The Effect of High Doses of Dextromethorphan on The Human Nervous System
DOI:
https://doi.org/10.61132/obat.v3i5.1518Keywords:
Dextromethorphan, Nervous system, OpioidsAbstract
Dextromethorphan (DXM) is a commonly used nonprescription cough suppressant that has gained field of science attention with its growing complex pharmacological effects and increased incidences of nonmedical use. This review is focused on pharmacokinetic, pharmacodynamics and CNS effects of DXM, especially on its action mechanism and the interaction with neural circuits and neurotransmitter systems. Although DXM has retained clinical utility as an antitussive, and has demonstrated potential as an off-label agent for neuropsychiatric disease, the recreational use of high doses can have harmful effects on the nervous system. At high doses DXM is capable of dissociation and hallucination similar to those induced by some opioids and NMDA antagonists, altering both mental status and cognition while being associated with neurotoxic effects. In this article, review and compare the similarities and differences between DXM and classic opioids in terms of their potential for abuse and their neurological effects. By case examples and existing epidemiological data, it also highlights the mounting abuse of DXM, most notably by children and young adults, posing a pressing public health challenge. Legislation on DXM is also described and differences in legislative response worldwide are highlighted. Finally, the article finishes by emphasizing the requirement for further studies involving other disciplines to detail the long-term neurological consequences of DXM abuse and to promote integrated public health interventions targeting education, prevention, and clinical treatment.
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Aldubayan, M. A., Alsharidah, A. S., Alenezi, S. K., & Alhowail, A. H. (2024). Galantamine mitigates neurotoxicity caused by doxorubicin via reduced neuroinflammation, oxidative stress, and apoptosis in rat model. European Review for Medical & Pharmacological Sciences, 28(2). https://www.europeanreview.org
Chiu, C. H., Ma, K. H., Huang, E. Y. K., Chang, H. W., Weng, S. J., Yu, T. H., ... & Yeh, S. H. H. (2024). Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals. Journal of the Chinese Medical Association, 87(5), 538–549. https://www.lww.com
Correia, A. S., & Vale, N. (2024). Advancements exploring major depressive disorder: Insights on oxidative stress, serotonin metabolism, BDNF, HPA axis dysfunction, and pharmacotherapy advances. International Journal of Translational Medicine. https://www.mdpi.com
Correll, C. U., Solmi, M., Cortese, S., Fava, M., Højlund, M., Kraemer, H. C., ... & Kane, J. M. (2023). The future of psychopharmacology: A critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents. World Psychiatry, 22(1), 48–74. https://www.wiley.com
Deitche, A. L., & Burda, A. M. (2022). Management of toxicological emergencies in the school setting: An overview for school nurses part 2. NASN School Nurse. [HTML]
Di Martino, R. M. C., Maxwell, B. D., & Pirali, T. (2023). Deuterium in drug discovery: Progress, opportunities and challenges. Nature Reviews Drug Discovery. https://www.nih.gov
Donaghy, R., Singer, L., & Dixit, K. (2024). Intrathecal methotrexate, central nervous system toxicity, and response to N-methyl-D-aspartate antagonism: An adult case series. Neuro-Oncology Practice, 11(5), 665–669. https://academic.oup.com/nop
Driver, C., Jackson, T. N., Lagopoulos, J., & Hermens, D. F. (2022). Molecular mechanisms underlying the N-methyl-D-aspartate receptor antagonists: Highlighting their potential for transdiagnostic therapeutics. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 119, 110609.
Fahmi, A., Aji, Y. K., Aprianto, D. R., Wido, A., Asadullah, A., Roufi, N., ... & Turchan, A. (2021). The effect of intrathecal injection of dextromethorphan on the experimental neuropathic pain model. Anesthesiology and Pain Medicine, 11(3), e114318. https://www.ncbi.nlm.nih.gov
Freudenberg, F., Reif-Leonhard, C., & Reif, A. (2024). Advancing past ketamine: Emerging glutamatergic compounds for the treatment of depression. European Archives of Psychiatry and Clinical Neuroscience, 1–11. https://link.springer.com
Gong, H., Xu, X., Talifu, Z., Zhang, C. J., Sun, Y. Z., Yue, Z. M., ... & Du, X. X. (2025). Prospects and challenges in NMDAR signaling in spinal cord injury recovery and neural circuit remodeling. Regenerative Therapy, 29, 381–389. https://www.sciencedirect.com
Hanfi, A. T., & Ahmad, S. (2024). Diagnosis and management of chronic obstructive pulmonary disease. In COPD – Pathology, Diagnosis, Treatment, and Future Directions. IntechOpen. https://www.intechopen.com
Hanson, R. L. W., Airody, A., Sivaprasad, S., & Gale, R. P. (2023). Optical coherence tomography imaging biomarkers associated with neovascular age-related macular degeneration: A systematic review. Eye. https://www.nature.com
Hashimoto, K. (2024). Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience, 1–14. https://www.springer.com
Healy, C. J. (2021). The acute effects of classic psychedelics on memory in humans. Psychopharmacology. https://www.researchgate.net
Kandiwa, K. T., Thom, L., & Schellack, N. (2022). A modern approach to cough management. SA Pharmaceutical Journal. https://www.academia.edu
Karrouri, R., Hammani, Z., Benjelloun, R., & Otheman, Y. (2021). Major depressive disorder: Validated treatments and future challenges. World Journal of Clinical Cases, 9(31), 9350–9363. https://www.ncbi.nlm.nih.gov
Majeed, A., Xiong, J., Teopiz, K. M., Ng, J., Ho, R., Rosenblat, J. D., ... & McIntyre, R. S. (2021). Efficacy of dextromethorphan for the treatment of depression: A systematic review of preclinical and clinical trials. Expert Opinion on Emerging Drugs, 26(1), 63–74. https://www.researchgate.net
Margotta, C. (2024). More than a bystander: The contribution of the skeletal muscle as source of biomarkers and molecular targets in amyotrophic lateral sclerosis. https://www.open.ac.uk
Mathai, D. S., Hilbert, S., Sepeda, N. D., Strickland, J. C., Griffiths, R. R., & Garcia-Romeu, A. (2023). Double-blind comparison of the two hallucinogens dextromethorphan and psilocybin: Experience-dependent and enduring psychological effects in healthy volunteers. Psychedelic Medicine, 1(4), 241–252. https://www.researchgate.net
Mayberry, K. M., & Ray, S. D. (2023). Side effects of drugs of abuse. In Side Effects of Drugs Annual (Vol. 45, pp. 9–26). Elsevier.
McClure, E. W., & Daniels, R. N. (2023). Classics in chemical neuroscience: Dextromethorphan (DXM). ACS Chemical Neuroscience.
Moharir, S., Akotkar, L., Aswar, U., Kumar, D., Gawade, B., Pal, K., & Rane, R. (2024). Improved pharmacokinetic and pharmacodynamic profile of deuterium-reinforced tricyclic antidepressants doxepin, dosulepin, and clomipramine in animal models. European Journal of Drug Metabolism and Pharmacokinetics, 49(2), 181–190.
Murray, C. H., Frohlich, J., Haggarty, C. J., Tare, I., Lee, R., & de Wit, H. (2024). Neural complexity is increased after low doses of LSD, but not moderate to high doses of oral THC or methamphetamine. Neuropsychopharmacology, 49(7), 1120–1128.
Nayak, S. M., & Johnson, M. W. (2023). Disorders due to substance use: Hallucinogens and MDMA-related substances. In Tasman’s Psychiatry. https://www.researchgate.net
Okamoto, A., Yonezawa, N., Yoshizawa, K., Kumashiro, R., & Suzuki, S. (2025). Dextromethorphan overdose with refractory status epilepticus and reversible cranial nerve reflex loss: A case report. The American Journal of Case Reports, 26, e946447. https://www.ncbi.nlm.nih.gov
Parincu, Z., & Iosifescu, D. V. (2023). Combinations of dextromethorphan for the treatment of mood disorders: A review of the evidence. Expert Review of Neurotherapeutics. https://www.researchgate.net
Plewa, S., Pietkiewicz, D., Kokot, Z. J., & Matysiak, J. (2024). A review of wastewater-based epidemiology studies for the assessment of over-the-counter medicines used as recreational drugs: The example of dextromethorphan. Medical Science Monitor, 30, e944120-1. https://www.nih.gov
Pompili, M., Berardelli, I., Erbuto, D., & Caraci, F. (2025). Can dextromethorphan-bupropion reduce mental pain in depressed individuals? A generating hypothesis overview perspective. Annals of General Psychiatry. https://www.springer.com
Presigny, C., & De Vico Fallani, F. (2022). Colloquium: Multiscale modeling of brain network organization. Reviews of Modern Physics.
Raiborde, M. D., Kumar, G., Singh, P., & Sharma, S. (2022). Dextromethorphan: An emerging drug of abuse. Journal of Pharmaceutical Negative Results. https://www.academia.edu
Rajput, R., Al Harakeh, K., Figueras, G., Mahi, A., Minhas, M., Sobolevskaia, D., ... & Rajput, A. (2025). Dextromethorphan as an opioid-sparing analgesic in postoperative pain. Clinical Neuropharmacology.
Ricci, V., De Berardis, D., Shoib, S., Martinotti, G., & Maina, G. (2025). Psychotic-like experiences in young recreational users of ketamine: A case study. Journal of Psychoactive Drugs, 1–10.
Rusz, C. M., Ősz, B. E., Jîtcă, G., Miklos, A., Bătrînu, M. G., & Imre, S. (2021). Off-label medication: From a simple concept to complex practical aspects. International Journal of Environmental Research and Public Health, 18(19), 10447. https://www.mdpi.com
Santos, I. C., Maia, D., Dinis-Oliveira, R. J., & Barbosa, D. J. (2024). New psychoactive substances: Health and legal challenges. Psychoactives. https://www.mdpi.com
Schlag, A. K., Aday, J., Salam, I., Neill, J. C., & Nutt, D. J. (2022). Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. Journal of Psychopharmacology, 36(3), 258–272. https://www.sagepub.com
Shimozawa, S., Usuda, D., Sasaki, T., Tsuge, S., Sakurai, R., Kawai, K., ... & Sugita, M. (2023). High doses of dextromethorphan induced shock and convulsions in a 19-year-old female: A case report. World Journal of Clinical Cases, 11(16), 3870. https://www.nih.gov
Shiromwar, S. S., Chidrawar, V. R., Singh, S., Chitme, H. R., Maheshwari, R., & Sultana, S. (2024). Multi-faceted anti-obesity effects of N-methyl-D-aspartate (NMDA) receptor modulators: Central-peripheral crosstalk. Journal of Molecular Neuroscience, 74(1), 13. https://www.researchsquare.com
Singla, R., Mishra, A., Joshi, R., Kumar, R., Sarma, P., Sharma, A. R., ... & Medhi, B. (2021). Inhibition of the ERK1/2 phosphorylation by dextromethorphan protects against core autistic symptoms in VPA-induced autistic rats: In silico and in vivo drug repurposition study. ACS Chemical Neuroscience, 12(10), 1749–1767.
Stewart, T. (2024). Schizophrenia, psychosis, and delusions. In Psychiatric-Mental Health Nurse Practitioner Program Companion and Board Certification Exam Review Workbook (pp. 261–292). Cham: Springer Nature Switzerland.
Taflaj, B., La Maida, N., Tittarelli, R., Di Trana, A., & D’Acquarica, I. (2024). New psychoactive substances toxicity: A systematic review of acute and chronic psychiatric effects. International Journal of Molecular Sciences, 25(17), 9484. https://www.mdpi.com
Thiankhaw, K., Chattipakorn, N., & Chattipakorn, S. C. (2022). PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes. Environmental Pollution.
Wang, Y. M., Xia, C. Y., Jia, H. M., He, J., Lian, W. W., Yan, Y., ... & Xu, J. K. (2022). Sigma-1 receptor: A potential target for the development of antidepressants. Neurochemistry International, 159, 105390.
Witkin, J. M., Newman, A. H., Izenwasser, S., & Smith, J. L. (2021). N-substituted-3-alkoxy-derivatives of dextromethorphan are functional NMDA receptor antagonists in vivo: Evidence from an NMDA-induced seizure model in rats. Pharmacology. https://www.sciencedirect.com
Wörmeyer, L., Nortmann, O., Hamacher, A., Uhlemeyer, C., Belgardt, B., Eberhard, D., ... & Welters, A. (2024). The N-methyl-D-aspartate receptor antagonist dextromethorphan improves glucose homeostasis and preserves pancreatic islets in NOD mice. Hormone and Metabolic Research, 56(3), 223–234. https://www.thieme-connect.com
Yang, H., Deng, H. M., Chen, H. Y., Tang, S. H., Deng, F., Lu, Y. G., & Song, J. C. (2022). The impact of age on propofol requirement for inducing loss of consciousness in elderly surgical patients. Frontiers in Pharmacology, 13, 739552. https://www.frontiersin.org
Zaremba, M., Serafin, P., & Kleczkowska, P. (2023). Antipsychotic drugs efficacy in dextromethorphan-induced psychosis. Biomedicines. https://www.mdpi.com
Zhang, J. (2024). Population scale and public measures of drug use, alcohol use, and tobacco use. Lecture Notes in Education Psychology and Public Media, 67, 77–82. https://www.ewadirect.com
Zuo, H. L., Huang, H. Y., Lin, Y. C. D., Cai, X. X., Kong, X. J., Luo, D. L., ... & Huang, H. D. (2022). Enzyme activity of natural products on cytochrome P450. Molecules, 27(2), 515. https://www.mdpi.com
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