Association between NMDAR antagonists, drug abuse and dependence: A disproportionality analysis from the WHO pharmacovigilance database.
Bruno Revol, Maryse Lapeyre-Mestre, Nathalie Fouilhé Sam-Lai, Emilie Jouanjus
British journal of clinical pharmacology November 1, 2022 DOI: 10.1111/bcp.15430 via PubMed
Summary
All four N-methyl-D-aspartate receptor (NMDAR) antagonists examined—dextromethorphan, ketamine, amantadine, and memantine—showed a statistically significant association with reports of drug abuse and dependence in the World Health Organization pharmacovigilance database (VigiBase®), which contains over 21 million case reports from more than 130 countries. The strongest signal was for dextromethorphan, followed by ketamine, with weaker but still significant signals for amantadine and memantine. This suggests a possible class effect for abuse potential among NMDAR antagonists. The authors call for further investigation and alert health professionals to this risk, especially given growing interest in these drugs as non-opioid pain treatments during the opioid epidemic.
Study at a glance
| Characteristics | Disproportionality analysis Peer reviewed |
|---|---|
| Population | Individual case safety reports in VigiBase® (>21 million reports from >130 countries) |
| Topics | Addiction |
| Keywords | Nmda-r antagonists Vigibase® Addictovigilance Drug abuse |
| Key finding | All four NMDAR antagonists (dextromethorphan, ketamine, amantadine, and memantine) were significantly associated with reporting of drug abuse and dependence, suggesting a class effect. |
Abstract
Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs.