Designer Drugs and Novel Psychoactive Substances: Chemistry, Toxicological Effects, Abuse Trends, and Forensic Challenges

Abstract

Designer drugs or Novel Psychoactive Substances (NPSs) are synthetic compounds developed to mimic the pharmacological effects of controlled substances, but circumventing legal restrictions. The swift appearance of these compounds has become a significant concern to the global public health and forensic science owing to their increasing abuse potential, unpredictable toxicity, and continuous structural modifications. This review article offers a comprehensive overview of designer drugs, covering their classification, chemistry, pharmacological properties, street names, mechanisms of action, physiological and psychological effects, and current trends in abuse. The review also considers their side-effects on the cardiovascular, neurological, renal, hepatic and psychiatric systems including psychosis, hallucinations, aggression, addiction and fatal overdose. It critically analyses current global patterns of abuse, online drug markets and social media driven distribution. The forensic toxicology challenges in connection with detection, identification and interpretation of designer drugs are also reviewed with emphasis on the use of advanced analytical techniques including GC–MS, LC–MS/MS, high-resolution mass spectrometry and emerging AI-assisted forensic approaches. The review highlights the urgent need for more extensive forensic monitoring, regulatory changes, and multidisciplinary strategies to combat the rapidly evolving epidemic of designer drugs.

Introduction

Novel Psychoactive Substances (NPSs), commonly known as designer drugs, are synthetic chemicals created to mimic the effects of controlled drugs such as cannabis, cocaine, methamphetamine, LSD, and opioids while avoiding legal restrictions through slight chemical modifications. Their rapid emergence, widespread availability, and unpredictable toxicity have become major global public health and forensic concerns.

Evolution and Classification

Designer drugs are continuously modified by illicit manufacturers to bypass drug laws and evade detection. They are commonly marketed as “legal highs,” “research chemicals,” “bath salts,” or “herbal incense.” Major categories include:

• Synthetic Cannabinoids (e.g., JWH-018, AB-FUBINACA; sold as “Spice” and “K2”)
• Synthetic Cathinones (e.g., mephedrone, MDPV, α-PVP; sold as “Flakka” and “bath salts”)
• Phenethylamines and NBOMe Compounds (e.g., 25I-NBOMe)
• Synthetic Opioids and Fentanyl Analogs (e.g., carfentanil, acetylfentanyl, nitazenes)
• Tryptamines and Dissociative Drugs (e.g., methoxetamine)
• Designer Benzodiazepines (e.g., etizolam, flualprazolam)

Chemistry and Structural Modifications

The rapid growth of NPSs is driven by small chemical changes such as fluorination, alkyl-chain modification, ring substitution, and bioisosteric replacement. These modifications can:

• Increase drug potency and toxicity.
• Alter receptor interactions and metabolism.
• Help drugs evade legal controls and traditional drug screening methods.

Some synthetic opioids, such as Carfentanil, are thousands of times more potent than morphine, making overdose risks extremely high.

Physiological and Psychological Effects

Designer drugs can produce severe and unpredictable health effects because they strongly affect neurotransmitter systems.

Physical effects include:

• Rapid heart rate and high blood pressure
• Hyperthermia
• Seizures
• Kidney and liver damage
• Respiratory depression
• Cardiac arrest
• Fatal overdose

Psychological effects include:

• Anxiety and paranoia
• Hallucinations
• Psychosis
• Aggression and violent behavior
• Insomnia
• Suicidal thoughts
• Long-term cognitive impairment and addiction

Synthetic opioids are particularly dangerous due to their ability to cause fatal respiratory depression at extremely small doses.

Forensic and Detection Challenges

The constantly changing chemical structures of designer drugs make detection difficult. Traditional toxicology tests often fail to identify new compounds. Therefore, advanced analytical techniques are required, including:

• Gas Chromatography–Mass Spectrometry (GC–MS)
• Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)
• High-Resolution Mass Spectrometry (HRMS)
• Nuclear Magnetic Resonance (NMR)
• AI-assisted forensic toxicology tools

Public Health Concerns

Designer drugs are widely sold through street markets, online platforms, and dark web marketplaces, often targeting adolescents and young adults. Their unknown composition, high potency, and misleading marketing as “safe” or “legal” alternatives contribute to increasing abuse and overdose deaths worldwide.

Conclusion

Designer drugs and novel psychoactive substances represent one of the most rapidly evolving threats in modern forensic toxicology and public health. Continuous structural modification of these compounds has resulted in highly potent psychoactive substances capable of producing severe physiological toxicity, psychiatric complications, addiction, and fatal overdose. Synthetic cannabinoids, synthetic cathinones, fentanyl analogs, NBOMe compounds, and emerging synthetic opioids have demonstrated toxicological effects that frequently exceed those associated with conventional illicit drugs. The increasing global abuse of designer drugs, particularly among adolescents and young adults, highlights the urgent need for improved public awareness, toxicological surveillance, forensic monitoring, and international regulatory cooperation. The unpredictable chemistry and pharmacology of these compounds significantly complicate clinical management and forensic investigation because newly emerging analogs often remain poorly characterized. Overall, designer drugs are not harmless or safer alternatives to conventional narcotics. Instead, they represent highly dangerous synthetic substances with serious physiological and psychological consequences that can lead to irreversible organ damage, severe psychiatric disorders, and death. Continued multidisciplinary collaboration among forensic scientists, toxicologists, healthcare professionals, policymakers, and public health agencies is essential to effectively address the growing global crisis associated with designer drug abuse.

References

[1] Shafi, A. J. Berry, H. Sumnall, D. M. Wood, and D. K. Tracy, “New psychoactive substances: a review and updates,” Ther. Adv. Psychopharmacol., vol. 10, p. 2045125320967197, 2020, doi: 10.1177/2045125320967197. [2] M. J. Y. Neoh, A. Carollo, M. Lim, O. Corazza, A. Coppola, and G. Esposito, “The novel psychoactive substances epidemic: A scientometric perspective,” Addiction Neuroscience, vol. 5, p. 100060, Mar. 2023, doi: 10.1016/J.ADDICN.2022.100060. [3] H. Upadhyay, U. Harikrishnan, D. Bhatt, N. Dhadnekar, K. Kumar, and M. Panchal, “Calixarene: The Dawn of a New Era in Forensic Chemistry,” Curr. Org. Chem., vol. 26, no. 22, pp. 2005–2015, Jan. 2023, doi: 10.2174/1385272827666230118094847/CITE/REFWORKS. [4] S. M. Haque, A. Kabir, N. Y. Abu-Thabit, A. S. Kachhawaha, H. Upadhyay, and M. R. Siddiqui, “Application of Molecularly Imprinted Polymers Combined with Gas Chromatography–Mass Spectrophotometry for Detecting Organic Pollutants in Environmental, Biological, and Food Matrices,” Crit. Rev. Anal. Chem., 2025, doi: 10.1080/10408347.2025.2569703. [5] E. Ferrari Júnior, B. H. M. Leite, E. B. Gomes, T. M. Vieira, P. Sepulveda, and E. D. Caldas, “Fatal cases involving new psychoactive substances and trends in analytical techniques,” Frontiers in Toxicology, vol. 4, p. 1033733, Oct. 2022, doi: 10.3389/FTOX.2022.1033733/FULL. [6] N. Dhadnekar, K. Kumar, D. Bhatt, H. Upadhyay, S. Pillai, and U. Harikrishnan, “Detection of Amisulpride Using a Chromium-Salophen Optical Probe,” Arab Journal of Forensic Sciences and Forensic Medicine, vol. 6, no. Special Issue, pp. 155–164, 2024, doi: 10.26735/TZYP3860. [7] H. Upadhyay et al., “A Highly Selective Pyrene Appended Oxacalixarene Receptor for MNA and 4-NP Detection: an Experimental and Computational Study,” Journal of Fluorescence, vol. 34, no. 6, pp. 2825–2835, Nov. 2023, doi: 10.1007/S10895-023-03470-2. [8] H. Upadhyay et al., “Selective detection of 2,4-DNT using sulfonyl chloride-appended oxacalix[4]arene: synthesis, spectroscopic analysis and biological evaluation,” Discover Molecules, vol. 3, no. 1, pp. 1–12, Jan. 2026, doi: 10.1007/S44345-025-00040-W. [9] “Novel Psychoactive Substances | NMS Labs.” Accessed: May 25, 2026. [Online]. Available: https://nmslabs.com/forensic-testing/novel-psychoactive-substances [10] J. B. Zawilska, M. Kacela, and P. Adamowicz, “NBOMes–Highly Potent and Toxic Alternatives of LSD,” Front. Neurosci., vol. 14, Feb. 2020, doi: 10.3389/fnins.2020.00078. [11] “Reports of Adverse Events Associated with Use of Novel Psychoactive Substances, 2017–2020: A Review.” Accessed: May 25, 2026. [Online]. Available: https://www.cfsre.org/resources/publications/reports-of-adverse-events-associated-with-use-of-novel-psychoactive-substances-2017-2020-a-review [12] “Novel psychoactive substances | National Institute of Justice.” Accessed: May 25, 2026. [Online]. Available: https://nij.ojp.gov/taxonomy/term/novel-psychoactive-substances [13] D. Luethi and M. E. Liechti, “Designer drugs: mechanism of action and adverse effects,” Arch. Toxicol., vol. 94, no. 4, pp. 1085–1133, 2020, doi: 10.1007/s00204-020-02693-7. [14] M. H. Baumann and N. D. Volkow, “Abuse of new psychoactive substances: threats and solutions,” Neuropsychopharmacology, vol. 41, no. 3, pp. 663–665, 2016, doi: 10.1038/npp.2015.264. [15] S. D. Banister and M. Connor, “The chemistry and pharmacology of synthetic cannabinoid receptor agonists as new psychoactive substances,” Handb. Exp. Pharmacol., vol. 252, pp. 191–226, 2018, doi: 10.1007/164_2018_144. [16] A. Shafi, A. J. Berry, H. Sumnall, D. M. Wood, and D. K. Tracy, “New psychoactive substances: a review and updates,” Ther. Adv. Psychopharmacol., vol. 10, p. 2045125320967197, 2020, doi: 10.1177/2045125320967197. [17] R. Roque-Bravo et al., “Synthetic cannabinoids: a pharmacological and toxicological review,” Annu. Rev. Pharmacol. Toxicol., vol. 63, pp. 363–387, 2023, doi: 10.1146/annurev-pharmtox-031122-113758. [18] A. Alipour et al., “Review of the many faces of synthetic cannabinoid toxicities,” Int. J. High Risk Behav. Addict., vol. 8, no. 1, 2019, doi: 10.5812/ijhrba.64147. [19] L. D. Simmler et al., “Pharmacological characterization of designer cathinones in vitro,” Br. J. Pharmacol., vol. 168, no. 2, pp. 458–470, 2013, doi: 10.1111/j.1476-5381.2012.02145.x. [20] M. H. Baumann et al., “Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products,” Neuropsychopharmacology, vol. 38, no. 4, pp. 552–562, 2013, doi: 10.1038/npp.2012.204. [21] E. Ferrari Júnior et al., “Fatal cases involving new psychoactive substances and trends in analytical techniques,” Front. Toxicol., vol. 4, p. 1033733, 2022, doi: 10.3389/ftox.2022.1033733. [22] J. B. Zawilska and D. Andrzejczak, “Next generation of novel psychoactive substances on the horizon – A complex problem to face,” Drug Alcohol Depend., vol. 157, pp. 1–17, 2015, doi: 10.1016/j.drugalcdep.2015.09.030. [23] J. B. Zawilska, M. Kacela, and P. Adamowicz, “NBOMes–Highly Potent and Toxic Alternatives of LSD,” Front. Neurosci., vol. 14, 2020, doi: 10.3389/fnins.2020.00078. [24] P. Armenian, K. T. Vo, J. Barr-Walker, and O. M. Lynch, “Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review,” Neuropharmacology, vol. 134, pp. 121–132, 2018, doi: 10.1016/j.neuropharm.2017.10.016. [25] R. S. Vardanyan and V. J. Hruby, “Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications,” Future Med. Chem., vol. 6, no. 4, pp. 385–412, 2014, doi: 10.4155/fmc.13.215. [26] J. M. Corkery et al., “The recreational tryptamines: an emerging class of hallucinogenic psychoactive drugs,” Prog. Neuropsychopharmacol. Biol. Psychiatry, vol. 39, no. 2, pp. 259–268, 2012, doi: 10.1016/j.pnpbp.2012.07.017. [27] M. R. Morris and R. J. Wallach, “From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs,” Drug Testing and Analysis, vol. 6, no. 7–8, pp. 614–632, 2014, doi: 10.1002/dta.1620. [28] M. R. Meyer, F. T. Peters, and H. H. Maurer, “The role of metabolism in drug discovery and development of new psychoactive substances,” Curr. Drug Metab., vol. 11, no. 5, pp. 468–482, 2010, doi: 10.2174/138920010791514225. [29] J. B. Zawilska, “An expanding world of novel psychoactive substances: opioids,” Front. Psychiatry, vol. 8, p. 110, 2017, doi: 10.3389/fpsyt.2017.00110. [30] S. D. Banister et al., “Pharmacology of indole and indazole synthetic cannabinoid designer drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, and 5F-ADB-PINACA,” ACS Chem. Neurosci., vol. 7, no. 9, pp. 1241–1254, 2016, doi: 10.1021/acschemneuro.6b00137. [31] M. H. Baumann et al., “Bath salts, spice, and related designer drugs: the science behind the headlines,” J. Neurosci., vol. 34, no. 46, pp. 15150–15158, 2014, doi: 10.1523/JNEUROSCI.3223-14.2014. [32] R. J. Wallach, S. M. Brandt, and M. H. Baumann, “The NBOMe hallucinogenic drug series: pharmacology, toxicology, and structure–activity relationships,” Drug Test. Anal., vol. 10, no. 1, pp. 114–125, 2018, doi: 10.1002/dta.2219. [33] P. Armenian et al., “Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review,” Neuropharmacology, vol. 134, pp. 121–132, 2018, doi: 10.1016/j.neuropharm.2017.10.016. [34] J. Moosmann and V. Auwärter, “Designer benzodiazepines: another class of new psychoactive substances,” Handb. Exp. Pharmacol., vol. 252, pp. 383–410, 2018, doi: 10.1007/164_2018_154. [35] H. H. Maurer, “Mass spectrometry in toxicological analysis of drugs and poisons,” Anal. Bioanal. Chem., vol. 381, no. 1, pp. 110–118, 2005, doi: 10.1007/s00216-004-2947-4. [36] F. T. Peters, O. H. Drummer, and F. Musshoff, “Validation of new methods,” Forensic Sci. Int., vol. 165, no. 2–3, pp. 216–224, 2007, doi: 10.1016/j.forsciint.2006.05.021. [37] D. Luethi and M. E. Liechti, “Designer drugs: mechanism of action and adverse effects,” Arch. Toxicol., vol. 94, no. 4, pp. 1085–1133, 2020, doi: 10.1007/s00204-020-02693-7. [38] S. D. Banister and M. Connor, “The chemistry and pharmacology of synthetic cannabinoid receptor agonists as new psychoactive substances,” Handb. Exp. Pharmacol., vol. 252, pp. 191–226, 2018, doi: 10.1007/164_2018_144. [39] B. Bhanushali et al., “AKI associated with synthetic cannabinoids,” Clin. J. Am. Soc. Nephrol., vol. 8, no. 4, pp. 523–526, 2013, doi: 10.2215/CJN.05690612. [40] M. H. Baumann et al., “Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products,” Neuropsychopharmacology, vol. 38, no. 4, pp. 552–562, 2013, doi: 10.1038/npp.2012.204. [41] E. Ferrari Júnior et al., “Fatal cases involving new psychoactive substances and trends in analytical techniques,” Front. Toxicol., vol. 4, p. 1033733, 2022, doi: 10.3389/ftox.2022.1033733. [42] P. Armenian et al., “Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review,” Neuropharmacology, vol. 134, pp. 121–132, 2018, doi: 10.1016/j.neuropharm.2017.10.016. [43] V. Ricci et al., “Novel psychoactive substances and psychosis,” Neurosci. Biobehav. Rev., vol. 168, p. 105962, 2025, doi: 10.1016/j.neubiorev.2024.105962. [44] A. Alipour et al., “Review of the many faces of synthetic cannabinoid toxicities,” Int. J. High Risk Behav. Addict., vol. 8, no. 1, 2019, doi: 10.5812/ijhrba.64147. [45] J. B. Zawilska, M. Kacela, and P. Adamowicz, “NBOMes–Highly Potent and Toxic Alternatives of LSD,” Front. Neurosci., vol. 14, 2020, doi: 10.3389/fnins.2020.00078. [46] M. H. Baumann and N. D. Volkow, “Abuse of new psychoactive substances: threats and solutions,” Neuropsychopharmacology, vol. 41, no. 3, pp. 663–665, 2016, doi: 10.1038/npp.2015.264. [47] S. Tai and W. E. Fantegrossi, “Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites,” Curr. Top. Behav. Neurosci., vol. 32, pp. 249–262, 2017, doi: 10.1007/7854_2016_60.

Copyright

Copyright © 2026 Dr. Himali Upadhyay. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.