate the dependence liability of deschloroketamine and diphenidine via animal behavioral experiments. We evaluated the rewarding and reinforcing effects of these NPSs using the conditioned place preference (CPP) and the self-administration (SA) paradigms in mice. Psychomotor effects and behavioral features of these compounds were assessed by quantifying locomotor activity, stereotypic movements, and dopaminergic neurotransmission. Both deschloroketamine (10 mg/kg) and diphenidine (10-60 mg/kg) produced increased locomotor activation and stereotypy that were similar to the effects of ketamine (10 mg/kg). Both deschloroketamine (10 mg/kg) and diphenidine (10, 20 mg/kg) increased the animals' preference for the drug-paired compartment in the CPP testing. In the SA testing, deschloroketamine (1 mg/kg/infusion) increased the number of active lever presses and the number of infusions received, whereas diphenidine administration (1, 2 mg/kg/infusion) did not alter either of these. Furthermore, both deschloroketamine and diphenidine increased dopamine levels in PC-12 cells. Collectively, the data suggest that deschloroketamine may have both rewarding and reinforcing effects, whereas diphenidine only induced rewarding effect.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 4
- Zebrafish embryo-larval testing reveals differential toxicity of new psychoactive substances. Toxicology Reports June 1, 2025
- The acute effects of methoxphenidine on behaviour and pharmacokinetics profile in animal model. Progress in Neuro-Psychopharmacology and Biological Psychiatry March 20, 2025
- Structural basis of opioid receptor activation by PCP and ketamine Nature Structural & Molecular Biology June 22, 2026
- Comprehensive in vitro profiling of traditional and emerging stimulants at monoamine transporters and the 5-HT2A receptor. British Journal of Pharmacology July 14, 2026
Cites 9
- From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Testing and Analysis 2014
- Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues PLoS One June 17, 2016
- Effects of the new psychoactive substances diclofensine, diphenidine, and methoxphenidine on monoaminergic systems European Journal of Pharmacology December 8, 2017
- Synthesis, absolute configuration and in vitro cytotoxicity of deschloroketamine enantiomers: rediscovered and abused dissociative anaesthetic New Journal of Chemistry 2018
- Mechanistic Insights into the Stimulant Properties of Novel Psychoactive Substances (NPS) and Their Discrimination by the Dopamine Transporter-In Silico and In Vitro Exploration of Dissociative Diarylethylamines. Brain Sciences April 7, 2018
and 4 more in the library