Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Current Psychiatry Reports
Published in: Current Psychiatry Reports 5/2016

01-05-2016 | Substance Use and Related Disorders (F Levin and E Dakwar, Section Editors)

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

Author: Ziva D. Cooper

Published in: Current Psychiatry Reports | Issue 5/2016

Login to get access

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.
Literature
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.
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.
3.
United States Drug Enforcement Administration. DEA makes three more “fake pot” drugs temporarily illegal today. Washington: United States Department of Justice; 2013.
4.
United States Drug Enforcement Administration. DEA news: huge synthetic drug takedown. Washington: United States Department of Justice; 2014.
5.
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
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.CrossRefPubMed
8.
9.
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.CrossRef
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.CrossRefPubMedPubMedCentral
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.PubMed
14.
Hsieh C, Brown S, Derleth C, Mackie K. Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem. 1999;73:493–501.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
26.
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
32.
Hovav E, Weinstock M. Temporal factors influencing the development of acute tolerance to opiates. J Pharmacol Exp Ther. 1987;242:251–6.PubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
35.
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.CrossRefPubMed
37.
Meijer KA, Russo RR, Adhvaryu DV. Smoking synthetic marijuana leads to self-mutilation requiring bilateral amputations. Orthopedics. 2014;37:391–4.CrossRef
38.
Jinwala FN, Gupta M. Synthetic cannabis and respiratory depression. J Child Adolesc Psychopharmacol. 2012;22:459–62.CrossRefPubMed
39.
Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics. 2011;128:1622–7.CrossRef
40.
Davis C, Boddington D. Teenage cardiac arrest following abuse of synthetic cannabis. Heart Lung Circ. 2015;24:e162–3.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
42.
Hopkins CY, Gilchrist BL. A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. J Emerg Med. 2013;45:544–6.CrossRefPubMed
43.
Bick BL, Szostek JH, Mangan TF. Synthetic cannabinoid leading to cannabinoid hyperemesis syndrome. Mayo Clin Proc. 2014;89:1168–9.CrossRefPubMed
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.PubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
46.
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.CrossRef
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
51.
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.
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.CrossRefPubMed
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.PubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
57.
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
62.
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
Metadata
Title
Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal
Author
Ziva D. Cooper
Publication date
01-05-2016
Publisher
Springer US
Published in
Current Psychiatry Reports / Issue 5/2016
Print ISSN: 1523-3812
Electronic ISSN: 1535-1645
DOI
https://doi.org/10.1007/s11920-016-0694-1

Other articles of this Issue 5/2016

Current Psychiatry Reports 5/2016 Go to the issue

Child and Family Disaster Psychiatry (B Pfefferbaum, Section Editor)

Approaches to the Assessment of Children in the Context of Disasters

Substance Use and Related Disorders (F Levin and E Dakwar, Section Editors)

Alcohol and Drug Use and the Developing Brain

Complex Medical-Psychiatric Issues (MB Riba, Section Editor)

Update on Smoking Cessation: E-Cigarettes, Emerging Tobacco Products Trends, and New Technology-Based Interventions

Child and Family Disaster Psychiatry (B Pfefferbaum, Section Editor)

Children’s Cognitive Functioning in Disasters and Terrorism

Child and Family Disaster Psychiatry (B Pfefferbaum, Section Editor)

Youth Exposed to Terrorism: the Moderating Role of Ideology

Child and Adolescent Disorders (TD Benton, Section Editor)

Insomnia: the Sleeping Giant of Pediatric Public Health