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Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal

  • Substance Use and Related Disorders (F Levin and E Dakwar, Section Editors)
  • Published:
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Abstract

Although several chemical structural classes of synthetic cannabinoids (SCs) were recently classified as Schedule I substances, rates of use and cases of serious toxic effects remain high. While case reports and media bring attention to severe SC toxicity, daily SC use resulting in dependence and withdrawal is a significant concern that is often overlooked when discussing the risks of these drugs. There is a rich literature on evidence-based approaches to treating substance use disorders associated with most abused drugs, yet little has been published regarding how to best treat symptoms related to SC dependence given its recency as an emerging clinically significant issue. This review provides a background of the pharmacology of SCs, recent findings of adverse effects associated with both acute intoxication and withdrawal as a consequence of daily use, and treatment approaches that have been implemented to address these issues, with an emphasis on pharmacotherapies for managing detoxification. In order to determine prevalence of use in cannabis smokers, a population at high risk for SC use, we obtained data on demographics of SC users, frequency of use, and adverse effects over a 3.5-year period (2012–2015) in the New York City metropolitan area, a region with a recent history of high SC use. While controlled studies on the physiological and behavioral effects of SCs are lacking, it is clear that risks associated with using these drugs pertain not only to the unpredictable and severe nature of acute intoxication but also to the effects of long-term, chronic use. Recent reports in the literature parallel findings from our survey, indicating that there is a subset of people who use SCs daily. Although withdrawal has not been systematically characterized and effective treatments have yet to be elucidated, some symptom relief has been reported with benzodiazepines and the atypical antipsychotic, quetiapine. Given the continued use and abuse of SCs, empirical studies characterizing (1) SCs acute effects, (2) withdrawal upon cessation of use, and (3) effective treatment strategies for SC use disorder are urgently needed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wehrman J. Fake marijuana spurs more than 2,500 calls to U.S. poison centers this year alone. Alexandra: American Association of Poison Control Centers; 2010.

    Google Scholar 

  2. United States Drug Enforcement Administration. Schedules of controlled substances: placement of five synthetic cannabinoids into Schedule I, 21 CFR Part 1308 [Docket No. DEA-345]. Fed Regist. 2012;77:12508–14.

    Google Scholar 

  3. United States Drug Enforcement Administration. DEA makes three more “fake pot” drugs temporarily illegal today. Washington: United States Department of Justice; 2013.

    Google Scholar 

  4. United States Drug Enforcement Administration. DEA news: huge synthetic drug takedown. Washington: United States Department of Justice; 2014.

    Google Scholar 

  5. United States Drug Enforcement Administration. Schedules of controlled substances: temporary placement of the synthetic cannabinoid MAB-CHMINACA into Schedule I. United States Department of Justice, Washington, D.C. 2015. Retrieved on November 11, 2015. http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0916_2.htm

  6. Law R, Schier C, Martin A, Chang A, Wolkin A, Centers for Disease Control (CDC). Notes from the field: increase in reported adverse health effects related to synthetic cannabinoid use—United States, January–May 2015. MMWR Morb Mortal Wkly Rep. 2015;64:618–9.

    PubMed  Google Scholar 

  7. Kasper AM, Ridpath AD, Arnold JK, Chatham-Stephens K, Morrison M, Olayinka O, et al. Severe illness associated with reported use of synthetic cannabinoids—Mississippi, April 2015. MMWR Morb Mortal Wkly Rep. 2015;64:1121–2.

    Article  PubMed  Google Scholar 

  8. New York City Department of Health and Mental Hygiene. Increase in synthetic cannabinoid (marijuana)-related adverse events and emergency department visits. April, 2015. http://www.nyc.gov/html/doh/downloads/pdf/ah/marijuana-alert.pdf. Accessed 20 November 2015.

  9. New York City Department of Health and Mental Hygiene. Increase in synthetic cannabinoid (K2)-related adverse events and emergency department visits. September 2015. https://a816-health30ssl.nyc.gov/sites/nychan/Lists/AlertUpdateAdvisoryDocuments/Synthetic%20cannabinoids-HAN-advisory_Summer%202015%20-penultimate8.pdf. Accessed 20 November 2015.

  10. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend. 2014.

  11. Atwood BK, Huffman J, Straiker A, Mackie K. JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol. 2010;60:585–93.

    Article  Google Scholar 

  12. Atwood BK, Lee D, Straiker A, Widlanski TS, Mackie K. CP47,497-C8 and JWH073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists. Eur J Pharmacol. 2011;659:139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chin CN, Murphy JW, Huffman JW, Kendall DA. The third transmembrane helix of the cannabinoid receptor plays a role in the selectivity of aminoalkylindoles for CB2, peripheral cannabinoid receptor. J Pharmacol Exp Ther. 1999;291:837–44.

    CAS  PubMed  Google Scholar 

  14. Hsieh C, Brown S, Derleth C, Mackie K. Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem. 1999;73:493–501.

    Article  CAS  PubMed  Google Scholar 

  15. Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ. β-Arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol Psychiatry. 2012;71:714–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodriguez JS, McMahon LR. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. Eur J Pharmacol. 2014;740:151–9.

    Article  CAS  PubMed  Google Scholar 

  17. Tai S, Hyatt WS, Gu C, Franks LN, Vasiljevik T, Brents LK, et al. Repeated administration of phytocannabinoid Δ9-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacol Res. 2015;102:22–32.

    Article  CAS  PubMed  Google Scholar 

  18. González S, Cebeira M, Fernández-Ruiz J. Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol Biochem Behav. 2005;81:300–18.

    Article  PubMed  Google Scholar 

  19. Wiley JL, Compton DR, Dai D, Lainton JA, Phillips M, Huffman JW, et al. Structure-activity relationships of indole- and pyrrole-derived cannabinoids. J Pharmacol Exp Ther. 1998;285:995–1004.

    CAS  PubMed  Google Scholar 

  20. Jarbe TU, Deng H, Vadivel SK, Makriyannis A. Cannabinergic aminoalkylindoles, including AM678=JWH018 found in ‘Spice’, examined using drug (delta(9)-tetrahydrocannabinol) discrimination for rats. Behav Pharmacol. 2011;22:498–507.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ginsburg BC, Schulze DR, Hruba L, McMahon LR. JWH-018 and JWH-073: delta-tetrahydrocannabinol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther. 2012;340:37–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: mechanism underlying greater toxicity? Life Sci. 2013;97:45–54. A comprehensive review of preclinical studies that demonstrate pharmacological differences between synthetic cannabinoids and THC that contribute to their enhanced toxic effects.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Marusich JA, Huffman JW. Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sci. 2014;97:55–63.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, et al. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol. 2012;83:952–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Auwarter V, Dresen S, Weinmann W, Muller M, Putz M, Ferreiros N. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom. 2009;44:832–7.

    Article  PubMed  Google Scholar 

  26. Renner KE. Delay of reinforcement: a historical review. Psychol Bull. 1964;61:341–61.

    Article  CAS  PubMed  Google Scholar 

  27. de Villiers P. Choice in concurrent schedules and a quantitative formulation of the law of effect. Handbook of Operant Behavior. 1977;233–287.

  28. Mello NK, Lukas SE, Bree MP, Mendelson JH. Progressive ratio performance maintained by buprenorphine, heroin and methadone in Macaque monkeys. Drug Alcohol Depend. 1977;21(2):81–97.

    Article  Google Scholar 

  29. Winger G, Hursh SR, Casey KL, Woods JH. Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action. J Pharmacol Exp Ther. 2002;301(2):690–7.

    Article  CAS  PubMed  Google Scholar 

  30. Burkey TH, Quock RM, Consroe P, Roeske WR, Yamamura HI. Delta 9 tetrahydrocannabinol is a partial agonist of cannabinoid receptors in mouse brain. Eur J Pharmacol. 1997;323:R3–4.

    Article  CAS  PubMed  Google Scholar 

  31. Hruba L, McMahon LR. The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. Eur J Pharmacol. 2014;727:35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hovav E, Weinstock M. Temporal factors influencing the development of acute tolerance to opiates. J Pharmacol Exp Ther. 1987;242:251–6.

    CAS  PubMed  Google Scholar 

  33. Baumann MH, Solis E, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL. Bath salts, Spice, and related designer drugs: the science behind the headline. J Neurosci. 2014;34:15150–8.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Seely KA, Patton AL, Moran CL, Womack ML, Prather PL, Fantegrossi WE, et al. Forensic investigation of K2, Spice, and “bath salt” commercial preparations: a three-year study of new designer drug products containing synthetic cannabinoid, stimulant, and hallucinogenic compounds. Forensic Sci Int. 2013;233:416–22. This article describes findings from a forensic analyses of 3000 drug-related products confiscated over a three year period. This analysis describes the prevalence of synthetic cannabinoid compounds in confiscated items, and the wide range of compounds detected within and across products.

    Article  CAS  PubMed  Google Scholar 

  35. Fattore L, Fratta W. Beyond THC: the new generation of cannabinoid designer drugs. Front Behav Neurosci. 2011;5:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction. 2013;108:534–44. This article provides a comprehensive description of acute toxic effects due to confirmed synthetic cannabinoid use including onset, duration, and severity of symptom, and symptom management as a function of specific synthetic cannabinoids detected by serum and urine toxicology.

    Article  PubMed  Google Scholar 

  37. Meijer KA, Russo RR, Adhvaryu DV. Smoking synthetic marijuana leads to self-mutilation requiring bilateral amputations. Orthopedics. 2014;37:391–4.

    Article  Google Scholar 

  38. Jinwala FN, Gupta M. Synthetic cannabis and respiratory depression. J Child Adolesc Psychopharmacol. 2012;22:459–62.

    Article  CAS  PubMed  Google Scholar 

  39. Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics. 2011;128:1622–7.

    Article  Google Scholar 

  40. Davis C, Boddington D. Teenage cardiac arrest following abuse of synthetic cannabis. Heart Lung Circ. 2015;24:e162–3.

    Article  CAS  PubMed  Google Scholar 

  41. Bhanushali GK, Jain G, Fatima H, Leisch LJ, Thomley-Brown D. AKI associated with synthetic cannabinoids: a case series. Clin J Am Soc Nephrol. 2013;8:523–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hopkins CY, Gilchrist BL. A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. J Emerg Med. 2013;45:544–6.

    Article  PubMed  Google Scholar 

  43. Bick BL, Szostek JH, Mangan TF. Synthetic cannabinoid leading to cannabinoid hyperemesis syndrome. Mayo Clin Proc. 2014;89:1168–9.

    Article  PubMed  Google Scholar 

  44. Ukaigwe A, Karmacharya P, Donato A. A gut gone to pot: a case of cannabinoid hyperemesis syndrome due to K2, a synthetic cannabinoid. Case Rep Emerg Med. 2014;2014:167098.

    PubMed  PubMed Central  Google Scholar 

  45. Sevinc MM, Kinaci E, Bayrak S, Yardimci AH, Cakar E, Bektaş H. Extraordinary cause of acute gastric dilatation and hepatic portal venous gas: chronic use of synthetic cannabinoid. World J Gastroenterol. 2015;21:10704–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sweeney B, Talebi S, Toro D, Gonzalez K, Menoscal JP, Shaw R, et al. Hyperthermia and severe rhabdomyolysis from synthetic cannabinoids. Am J Emerg Med. 2015. doi:10.1016/j.ajem.2015.05.052.

    Google Scholar 

  47. Takematsu M, Hoffman RS, Nelson LS, Schechter JM, Moran JH, Wiener SW. A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid. Clin Toxicol. 2014;52:973–5.

    Article  CAS  Google Scholar 

  48. Lapoint J, James LP, Moran CL, Nelson LS, Hoffman RS, Moran JH. Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol. 2011;49:760–4.

    Article  CAS  Google Scholar 

  49. Schep LJ, Slaughter RJ, Hudson S, Place R, Watts M. Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues. Hum Exp Toxicol. 2015;34:557–60.

    Article  CAS  PubMed  Google Scholar 

  50. Durand D, Delgado LL, de la Parra-Pellot DM, Nichols-Vinueza D. Psychosis and severe rhabdomyolysis associated with synthetic cannabinoid use: a case report. Clin Schizophr Relat Psychoses. 2015;8:205–8.

    Article  PubMed  Google Scholar 

  51. Ustundag MF, Ozhan Ibis E, Yucel A, Ozcan H. Synthetic cannabis-induced mania. Case Rep Psychiatry. 2015. doi:10.1155/2015/310930.

    Google Scholar 

  52. Rodgman CJ, Verrico CD, Worthy RB, Lewis EE. Inpatient detoxification from a synthetic cannabinoid and control of postdetoxification cravings with naltrexone. Prim Care Companion CNS. 2014;16:4.

    Google Scholar 

  53. Macfarlane V, Christie G. Synthetic cannabinoid withdrawal: a new demand on detoxification services. Drug Alcohol Rev. 2015;34:147–53. This article reports on demographics of a population presenting for treatment for problematic synthetic cannabinoid use, withdrawal symptoms, and treatment strategies.

    Article  PubMed  Google Scholar 

  54. Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K. Withdrawal phenomena and dependence syndrome after the consumption of “spice gold”. Dtsch Arztebl Int. 2009;106:464–7.

    PubMed  PubMed Central  Google Scholar 

  55. Nacca N, Vatti D, Sullivan R, Sud P, Su M, Marraffa J. The synthetic cannabinoid withdrawal syndrome. J Addict Med. 2013;7:296–8.

    Article  CAS  PubMed  Google Scholar 

  56. Sampson CS, Bedy SM, Carlisle T. Withdrawal seizures seen in the setting of synthetic cannabinoid abuse. Am J Emerg Med. 2015;33:1712.e3.

    Article  PubMed  Google Scholar 

  57. Cooper ZD, Haney M. Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor. Addict Biol. 2008;13:188–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Oluwabusi OO, Lobach L, Akhtar U, Youngman B, Ambrosini PJ. Synthetic cannabinoid-induced psychosis: two adolescent cases. J Child Adolesc Psychopharmacol. 2012;22:393–5.

    Article  PubMed  Google Scholar 

  59. Hu X, Primack BA, Barnett TE, Cook RL. College students and use of K2: an emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy. 2011;6:16.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend. 2012;120:238–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kelly BC, Wells BE, Pawson M, Leclair A, Parsons JT, Golub SA. Novel psychoactive drug use among younger adults involved in US nightlife scenes. Drug Alcohol Rev. 2013;32:588–93.

    Article  PubMed  Google Scholar 

  62. Spaderna M, Addy PH, D’Souza DC. Spicing things up: synthetic cannabinoids. Psychopharmacology. 2013;228:525–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Winstock AR, Barratt MJ. Synthetic cannabis: a comparison of patterns of use and effect profile with natural cannabis in a large global sample. Drug Alcohol Depend. 2013;131:106–11.

    Article  CAS  PubMed  Google Scholar 

  64. Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology. 2013;38:1557–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by the US National Institute on Drug Abuse Grants DA039123, DA036809, and DA02775. The authors acknowledge and appreciate Dr. Margaret Haney for the discussion and feedback throughout manuscript preparation and the exceptional assistance of Damaris Rocha, Vivian Mao, Nicole Ann Borchard, Ursula Rogers, Olivia Derella, Bennett Wechsler, Stephanie Rivera, Chananda Thavisin, Divya Ramesh, and Jorge Ginory-Perez for interviewing participants and data collection.

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  1. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY, 10032, USA

    Ziva D. Cooper

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Correspondence to Ziva D. Cooper.

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All study procedures were approved by the Institutional Review Board of the New York State Psychiatric Institute and were in accord with the Declaration of Helsinki.

Conflict of Interest

Ziva D. Cooper is a non-compensated board member of KannaLife, Inc. and has received consultancy fees from PharmaCann, LLC. Dr. Cooper has received research funds from Insys Therapeutics.

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This manuscript does include data obtained from human subjects.

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This article is part of the Topical Collection on Substance Use and Related Disorders

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Cooper, Z.D. Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal. Curr Psychiatry Rep 18, 52 (2016). https://doi.org/10.1007/s11920-016-0694-1

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