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Anesthesiology28 papers

Delirium caused by synthetic cannabinoid

Last edited: 3 h ago

Overview

Delirium caused by synthetic cannabinoids is a neuropsychiatric syndrome characterized by acute changes in mental status, including fluctuating consciousness, attention deficits, and perceptual disturbances. This condition primarily affects individuals who misuse synthetic cannabinoids, often referred to as "spice" or "K2," which can have unpredictable psychoactive effects due to their structural variability and potency. Synthetic cannabinoids exert their effects primarily through agonism of cannabinoid receptors (CB1), leading to a spectrum of neurological and psychiatric symptoms. Recognizing and managing this condition is crucial in emergency departments and psychiatric units, as it can rapidly deteriorate patient outcomes if not promptly addressed. 121718

Pathophysiology

The pathophysiology of delirium induced by synthetic cannabinoids involves complex interactions at both molecular and cellular levels. Synthetic cannabinoids bind to CB1 receptors predominantly located in the brain, particularly in regions such as the hippocampus, prefrontal cortex, and basal ganglia, which are crucial for cognitive function and emotional regulation. Activation of these receptors disrupts normal neurotransmitter dynamics, including modulation of glutamate and GABA signaling pathways. Excessive glutamate release can lead to excitotoxicity, contributing to neuronal dysfunction and cognitive impairment characteristic of delirium. Additionally, synthetic cannabinoids can interfere with endogenous cannabinoid systems, potentially leading to dysregulation of mood, perception, and consciousness. The variability in chemical composition of synthetic cannabinoids exacerbates their unpredictable effects, making the clinical presentation heterogeneous and challenging to manage. 12152426

Epidemiology

The incidence of synthetic cannabinoid-induced delirium is difficult to quantify precisely due to underreporting and the evolving nature of these substances. However, cases have been increasingly reported in various geographic regions, particularly among younger populations and urban areas where synthetic cannabinoids are more accessible. Risk factors include frequent use, high potency of the substances, and co-use with other psychoactive drugs. There is a notable trend towards increased emergency department visits related to synthetic cannabinoid intoxication, highlighting a growing public health concern. Demographic data suggest a slight male predominance, though this can vary by region and reporting biases. 17182021

Clinical Presentation

Synthetic cannabinoid-induced delirium typically presents with acute onset of altered mental status, often accompanied by:
  • Fluctuating levels of consciousness
  • Disorganized thinking and incoherent speech
  • Hallucinations (visual, auditory, or tactile)
  • Agitation or hypoactive motor activity
  • Disrupted sleep-wake cycles
  • Anxiety or paranoia
  • Cognitive impairments affecting attention and memory

    • Red-flag features include severe agitation, autonomic instability, and signs of neuroleptic malignant syndrome, which may necessitate urgent intervention. Prompt recognition of these symptoms is crucial for timely management and to differentiate from other acute psychiatric or medical conditions. 171820

    Diagnosis

    The diagnosis of synthetic cannabinoid-induced delirium involves a comprehensive clinical assessment and exclusion of other potential causes. Key diagnostic criteria include:
  • Clinical History: Detailed history of synthetic cannabinoid use, onset of symptoms, and temporal relationship between use and delirium onset.
  • Physical Examination: Assessment for signs of intoxication, neurological deficits, and systemic effects.
  • Laboratory Tests:
    • - Toxicology screening (urine or blood) to detect synthetic cannabinoids. - Complete blood count (CBC), electrolytes, renal function tests, and liver function tests to rule out metabolic derangements.
  • Neuroimaging: Not routinely required but may be indicated if structural brain abnormalities are suspected.
  • Differential Diagnosis:
    • - Infectious Causes: Meningitis, encephalitis - Metabolic Disorders: Hyponatremia, uremia - Neuropsychiatric Disorders: Schizophrenia, bipolar disorder - Toxic-Ingestion Syndromes: Other drug intoxications (e.g., stimulants, sedatives)

    Specific Criteria:

  • History of Synthetic Cannabinoid Use: Confirmed through patient report or toxicology screening.
  • Acute Onset of Symptoms: Within hours to days following exposure.
  • Fluctuating Course: Mental status changes over short periods.
  • Cognitive Impairment: Attention deficits, disorganized thinking.
  • Perceptual Disturbances: Hallucinations, illusions.
  • Exclusion of Other Causes: Ruling out alternative etiologies through clinical evaluation and laboratory tests.

    • (Evidence: Moderate) 11718

    Differential Diagnosis

  • Acute Psychosis: Typically lacks the temporal link to substance use; requires psychiatric history evaluation.
  • Neuroleptic Malignant Syndrome: Presents with rigidity, hyperthermia, and autonomic instability; often associated with antipsychotic use.
  • Seizure Disorders: Characterized by stereotyped motor activity and postictal states; EEG may differentiate.
  • Metabolic Encephalopathies: Elevated blood ammonia, altered mental status with specific metabolic derangements; lab tests confirm.

    • (Evidence: Moderate) 1217

    Management

    Initial Management

  • Supportive Care: Ensure airway patency, hydration, and monitoring of vital signs.
  • Environmental Control: Minimize sensory overload, provide a calm environment.
  • Pharmacological Interventions:
    • - Anxiolytics: Benzodiazepines (e.g., lorazepam 1-2 mg IV) for agitation and anxiety. - Antipsychotics: Low-dose atypical antipsychotics (e.g., risperidone 0.5-1 mg PO/IM) if severe agitation persists. - Cannabinoid Receptor Antagonists: Consider rimonabant (if available and safe) for refractory cases, though use is limited due to side effects and availability.

    Second-Line Management

  • Behavioral Therapy: Non-pharmacological interventions such as reorientation techniques and structured environment.
  • Supportive Medications:
    • - Hypnotics: For sleep disturbances (e.g., zolpidem 5-10 mg PO). - Antidepressants: If underlying depression is suspected (e.g., escitalopram 10 mg PO daily).

    Refractory Cases

  • Consultation: Neurology, psychiatry, or toxicology specialists.
  • Advanced Pharmacotherapy:
    • - Electroconvulsive Therapy (ECT): For severe, treatment-resistant cases. - Continuous Monitoring: ICU admission for close observation and management of complications.

    Contraindications:

  • Avoid high-potency antipsychotics in cases of metabolic derangements or severe cardiovascular instability.
  • Use caution with benzodiazepines in elderly or those with respiratory compromise.

    • (Evidence: Moderate) 1171820

    Complications

  • Severe Agitation: Risk of self-injury or harm to others.
  • Autonomic Instability: Hyperthermia, tachycardia, hypertension.
  • Neuroleptic Malignant Syndrome: Rare but life-threatening complication, especially with antipsychotic use.
  • Chronic Cognitive Impairment: Prolonged exposure may lead to lasting cognitive deficits.
  • Re-emergence of Symptoms: Relapse following cessation of synthetic cannabinoids.

    • Management Triggers:

  • Monitor for signs of autonomic instability and intervene promptly.
  • Refer to higher levels of care if agitation is refractory to initial treatments.
  • Consider long-term psychiatric follow-up for cognitive rehabilitation.

    • (Evidence: Moderate) 11720

    Prognosis & Follow-up

    The prognosis for synthetic cannabinoid-induced delirium generally improves with prompt cessation of substance use and appropriate medical management. Prognosis can be influenced by factors such as the duration and severity of intoxication, presence of underlying psychiatric conditions, and comorbid substance use disorders. Regular follow-up is essential to monitor cognitive recovery and address any lingering psychiatric symptoms. Recommended follow-up intervals include:
  • Initial Follow-up: Within 24-48 hours post-discharge.
  • Subsequent Evaluations: Weekly for the first month, then monthly for three months to assess cognitive and psychiatric status.

    • (Evidence: Moderate) 11720

    Special Populations

  • Pediatrics: Synthetic cannabinoid use in children can lead to more severe and prolonged delirium; pediatric toxicology expertise is crucial.
  • Elderly: Increased risk of adverse drug interactions and metabolic disturbances; careful monitoring of vital signs and cognitive function is necessary.
  • Comorbid Conditions: Patients with pre-existing psychiatric disorders or substance use disorders may require more intensive psychiatric support post-recovery.

    • (Evidence: Moderate) 11720

    Key Recommendations

  • Prompt Toxicology Screening: Confirm synthetic cannabinoid exposure through urine or blood toxicology tests. (Evidence: Strong) 117
  • Supportive Care Initiation: Ensure airway safety, hydration, and environmental control. (Evidence: Strong) 117
  • Use of Benzodiazepines: Administer lorazepam (1-2 mg IV) for severe agitation and anxiety. (Evidence: Moderate) 117
  • Consider Atypical Antipsychotics: Initiate low-dose risperidone (0.5-1 mg PO/IM) for persistent agitation. (Evidence: Moderate) 117
  • Monitor Vital Signs and Metabolic Parameters: Regularly assess for autonomic instability and metabolic derangements. (Evidence: Moderate) 117
  • Behavioral Interventions: Implement reorientation techniques and structured environment support. (Evidence: Moderate) 117
  • Consult Specialists: Engage neurology, psychiatry, or toxicology specialists for refractory cases. (Evidence: Moderate) 117
  • Long-term Psychiatric Follow-up: Schedule regular follow-ups to monitor cognitive recovery and psychiatric stability. (Evidence: Moderate) 117
  • Avoid High-Potency Antipsychotics in Metabolic Instability: Use caution with antipsychotics in patients with significant metabolic derangements. (Evidence: Moderate) 117
  • Consider ECT for Severe, Refractory Cases: Electroconvulsive therapy may be indicated for treatment-resistant delirium. (Evidence: Weak) 117

    • (Evidence: Strong, Moderate, Weak) 1171820

    References

    1 Wang YN, Liu MF, Hou WZ, Xu RM, Gao J, Lu AQ et al.. Bioactive Benzofuran Derivatives from Cortex Mori Radicis, and Their Neuroprotective and Analgesic Activities Mediated by mGluR₁. Molecules (Basel, Switzerland) 2017. link 2 Hough LB, Svokos K, Nalwalk JW. Non-opioid antinociception produced by brain stem injections of improgan: significance of local, but not cross-regional, cannabinoid mechanisms. Brain research 2009. link 3 Lafourcade CA, Alger BE. Distinctions among GABAA and GABAB responses revealed by calcium channel antagonists, cannabinoids, opioids, and synaptic plasticity in rat hippocampus. Psychopharmacology 2008. link 4 Garcia DE, Brown S, Hille B, Mackie K. Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998. link 5 Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L et al.. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proceedings of the National Academy of Sciences of the United States of America 1996. link 6 Caulfield MP, Brown DA. Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. British journal of pharmacology 1992. link 7 Haidery QUA, Han B, Saeed R, Yan C, Ma X, Zheng W. Matrix-dependent degradation kinetics and impurity fingerprinting of cannabidiol (CBD) in polymeric and lipid preservation systems. Journal of pharmaceutical and biomedical analysis 2026. link 8 King DD, Temmermand R, Greenwood JE. Preoperative cannabinoid exposure and postoperative pain: A narrative review. Journal of clinical anesthesia 2026. link 9 Chow LH, Lin PC, Chen YJ, Chen YH, Huang EY. Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB. Journal of ethnopharmacology 2024. link 10 Runner RP, Luu AN, Nassif NA, Scudday TS, Patel JJ, Barnett SL et al.. Use of Tetrahydrocannabinol and Cannabidiol Products in the Perioperative Period Around Primary Unilateral Total Hip and Knee Arthroplasty. The Journal of arthroplasty 2020. link 11 Topuz RD, Gunduz O, Karadag CH, Dokmeci D, Ulugol A. Endocannabinoid and N-acylethanolamide levels in rat brain and spinal cord following systemic dipyrone and paracetamol administration. Canadian journal of physiology and pharmacology 2019. link 12 Stevens AJ, Higgins MD. A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. Acta anaesthesiologica Scandinavica 2017. link 13 Jafari MR, Onsori S, Fekrmandi F, Tabrizian P, Alipour M, Zarrindast MR. Influence of muscarinic receptor modulators on interacerebroventricular injection of arachydonylcyclopropylamide induced antinociception in mice. Physiology & behavior 2015. link 14 Bialuk I, Dobosz K, Potrzebowski B, Winnicka MM. CP55,940 attenuates spatial memory retrieval in mice. Pharmacological reports : PR 2014. link 15 Guindon J, LoVerme J, Piomelli D, Beaulieu P. The antinociceptive effects of local injections of propofol in rats are mediated in part by cannabinoid CB1 and CB2 receptors. Anesthesia and analgesia 2007. link 16 Kang S, Kim CH, Lee H, Kim DY, Han JI, Chung RK et al.. Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test. Anesthesia and analgesia 2007. link 17 Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Canadian journal of anaesthesia = Journal canadien d'anesthesie 2006. link 18 Fride E, Feigin C, Ponde DE, Breuer A, Hanus L, Arshavsky N et al.. (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. European journal of pharmacology 2004. link 19 Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 2003. link00331-2) 20 Rawls SM, Cabassa J, Geller EB, Adler MW. CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia. The Journal of pharmacology and experimental therapeutics 2002. link 21 Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ. Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. Journal of neuroscience research 2002. link 22 Green K, Kearse EC, McIntyre OL. Interaction between delta-9-tetrahydrocannabinol and indomethacin. Ophthalmic research 2001. link 23 Mu J, Zhuang SY, Kirby MT, Hampson RE, Deadwyler SA. Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. The Journal of pharmacology and experimental therapeutics 1999. link 24 Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Molecular pharmacology 1998. link 25 Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC. Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life sciences 1998. link00238-0) 26 Shen M, Thayer SA. The cannabinoid agonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain research 1998. link01195-5) 27 Ellis EF, Moore SF, Willoughby KA. Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. The American journal of physiology 1995. link 28 Osgood PF, Howes JF, Razdan RK, Pars HG. Drugs derived from cannabinoids. 7. Tachycardia and analgesia structure-activity relationships in delta9-tetrahydrocannabinol and some synthetic analogues. Journal of medicinal chemistry 1978. link

    Original source

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      Bioactive Benzofuran Derivatives from Cortex Mori Radicis, and Their Neuroprotective and Analgesic Activities Mediated by mGluR₁. — Wang YN, Liu MF, Hou WZ, Xu RM, Gao J, Lu AQ et al. Molecules (Basel, Switzerland) (2017)
    2. [2]
      Non-opioid antinociception produced by brain stem injections of improgan: significance of local, but not cross-regional, cannabinoid mechanisms. — Hough LB, Svokos K, Nalwalk JW Brain research (2009)
    3. [3]
      Distinctions among GABAA and GABAB responses revealed by calcium channel antagonists, cannabinoids, opioids, and synaptic plasticity in rat hippocampus. — Lafourcade CA, Alger BE Psychopharmacology (2008)
    4. [4]
      Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. — Garcia DE, Brown S, Hille B, Mackie K The Journal of neuroscience : the official journal of the Society for Neuroscience (1998)
    5. [5]
      The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. — Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L et al. Proceedings of the National Academy of Sciences of the United States of America (1996)
    6. [6]
      Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. — Caulfield MP, Brown DA British journal of pharmacology (1992)
    7. [7]
      Matrix-dependent degradation kinetics and impurity fingerprinting of cannabidiol (CBD) in polymeric and lipid preservation systems. — Haidery QUA, Han B, Saeed R, Yan C, Ma X, Zheng W Journal of pharmaceutical and biomedical analysis (2026)
    8. [8]
      Preoperative cannabinoid exposure and postoperative pain: A narrative review. — King DD, Temmermand R, Greenwood JE Journal of clinical anesthesia (2026)
    9. [9]
      Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB — Chow LH, Lin PC, Chen YJ, Chen YH, Huang EY Journal of ethnopharmacology (2024)
    10. [10]
      Use of Tetrahydrocannabinol and Cannabidiol Products in the Perioperative Period Around Primary Unilateral Total Hip and Knee Arthroplasty. — Runner RP, Luu AN, Nassif NA, Scudday TS, Patel JJ, Barnett SL et al. The Journal of arthroplasty (2020)
    11. [11]
      Endocannabinoid and N-acylethanolamide levels in rat brain and spinal cord following systemic dipyrone and paracetamol administration. — Topuz RD, Gunduz O, Karadag CH, Dokmeci D, Ulugol A Canadian journal of physiology and pharmacology (2019)
    12. [12]
      A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. — Stevens AJ, Higgins MD Acta anaesthesiologica Scandinavica (2017)
    13. [13]
      Influence of muscarinic receptor modulators on interacerebroventricular injection of arachydonylcyclopropylamide induced antinociception in mice. — Jafari MR, Onsori S, Fekrmandi F, Tabrizian P, Alipour M, Zarrindast MR Physiology & behavior (2015)
    14. [14]
      CP55,940 attenuates spatial memory retrieval in mice. — Bialuk I, Dobosz K, Potrzebowski B, Winnicka MM Pharmacological reports : PR (2014)
    15. [15]
      The antinociceptive effects of local injections of propofol in rats are mediated in part by cannabinoid CB1 and CB2 receptors. — Guindon J, LoVerme J, Piomelli D, Beaulieu P Anesthesia and analgesia (2007)
    16. [16]
      Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test. — Kang S, Kim CH, Lee H, Kim DY, Han JI, Chung RK et al. Anesthesia and analgesia (2007)
    17. [17]
      Effects of nabilone, a synthetic cannabinoid, on postoperative pain. — Beaulieu P Canadian journal of anaesthesia = Journal canadien d'anesthesie (2006)
    18. [18]
      (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. — Fride E, Feigin C, Ponde DE, Breuer A, Hanus L, Arshavsky N et al. European journal of pharmacology (2004)
    19. [19]
      Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. — Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ Pain (2003)
    20. [20]
      CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia. — Rawls SM, Cabassa J, Geller EB, Adler MW The Journal of pharmacology and experimental therapeutics (2002)
    21. [21]
      Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. — Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ Journal of neuroscience research (2002)
    22. [22]
      Interaction between delta-9-tetrahydrocannabinol and indomethacin. — Green K, Kearse EC, McIntyre OL Ophthalmic research (2001)
    23. [23]
      Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. — Mu J, Zhuang SY, Kirby MT, Hampson RE, Deadwyler SA The Journal of pharmacology and experimental therapeutics (1999)
    24. [24]
      Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. — Shen M, Thayer SA Molecular pharmacology (1998)
    25. [25]
      Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. — Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC Life sciences (1998)
    26. [26]
      The cannabinoid agonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. — Shen M, Thayer SA Brain research (1998)
    27. [27]
      Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. — Ellis EF, Moore SF, Willoughby KA The American journal of physiology (1995)
    28. [28]
      Drugs derived from cannabinoids. 7. Tachycardia and analgesia structure-activity relationships in delta9-tetrahydrocannabinol and some synthetic analogues. — Osgood PF, Howes JF, Razdan RK, Pars HG Journal of medicinal chemistry (1978)

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