Tag Archives: toxicology

Core EM: Hyperinsulinemia Euglycemia Therapy (HIET) for BB and CCB Toxicity

Originally published at CoreEM.net, who are dedicated to bringing Emergency Providers all things core content Emergency Medicine available to anyone, anywhere, anytime. Reposted with permission.

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Written by: Jenny Beck-Esmay, MD (@jbeckesmay) // Edited By:  Anand Swaminathan, MD (@EMSwami)


  • Cardiogenic shock due to beta-blocker (BB) or calcium channel blocker (CCB) toxicity is frequent and potentially lethal.
  • The most common cause of poison-induced cardiogenic shock is beta-blocker toxicity. In 2012 alone, there were 24,465 beta-blocker exposures(Mowry 2013).
  • Calcium channel blocker overdose is less frequent than that of beta-blockers, but has been associated with the highest mortality rates among the cardiovascular drug overdoses(Woodward 2014).

Mechanism of Toxicity (Kerns 2011):

  • BBs and CCBs lead to decreased intracellular calcium within the myocardial cells. This can lead to vasodilation, decreased systemic vascular resistance, bradycardia, conduction delay, decreased contractility, hypotension and cardiogenic shock.
  • As the myocardium becomes stressed, it switches from catabolizing free fatty acids to catabolizing carbohydrates. The liver responds to this increased demand by releasing glucose via gluconeogenesis, ultimately resulting in hyperglycemia.
  • Blockade of calcium channels leads to effects outside the cardiovascular system as well.
    • CCB inhibits insulin secretion from the beta-islet cells of the pancreas. As a result of lower insulin levels, glucose cannot move into the myocardial cells at a rate sufficient to respond to demand.
    • CCB inhibits lactate oxidation resulting in lactic acidosis

CCB Toxicity - www.healthforumworld.com

Traditional Management:

  • Traditional management includes fluid resuscitation, atropine, cardiac pacing, calcium, glucagon and vasopressors. When these fail care may escalate to ECMO.

High Dose Insulin – How it Works:

  • Under normal physiologic conditions the heart prefers to use free fatty acids as its primary energy source.
    • In a stressed state the heart turns to prefer carbohydrate and insulin appears to facilitate this preference.
    • In vitro and in vivo evidence has shown insulin’s positive inotropic and chronotropic effects(Reikeras 1985, Kline 1995).
    • Even in a CCB poisoned animal model insulin increases myocardial glucose uptake resulting in improved contractility.

Using Hyperinsulinemia Euglycemia Therapy(Lugassy 2015)

  • Hyperinsulinemia Euglycemia Therapy (HIET) Initiation:
    • Intravenous bolus of regular insulin at a dose of 1 unit/kg.
    • If serum glucose <250 mg/dL, concurrently administer a bolus of dextrose 25-50 g (or 0.5-1 g/kg) IV.
  • HIET Continuous Infusion
    • Regular insulin: 0.5 – 1 unit/kg/hr
    • Dextrose: 0.5 g/kg/hr (titrate to maintain glucose 110 – 150 mg/dL)
  • Continuous Monitoring
    • Serum glucose every 30 minutes for 1-2 hours until stable
    • Potassium every 1 hour
  • Insulin bolus infusion can take 20-30 minutes to induce clinical inotropic/chronotropic effect.
  • Increase insulin infusion by 0.5-1 unit/kg/hr every 60 minutes (similar to administration of a pressor to maintain desired hemodynamic effect.)
  • A wide range of continuous maintenance infusion of insulin for inotropic/chronotropic support have been reported with apparent safe use in the range of 3-5 Units/kg/hr.
  • In addition to monitoring glucose and electrolyte levels, it may be prudent to monitor ejection fraction. Obtain a bedside echocardiogram upon arrival to estimate the patient’s ejection fraction. Repeat after 1-2 hours of insulin therapy. An improvement in EF is a good sign the therapy is working.

Adverse Effects:

  • Most common adverse effects of HIET include hypoglycemia and electrolyte imbalances, especially hypokalemia. No irreversible adverse effects have been reported(Engebretsen 2011).
  • In a case series of seven patients with severe calcium-channel blocker overdoses in which HIET was used, serum glucose and potassium levels were monitored closely (every thirty minutes until stabilized and then every 1-2 hours). One patient had a serum glucose concentration of <65 mg/dL that was rapidly corrected. Two patients had potassium concentrations <3.5 mEq/L, but neither had ECG signs of hypokalemia of arrhythmias. No patient had clinically significant hypoglycemia or hypokalemia(Greene 2007).
  • Another case series examined twelve patients receiving HIET for drug-induced cardiogenic shock. Six patients developed a total of nineteen hypoglycemic effects and hypokalemia was seen in seven patients. No adverse arrhythmias were noted and no patients had adverse sequelae secondary to hypoglycemia or hypokalemia(Holger 2011).

Take Home Points

  • HIET has been shown to be a safe and effective treatment for BB and CCB toxicity
  • Although they have been rarely reported, hypoglycemia and hypokalemia are potential adverse events when using HIET. Monitor glucose and electrolytes closely while using this therapy.


Engebretsen KM et al High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol 2011; 49(4): 277-283. PMID: 21563902

Greene SL et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med 2007: 33(11): 2019-2024. PMID: 17622512

Holger JS et al. High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock.Clin Toxicol 2011; 49(7): 653-658. PMID: 21819291

Kerns, W. Antidotes in Depth (A18): Insulin-Euglycemia Therapy. Goldfrank’s Toxicologic Emergencies 2011, 9 e. L. S. Nelson, N. A. Lewin, M. Howland et al. New York, NY, McGraw-Hill.

Kline JA et al. (1995). Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995; 23(7): 1251-1263. PMID: 7600835

Lugassy DM et al. The Critically Ill Poisoned Patient. Emergency Department Resuscitation of the Critically Ill 2015. M. E. Winters, American College of Emergency Physicians.

Mowry JB et al. 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol 2012; 51(10): 949-1229. PMID: 24359283

Reikeras O et al. Haemodynamic effects of high doses of insulin during acute left ventricular failure in dogs. Eur Heart J 1985; 6(5): 451-457. PMID: 3899650

Woodward C et al. High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity. Daru 2014; 22(1): 36. PMID: 24713415

The Approach to the Poisoned Patient

Author: Levi Kitchen, MD (EM Chief Resident, Naval Medical Center – Portsmouth) // Edited by: Alex Koyfman, MD, (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

This article will discuss the initial assessment, identification of toxidromes, and stabilization of patients suspected of toxic exposures. This discussion is by no means to be considered comprehensive, as Toxicology is a vast subject that cannot be quickly covered in depth. When in doubt, in the US, always call 1-800-222-1222 to speak to your regional poison control center and obtain directed advice.

General Approach

Most toxicologic exposures involve ingestions or localized chemical/biologic exposures involving single individuals with limited risk to medical personnel. In the uncommon event of an exposure which could be transmitted to emergency personnel, be sure to perform decontamination FIRST and OUTSIDE of the Emergency Department in order to not contaminate your personnel or life-saving equipment. At a minimum, the readily available PPE (cap, gown, gloves, mask, and eye protection) should be worn by all personnel in order to prevent accidental exposure.

As with all unstable patients, the initial assessment (once safe) begins with the ABCs. A detailed history and physical examination is key. Knowledge of medications, medical problems, and potential ingestions or exposures are very important historical facts in order to narrow down the list of potential toxic agents.

The physical exam should be comprehensive with special attention directed at finding evidence of a specific toxidrome. Also be wary of anchoring on the diagnosis of toxin exposure: don’t forget to keep trauma, CNS infection, and the myriad of other causes of altered mental status on the differential.

Also don’t forget the generally harmless “quick fix” medications that can rapidly reverse altered mental status in a previously comatose patient – naloxone and dextrose. Generally, patients will not be harmed with the indiscriminate provision of sugar and opioid reversal… though care should be taken in the chronic opioid abuser: lower doses are probably better such as 0.04-0.1mg IV at a time.

There are many, many reasons why drugs become toxic so remember that not all patients did something nefarious… many things affect drug clearance/protein binding/metabolism including underlying renal disease, hepatic dysfunction, dietary changes, iatrogenic, etc.

Initial orders

Now is not the time to be frugal. Full laboratory panels should be drawn, especially electrolytes, serum osmolarity, hepatic function, coags, urine beta HCG, aspirin, tylenol, ethanol, and any other specific levels based on your history and physical exam.

An EKG is a must in all unknown toxic exposures, as interval derangements and electrocardiographic clues to underlying toxicities are very common. Imaging with a chest Xray can be helpful in assessing for pulmonary edema, pill fragments, or other radiopaque objects in the chest or abdomen.

GI Decontamination

There are several methods of GI decontamination for toxic ingestions; some are very useful/beneficial while others can be harmful.

Forced Emesis – Generally never indicated, as “natural” emesis is just as good as forcing expulsion of gastric contents.

Gastric Lavage

  • Lavage with a large bore >36 French tube (not just NGT suction with a narrow tube) in order to empty the stomach of toxic contents. Awake patients should be lavaged in left lateral decubitus position to prevent aspiration and facilitate more complete gastric emptying.
  • Controversial but thought to be potentially helpful if performed within 4 hours of ingestion; preferred if initiated within one hour of ingestion.
  • Indicated if the airway is protected, removal of toxin is feasible (within a reasonable time frame), and will be beneficial if even a small amount is removed.
  • Contraindicated for caustic ingestions, large contents unlikely to be removed by lavage, unprotected airway, or timeframe when toxin has probably moved out of the stomach. 

Activated Charcoal (AC)

  • Binds toxins; not indicated for caustics, heavy metals such as lithium, lead, zinc and iron, toxic alcohols, hydrocarbons, and small molecules like sodium, chloride, etc.
  • Adult dose for unknown exposure is 60 – 90 grams, kids 1g/kg; best if can obtain a ratio of 10:1 of AC:toxin.
  • No clear timeframe for AC: definite benefit within one hour, suggested benefit within 4 hours; generally no harm in giving for any timeframe if no contraindications exist especially for large ingestions or sustained release preparations.
  • Contraindicated if absence of gut motility, perforation, risk of aspiration or if endoscopy will be needed; aspirated AC can cause severe pneumonitis.

Whole Bowel Irrigation (WBI)

  • Instillation of up to 2L per hour (25mL/kg/h for children) of polyethylene glycol solution orally (or via NGT) until the rectal effluent is clear.
  • Can be used concurrently with AC but may actually compete with toxin for binding sites on AC.
  • Especially useful for body packers and stuffers.

Caustic Ingestions

Acids – Proton donators, cause injury with pH < 3, hydrogen ions desiccate mucosal cells and cause development of an eschar (coagulative necrosis) that prevents deep penetration.

  • Can lead to metabolic acidosis with systemic absorption of acids.
  • Toilet bowl cleaners, hydrofluoric acid, etc.

Alkalis – Proton acceptors, cause injury with pH > 11, hydroxide ions penetrate tissue surfaces and cause liquefactive necrosis until neutralized. Extent of injury is dependent on duration of contact, volume, pH, concentration, penetrating ability of the substance and the TAR (titratable acid or alkaline reserve) – basically the amount of neutralizing substance required to bring the substance to physiologic pH, the higher the TAR the more damaging the substance.

  • Most household cleaning agents are alkali – ammonium hydroxide (Windex), sodium hypochlorite (bleach), oven cleaners, Drano, detergents etc.

Initial symptoms can be misleading: all patients with stridor or oral lesions require early EGD (within 12-24 hours) in order to accurately diagnose the extent of injury and decrease the risk of iatrogenic perforation.

  • Combination of multiple symptoms such as drooling, emesis, and chest pain will also likely have high-grade lesions and will need early EGD.
  • No visible lesions does not mean there is not a high-grade lesion in the esophagus or lower: clinical history and physical exam should guide further investigation.

Initial management should be for decontamination of the patient’s skin and oropharynx as necessary, aggressive control of the airway by direct visualization (consider fiberoptics), and caution with paralytics in severe burns as this may distort airway anatomy with loss of muscular tone.

  • Consider IV decadron for airway edema.

Gastric decontamination is generally contraindicated unless very early presentation of large volume toxic exposure or with certain high-risk substances as guided by poison control.

  • Can consider NGT suction for the above if present within 30 minutes; after that there is a very high risk of iatrogenic perforation with NGT so placement should be under direct visualization with EGD.
  • Initial dilution of liquid caustic ingestions with milk or water may be beneficial but should be discussed with poison control first.

Most patients will require EGD for diagnosis. In the rare patient with late presentation and suspicion of perforation, esophagogram and CT of chest/abdomen are indicated. All high-grade lesions/perforations will require surgical consultation.

***All button batteries lodged in the esophagus require emergent endoscopic removal to prevent perforation***

Body Packers and Stuffers

Body stuffer – Spontaneous ingestion of poorly packaged drugs, for instance swallowing a bag of contraband just prior to arrest.

  • Likely will not require whole bowel irrigation, usually admitted for observation for 24 hours though some suggest 6 hour observation period and then discharge if no evidence of toxidrome.

Body packer – “Drug mule,” a carefully planned ingestion of presumably carefully packaged illicit drugs.

  • If asymptomatic but known packer, can CT scan to quantify packets, or just give AC and WBI until several clear stools without packets.
  • If second CT scan at this point is negative, then they are clear (if they remain asymptomatic).
  • If known or suspected cocaine packing and the patient is symptomatic, i.e. sympathomimetic toxidrome; highly likely one of the packets has burst or is leaking, which is an indication for emergent surgery.

General considerations for hemodialysis

  • Toxin must be very small particles (able to cross the membrane).
  • Toxin will produce harm if not removed.
  • Volume of distribution should be small (1L/kg) indicating most of the toxin is in serum.
  • Toxin should not be highly protein bound (some notable exceptions include aspirin and valproic acid which are almost entirely protein bound at therapeutic levels, but at toxic levels they saturate protein binding sites and the remainder is in serum and therefore dialyzable).
  • Toxin is unable to be cleared by the body (renal failure, hepatic failure, etc.).


Anticholinergic – The old mnemonic rules supreme here – blind as a bat (mydriasis), mad as a hatter (altered mental status), hot as Hades (hyperthermic), red as a beet (flushing), dry as a bone (no sweating), the bowel and bladder increase their tone (urinary retention, decreased bowel sounds), and the heart runs alone (tachycardia).

  • Commonly described symptoms
    • Lilliputian hallucinations (picking at unseen small objects on the body), “pleasantly altered.”
    • Synesthesia – crossed sensory stimuli such as “I can taste the music.”
  • Common offending agents (many)
    • Over-the-counter medicines such as antihistamines
    • Synthetic cannabinoids like spice
    • Antipsychotics, antidepressants, antiparkinsonian drugs, antiemetics (phenothiazines), muscle relaxants (cyclobenzaprine)
  • Differentiate from sympathomimetic toxidrome by:
    • Dry skin
    • Mydriasis with limited or absent pupillary response to light
      • In anticholinergic toxidrome there is inhibition of cholinergic input to the ciliary apparatus of the eye; therefore, pupillary response to light will be limited or absent, whereas the opposite is true in the sympathomimetic toxidrome.

***For treatment myths and pearls, please see prior post: http://www.emdocs.net/physostigmine-for-management-of-anticholinergic-toxidrome/***


Agents – Cocaine, MDMA (ecstasy), ephedrine, methamphetamine, khat, etc.

Toxidrome – Hypertension, tachycardia, diaphoresis, mydriasis, hyperthermia, CNS excitation and delirium.

  • Differentiate from anticholinergic toxidrome by diaphoresis and mydriasis with brisk pupillary response.

Treatment – Benzodiazepines are the mainstay of treatment in the patient suspected of a sympathomimetic ingestion/toxicity. Benzodiazepines restore inhibitory balance to the CNS to help prevent the tremendous sympathetic outflow stimulated by these agents. Life-threatening hyperthermia may also occur; aggressive cooling measures and benzodiazepine administration are keys to early treatment.

  • For refractory hypertension, consider phentolamine (pure alpha blocker).
  • Be wary of mixed alpha/beta antagonist drugs such as labetalol as the alpha:beta ratio is very much in favor of beta blockade, approx. 1:7 ratio. Efficient beta blockade of beta-2 receptors will worsen vasoconstriction, causing nearly unopposed alpha-agonism by the original toxic agent leading to worsening hypertension.
  • Beware dysrhythmias: SVT is common and sodium channel blockade often leads to wide complex tachycardia that may degenerate into non-perfusing rhythms.
    • SVT unresponsive to benzodiazepines and cooling can be treated with calcium channel blockade.
    • Wide complex tachyarrhythmia, especially in cocaine toxicity, should be treated with empiric bicarbonate bolus and ACLS measures.


Agents: Long/short acting opioids, heroin, methadone, buprenorphine, etc.

Toxidrome – Drowsy, hypoventilation, hypotension, apnea, miosis, decreased bowel sounds.

Treatment – Largely supportive (airway support, fluids, vasopressors), if acute overdose can use naloxone in higher doses (0.4-2mg IV).

    • Caution in the chronic opioid dependent patient or opioid abuser as may precipitate withdrawal, also the patient will become agitated and combative if completely reversed immediately so should start with lower doses of repeat aliquots of 0.04-0.2mg IV.
    • Generally the goal is to find the amount required to reverse the respiratory depression and allow spontaneous respiration: the total dose given to reach this goal should be multiplied by 2/3, and this amount given as a drip per hour.       Obviously the patient needs to be monitored but in a strict opioid overdose without other factors, reversal of respiratory depression is the most important step.


Agents: Barbiturates, benzodiazepines, alcohol, GHB, sleep aids, zolpidem, buspirone.

Toxidrome – Drowsy, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression.

Treatment is supportive, intubation as necessary for airway control, fluids/vasopressors for hypotension. Few specific antidotes, flumazenil is antidote for benzodiazepine overdose but should almost never be used… unless it is a known iatrogenic overdose of a pure benzodiazepine without any possible stimulant medication in a person that is not a chronic user of benzodiazepines nor has a history of seizures. Otherwise, may cause seizures refractory to benzodiazepine administration.

***Please see http://www.emdocs.net/wp-content/uploads/2014/10/Flumazenil-Bodford-.pdf for further details.***


Agents – Organophosphate and carbamate pesticides, nerve agents; mechanism is poisoning of acetyl cholinesterase at ganglionic and neuromuscular junctions leading to increased acetylcholine neurotransmitter stimulation, with both muscarinic and nicotinic receptor stimulation effects.

Toxidrome – DUMBBELLS (Diarrhea/Diaphoresis, Urination, Miosis, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Low BP, Salivation).

    • Killer B’s (from muscarinic stimulation) – Bradycardia, Bronchorrhea, Bronchospasm.
    • Will also get nicotinic stimulation effects such as fasciculations, tetany, paralysis and increased sympathetic ganglionic stimulation which may result in paradoxical tachycardia and hypertension early.
    • Seizures are common in overdose.

Treatment – These patients will commonly need prehospital decontamination, DO NOT bring into the ED until they have been adequately decontaminated. The most common cause of death is airway compromise so early securing of the airway is paramount.

  • Atropine in high doses of 2-4mg IV at a time, keep giving until oral secretions are dry.
  • Pralidoxime (2-PAM) in order to reverse acetyl cholinesterase inhibition. This must be given early before enzyme “aging.”
  • Benzodiazepines for seizures and agitation.

References / Further Reading

– Rosen’s Emergency Medicine – Concepts and Clinical Practice. 8th Edition.

– Goldfrank’s Toxicologic Emergencies 2002.

– An intensive review course in clinical toxicology. New York City Poison Control Center and Bellevue Hospital Center Course Syllabus March 13 and 14; 2014.

– Position paper update: gastric lavage for gastrointestinal decontamination. AACT/EAPCCT. Clin Toxicol. 2013;51:140-146.

– Havanond C, Havanond P. Initial signs and symptoms as prognostic indicators of severe gastrointestinal tract injury due to corrosive ingestion. J Emerg Med. 2007; 33:349-53.




Physostigmine for Management of Anticholinergic Toxidrome

Authors: Sahaphume Srisuma, MD and James Dazhe Cao, MD (Rocky Mountain Poison and Drug Center) // Editor: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)


Physostigmine, a carbamate extracted from Physostigma venenosum (Calabar bean), is a reversible acetylcholinesterase inhibitor that increases synaptic acetylcholine at both nicotinic and muscarinic receptors. Physostigmine’s primary therapeutic role aims to ameliorate delirium as a result of the anticholinergic (more accurately, antimuscarinic) toxidrome resultant from the blockade of muscarinic receptors by agents such as atropine, antihistamines, tricyclic antidepressant (TCA), amongst other xenobiotics. It can also be used diagnostically for undifferentiated altered mental status where anticholinergic delirium is suspected. Although physostigmine at one point historically was given liberally as part of the “coma cocktail”, more recent concerns regarding adverse events have made clinicians wary of its use. Knowledge of the evidence of physostigmine’s efficacy and adverse effects may ease hesitancy over the use of physostigmine.



Successful treatment of antimuscarinic toxicity by the use of physostigmine is limited to case series and reports. No randomized controlled trials have been conducted in humans demonstrating the efficacy of physostigmine. There are two retrospective chart reviews that evaluated the efficacy and adverse effects of physostigmine treatment.

Dr. Burns et al. in 1999 conducted a retrospective chart review comparing responses to physostigmine versus benzodiazepine in 52 antimuscarinic poisoning patients with delirium or hallucination. The authors found that physostigmine controlled agitation in 96% of patients as compared to only 24% of patients treated with benzodiazepines. Physostigmine also reversed delirium in 87% of patients, whereas none with benzodiazepines. Mean response time to physostigmine was 10.9 ± 5.3 minutes. Of the cases with response to physostigmine, 78% of patients had relapse of symptoms with a mean time of 100 ± 42 minutes. All patients receiving physostigmine received multiple doses. Time to recovery without further relapse was shorter in cases using physostigmine, but there was no significant difference in overall hospital length of stay.[1]

Schneir et al. in 2003 reviewed retrospectively 39 cases where physostigmine was administered diagnostically in cases of delirium.

 Adverse Effects and Toxicities

The principal adverse effects of physostigmine are related to cholinergic excess including bradycardia, bronchospasm, bronchorrhea, seizure, and motor weakness. Less severe symptoms are nausea, vomiting, diarrhea, miosis, tremor, and fasciculation.

The most concerning and also controversial adverse effects of physostigmine are bradydysrhythmias and asystole in case with use for TCA poisoning. Widespread concern for the use of physostigmine followed the landmark series of two cases by Drs. Pentel and Peterson in 1980. One case was a severe amitriptyline poisoning presented with alteration of consciousness with response only to deep pain. After intubation, patient developed status epilepticus. Initial EKG showed very wide QRS complex (approximately 240 msec) and first degree AV block. After administration of physostigmine 2 mg IV over three minutes, patient developed nodal bradycardia and further asystole. The second case was of imipramine and propranolol poisoning that had two episodes of seizure and hypotension. Physostigmine 2 mg IV was given over five minutes after each episode of seizure. After second dose of physostigmine, patient developed bradycardia and progressed to asystole. The authors concluded that the “use of physostigmine in patients who have ingested an overdose of TCAs carries the risk of life-threatening bradyarrhythmias.”[11] Although the authors correctly noted that bradycardia is uncommon in TCA overdose, bradydysrhythmias and asystole may be terminal events in the setting of severe TCA toxicity.[10] NaHCO3 was not given to treat sodium channel blockade effect of severe TCA toxicity prior to cardiac arrest. Additionally, underlying conduction delay demonstrated by the first degree AV block in case one and co-ingestion of propranolol in case two may have contributed to the adverse outcomes. Even so, the case series yielded significant concern for the use of physostigmine in the setting of TCA overdose, QRS prolongation, and/or PR prolongation.

In Burns’ 1999 publication, there was no difference in side effects defined as complications arising within 30 minutes of medication administration and between cases treated with physostigmine and with benzodiazepine. However in this study, PR prolongation (>200 msec) or QRS widening (>100 msec and not related to bundle branch block) were considered as contraindication to physostigmine. Side effects were reported in five of 45 cases with physostigmine – one of each of the following: diaphoresis, emesis, diarrhea, asymptomatic bradycardia @ 51 beats/minute, and increased respiratory secretions. In the 25 cases with benzodiazepine, there were side effects reported in four cases including two with excessive sedations, one fecal incontinence, and one paradoxical agitation. There were five cases with TCA poisoning in this series, all had ingested amitriptyline at least 12 hours before physostigmine administration. None had coma, seizures, hypotension, cardiac conduction disturbances, or significant dysrhythmias although significant TCA toxicity would have likely been excluded from the study.[1]

In Schneir’s series, one of 39 cases had brief convulsions without adverse sequelae after treatment with physostigmine. The patient ingested doxylamine and presented after a witnessed 1-2 minutes of seizure. He was later suspected to have antimuscarinic delirium for which he received physostigmine 0.5 mg IV with full reversal of delirium. Twelve minutes after administration of physostigmine, the patient had a 30 second generalized convulsion without further convulsions or sequelae during the remainder of the hospitalization. EKG was available in 37 cases. Only one case had QRS > 120 msec (138 msec) which was known to be a preexisting right bundle branch block. Of the three TCA cases in the series, none of the patients had dysrhythmias. There were no cases of cholinergic excess following physostigmine administration.

Three other case series have described incidence of seizures temporally after physostigmine administration. Newton et al. in 1975 reported convulsions in two of 21 patients treated with physostigmine for TCA overdoses.[12] Walker et al. in 1976 described convulsions in three out of 26 overdose patients treated with physostigmine. Of the 26 patients, 17 were reported to have ingested TCAs.[13] Knudsen et al. in 1984 described a series of 41 patients after ingestion of maprotiline where six of seven patients treated with physostigmine developed convulsions.[10]

Discussion and Recommendation

            From the understanding of physostigmine’s mechanism of action and the above data, we would like to summarize key points and recommendations regarding the use of physostigmine. First, physostigmine is beneficial in reversing central antimuscarinic symptoms including agitation, delirium, and/or hallucinations. When properly administered, physostigmine may be more efficacious than benzodiazepines for management and lowers risk of excessive sedation from high doses of benzodiazepine. Physostigmine can also be applied diagnostically for undifferentiated delirium; preventing unnecessary investigation, especially in children.

Second, physostigmine will NOT treat symptoms from pathophysiology other than antimuscarinic effects. Without any antimuscarinic symptoms, do NOT use physostigmine to treat unspecified coma or dysrhythmias. Physostigmine may help with antimuscarinic effect of tricyclic antidepressant but is unlikely to reverse serotonergic effect or alpha adrenergic blockade of TCAs. Physostigmine has no direct reversing properties for sodium channel blockade in TCAs. Theoretically by slowing the heart rate, physostigmine may improve cardiac sodium channel blockade. However, data for this hypothesis is virtually nonexistent in humans and conflicting in animal studies. Therefore in cases of TCA overdose, it is very important to focus on which clinical symptoms are significant and need to be treated.

Third, when using physostigmine, understand the risks and adverse effects. The concerning adverse effects of cholinergic excess include seizure, bradycardia, bronchospasm, and bronchorrhea. We recommend AGAINST using physostigmine for treatment of seizures caused by an anti-muscarinic agent. Benzodiazepine may be the most appropriate first choice. We also recommend AGAINST using physostigmine in cases with bradycardia or AV block. The use of physostigmine for cases with QRS widening remains controversial. We recommend focusing on therapies targeted at reversing cardiac sodium channel blockade by either administration of NaHCO3 or hypertonic saline.

Dosing Recommendations

We recommend 1-2 mg (0.05 mg/kg, maximum initial dose of 0.5 mg in children) IV slow infusion over at least 5 minutes to reduce the risk of seizures. Dose may be repeated for incomplete response after 5 to 10 minutes up to a maximum of 2 mg in children and 4 mg in adults. Always have atropine and a benzodiazepine at bedside in case of significant cholinergic excess symptoms or seizures, respectively. Response to physostigmine can occur rapidly (within minutes), but the duration of effect of physostigmine tends to be shorter than that of antimuscarinic agents. Observe for recurrence of antimuscarinic symptoms, and assess if the patient will need repeated dosing of physostigmine.


Physostigmine is beneficial for central and peripheral antimuscarinic symptoms. With appropriate use, it has a low risk of side effects and complications.


References / Further Reading

[1] Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Annals of emergency medicine. 2000;35:374-81.

[2] Schneir AB, Offerman SR, Ly BT, Davis JM, Baldwin RT, Williams SR, et al. Complications of diagnostic physostigmine administration to emergency department patients. Annals of emergency medicine. 2003;42:14-9.

[3] Glatstein MM, Alabdulrazzaq F, Garcia-Bournissen F, Scolnik D. Use of physostigmine for hallucinogenic plant poisoning in a teenager: case report and review of the literature. American journal of therapeutics. 2012;19:384-8.

[4] Johnson PB. Physostigmine in tricyclic antidepressant overdose. Jacep. 1976;5:443-5.

[5] Rumack BH. Anticholinergic poisoning: treatment with physostigmine. Pediatrics. 1973;52:449-51.

[6] Phillips MA, Acquisto NM, Gorodetsky RM, Wiegand TJ. Use of a physostigmine continuous infusion for the treatment of severe and recurrent antimuscarinic toxicity in a mixed drug overdose. Journal of medical toxicology: official journal of the American College of Medical Toxicology. 2014;10:205-9.

[7] Padilla RB, Pollack ML. The use of physostigmine in diphenhydramine overdose. The American journal of emergency medicine. 2002;20:569-70.

[8] Cole JB, Stellpflug SJ, Ellsworth H, Harris CR. Reversal of quetiapine-induced altered mental status with physostigmine: a case series. The American journal of emergency medicine. 2012;30:950-3.

[9] Weizberg M, Su M, Mazzola JL, Bird SB, Brush DE, Boyer EW. Altered Mental Status from Olanzapine Overdose Treated with Physostigmine. Clinical toxicology. 2006;44:319-25.

[10] Knudsen K, Heath A. Effects of self poisoning with maprotiline. Br Med J (Clin Res Ed). 1984;288:601-3.

[11] Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Annals of emergency medicine. 1980;9:588-90.

[12] Newton RW. Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA : the journal of the American Medical Association. 1975;231:941-3.

[13] Walker WE, Levy RC, Hanenson IB. Physostigmine–its use and abuse. Jacep. 1976;5:436-9.

[14] http://www.ncbi.nlm.nih.gov/pubmed/25510306

[15] http://www.ncbi.nlm.nih.gov/pubmed/22461927


Intern Report Collection, Vol. 5

To kick off your weekend reading pleasure, here’s another batch of excellent write-ups from the EM interns at UT Southwestern (@DallasEMed) courtesy of Alex Koyfman (@EMHighAK) . Our ongoing intern report series is the product of first-year residents exploring clinical questions they have found to be particularly intriguing, with an intended audience of med students & junior residents. Enjoy!

[Note: These are PDF files.]

Lipid Emulsion Therapy


Intravenous lipid emulsion (ILE, also known as lipid emulsion therapy, lipid resuscitation therapy, lipid rescue, intravenous fat emulsion and Intralipid®) has been used in the past for caloric supplementation and treatment of essential fatty acid deficiency.  Since 1998, ILE has been considered for resuscitative therapy in drug-induced cardiovascular and neurologic toxicity.  The use of ILE has been best described for cardiovascular collapse and seizures caused by local anesthetic systemic toxicity (LAST) with successful animal trials and human case reports.  Subsequent to these findings, the use of ILE in LAST is recommended by the latest guidelines for the American Heart Association, American Society of Regional Anesthesia and Pain Medicine (ASRA), and the Association of Anaesthetists of Great Britain and Ireland.  ILE has also been used as a resuscitative agent for a number of lipid- and water-soluble xenobiotics that induce cardiac and/or neurologic toxicity including tricyclic antidepressants, non-dihydropyridine calcium channel blockers, bupropion, citalopram, venlafaxine, atypical anti-psychotics, beta-blockers, diphenhydramine, etc.  See table 1 for a complete list of xenobiotics for which ILE has been attempted in case reports and abstracts.

Proposed Mechanisms

The exact mechanism of action has yet to be elucidated.  Two theoretical mechanisms of action have been widely described: partitioning and enhanced metabolism.  The partitioning theory or otherwise termed the “lipid sink” theory postulates that the administration of lipids compartmentalizes the offending xenobiotic into lipid phase and away from the target receptors.  Resuscitation of toxicity mediated by xenobiotics with high lipid solubility (defined as log P, octanol:water partition coefficient, greater than 2) are more likely to be successful although the intervention has worked for water-soluble xenobiotics.  The enhanced metabolism theory argues that the infusion of triglyceride and phospholipids are capable of providing fatty acid energy source to myocytes under toxic conditions.  Myocardium is capable of utilizing fatty acids for energy although in stressed states, cardiac myocytes preferentially utilized carbohydrates, a theory that gives credence to the use of high dose insulin therapy in calcium channel and beta blocker toxicity.

Administration Recommendations

Current recommendation from ARSA for 20% lipid emulsion therapy for LAST:

  1. Bolus 1.5 mL/kg (lean body mass) intravenously over one minute (Note that the dose is in volume, not weight)
    • 100 mL for a 70 kg patient
    • Repeat bolus for persistent cardiovascular collapse
  2. Continuous infusion 0.25 mL/kg/min
    • 18 mL/min for a 70 kg patient
    • Can double the infusion rate for persistent hemodynamic instability
    • Continue infusion for at least 10 minutes after hemodynamic recovery

In the setting of persistent cardiovascular collapse or hemodynamic instability, the upper limits of therapy are also not established.  ARSA recommends the upper limits of 10 mL/kg (700 mL in a 70 kg patient) over the first 30 minutes.


Elevated serum triglycerides may interfere and prevent routine laboratory analysis including serum electrolytes, hematocrit, liver function tests, and coagulation function.  A false negative aspartate transaminase (AST) resulted in the premature discontinuation of n-acetylcysteine in a co-ingestion of acetaminophen, amitriptyline, and diphenhydramine.  A 13-year-old female developed acute pancreatitis and acute respiratory distress syndrome after receiving the ARSA recommended dose of lipid emulsion therapy for a tricyclic antidepressant overdose.  Serum amylase elevations have also been reported.

Bottom Line

Unfortunately, the lack of high-quality controlled human studies precludes lipid emulsion therapy as a first-line agent for indications other than local anesthetic systemic toxicity.  In the setting of severe hemodynamic compromise caused by a lipid-soluble xenobiotic or drugs with cardiovascular and/or neurologic toxicity, lipid emulsion therapy should be considered early in the resuscitation but is not the standard of care at this time.

Discussion Questions

  • What is the evidence supporting the use of intravenous lipid emulsion (ILE) in this patient?
  • Under what other acute poisonings should emergency department providers consider the use of ILE?
  • How should ILE be administered?
  • What are reported and potential adverse effects of ILE?
  • How does ILE adversely impact laboratory monitoring?
  • What are the considerations for stocking ILE in emergency departments?

Further Reading

  1. Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117:180-7.
  2. Neal JM, Mulroy MF, Weinberg GL, American Society of Regional A, Pain M. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Regional Anesthesia and Pain Medicine. 2012;37:16-8.
  3. American College of Medical Toxicology. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. Journal of Medical Toxicology. 2011;7:81-2.
  4. http://www.ncbi.nlm.nih.gov/pubmed/24338451
  5. http://www.ncbi.nlm.nih.gov/pubmed/23518248
  6. http://www.ncbi.nlm.nih.gov/pubmed/23992445
  7. http://www.ncbi.nlm.nih.gov/pubmed/23685061
  8. http://www.ncbi.nlm.nih.gov/pubmed/20923546
  9. http://www.ncbi.nlm.nih.gov/pubmed/20688937
Edited by Alex Koyfman, MD


Table 1: Xenobiotic overdose responses to ILE from 2006 to 2013 in case reports and abstracts.

Electronic Cigarettes and Liquid Nicotine Poisoning

By Jhonny E Ordonez*, Larissa Velez**, and Kurt C Kleinschmidt**
*Toxicology Fellow, UTSW
**Professor of Emergency Medicine / Toxicology, UTSW


A 3 year-old boy is found by his parents with an open container of liquid nicotine, which his dad uses to refill his electronic cigarette. The toddler had just drunk some and the rest of the solution is spilled over his clothes and skin. The child soon becomes agitated and has vomiting, pallor, and tremor. He then has a generalized tonic clonic seizure. He is brought to the ED by ambulance.  What would you do?

What are e-cigarettes?

Electronic cigarettes, also known as e-cigarettes (e-cigs) or electronic nicotine delivery systems (ENDS) are battery-powered devices that heat a liquid solution of nicotine, or e-liquid. An e-cigarette contains a cartridge that is either disposable or refillable. This cartridge contains the liquid nicotine that is heated and vaporized, and inhaling this vapor is called “vaping.” E-cigarettes were first developed in China in 2003 and rapidly became very popular throughout Asia and Europe. They have become popular in the USA since first being marketed in 2007. E-cigs have become popular as reportedly safer alternatives to smoking. They do not expose smokers to some of the dangerous product of pyrolysis. There is no smoke produced; only vapor, which is more acceptable to those around the smoker. The use of these devices is often allowed in places where smoking is prohibited. In the past, e-cigs were also marketed as smoking cessation aids. Currently, there is no evidence that e-cigarettes are effective methods to quit smoking.20

There have been recent concerns about other chemicals in the e-liquid, besides nicotine. The vapor contents include cytotoxic substances; acrolein, acetaldehyde, and formaldehyde.7,8 Although found in small concentrations, the potential chronic effects of inhaling these is unknown. Propylene glycol and glycerin are also in e-cigs as moisturizers. There are reports of these agents causing slight irritation when inhaled.3,9

Nicotine poisoning

Nicotine is an agonist at the nicotinic acetylcholine receptors. Acute nicotine poisoning has a biphasic pattern. The early clinical phase is characterized by excessive stimulation, resulting in nausea, vomiting, pallor, abdominal pain, salivation, bronchorrhea, tachypnea, hypertension, tachycardia, miosis, ataxia, tremor, fasciculations, and seizures. The delayed phase consists of central nervous system and respiratory depression, dyspnea, bradycardia, hypotension, shock, mydriasis, weakness, muscle paralysis, and coma.13 There are few reports of fatal cases after exposure to nicotine-containing products and plants by several routes.11,15 To this date, there are no reports of deaths from accidental liquid nicotine exposure.

The management of acute nicotine poisoning is mainly supportive.  Decontamination by washing the skin and removing clothes is appropriate for dermal exposures. Benzodiazepines are used for seizures. Intubation might be needed for those with muscle weakness or ventilatory failure. Atropine can be used for symptomatic bradycardia.

Why are they dangerous?

Exposure to the nicotine solutions may be dangerous because they may be highly concentrated, with concentrations ranging from 6 to 100 mg/ml.18 The lethal dose of nicotine is uncertain but the oral LD50 is 6.5–13 mg/kg in dogs.12 Based on this LD50, the ingestion of only a few milliliters of some of the preparations could be toxic. In children, doses as low as 0.1 mg/kg can cause toxicity. For comparison, one cigarette has about 20-30 mg of nicotine, and historically, ingestion of one cigarette has caused clinical toxicity in a child. The volumes available for sale may be as large as 1 liter, compounding on the potential for significant morbidity.

The product packaging also yields potential problems. E-cigarettes are not subject to regulation by the FDA; therefore, there is no requirement for childproof packaging. Colorful packaging and attractive flavorings both make these solutions target for children. There is no current requirement to do any labeling regarding the dangers of these liquid solutions. Many people are not aware of the potential risk of toxicity if the liquid nicotine is ingested or absorbed through the skin, especially small children who can be exposed to these products at home. Many of these containers are left accessible and unattended, where small children can easily obtain them.

Another serious concern is the intentional use and abuse of e-cigs by older children and teenagers.  The CDC reports that the percentage of U.S middle and high school students who use e-cigs more than doubled from 2011 to 2012.  The percentage of high school students who reported ever using an e-cigarette rose from 4.7% in 2011 to 10% in 2012. Recently, a bill that prohibits advertisement, promotion, or marketing of electronic cigarettes to children under the age of 18 was approved.23 Although the sales of cigarettes have stayed relatively flat in the past years, the sales of e-cigarettes are growing.22

Little is known about the impact of exposure on overall public health. Poison Center calls have experienced a surge in the past year, averaging 200 calls per day in early 2014.21 Most of the exposures reported to US Poison Centers are unintentional, and about ½ of them are in the 0-5 years age group.21

Although no deaths have been reported after accidental exposures to liquid nicotine, the potential for significant morbidity and mortality exists.

So what happened to our patient?

The patient’s clothes had a strong odor of vanilla (the flavoring on the liquid nicotine), so they were removed and the skin was washed. He was admitted to the pediatrics service, where he remained sleepy for the next 4 hours. He did not have any other significant clinical findings of nicotine poisoning. There was no recurrence of the seizure. The parents were educated on the dangers of highly concentrated liquid nicotine solutions. The patient was discharged home 12 hours after the exposure.

References / Further Reading

  1. Bertholon J.F., Becquemin M.H., Annesi-Maesano I., & Dautzenberg B. (2013). Electronic Cigarettes: A Short Review. Respiration, 86, 433-438. doi: 10.1159/000353253
  2. Cantrell L. E. (2013). Cigarette exposures – nothing to get choked up about. Clinical Toxicology, 51, 684-685.
  3. Carmines EL, Gaworski CL. (2005). Toxicological evaluation of glycerin as a cigarette ingredient. Food Chem Toxicol 43(10):1521-39.
  4. Deyton L.R. (2013). Regulation of E-Cigarettes and Other Tobacco Products. FDA U.S. Food and Drug Administration.
  5. Etter J. F., & Bullen C. (2011). Electronic cigarette: users profile, utilization, satisfaction and perceived efficacy. Addiction, 106, 2017-2028. doi:10.1111/j.1360-0443.2011.03505.x
  6. Etter J.F., & Bullen C. (2013). A longitudinal study of electronic cigarette users. Addictive Behaviors, 39, 491-494.
  7. Goniewicz M.L., Knysak J., Gawron M., Knysak J., & Kosmider L. (2013). Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tobacco Control, doi: 10.1136/tobaccocontrol-2012-050859:1–7
  8. Goniewicz M.L., Kuma T., Gawron M., Knysak J. & Kosmider L. (2013). Nicotine Levels in Electronic Cigarettes. Nicotine & Tobacco Research, 15, 158-166. doi:10.1093/ntr/nts103
  9. Gaworski C, Oldhama MJ, Cogginsb C. (2010). Toxicological considerations on the use of propylene glycol as a humectant in cigarettes. Toxicology 269, 54–66
  10. Jun Ho Cho J.H., Shin E., & Sang-Sik Moon (2011). Electronic-Cigarette Smoking Experience Among Adolescents. Journal of Adolescent Health, 49, 542–546. doi:10.1016/j.jadohealth.2011.08.001
  11. Lavoie F.W., & Harris .TM. (1991). Fatal nicotine ingestion. The Journal of Emergency Medicine, 9, 133-136.
  12. Mayer B. (2014). How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Archives of Toxicology, 88, 5–7. doi: 10.1007/s00204-013-1127-0
  13. Metz C.N., Gregersen P.K., & Malhotra A.K. (2004). Metabolism and biochemical effects of nicotine for primary care providers. The Medical Clinics of North America, 88, 1399–1413. doi:10.1016/j.mcna.2004.06.004
  14. Pepper J.K., & Brewer N.T. (2013). Electronic nicotine delivery system (electronic cigarette) awareness, use, reactions and beliefs: a systematic review. Tobacco Control, 1-10. doi:10.1136/051122
  15. Solarino B., Rosenbaum F., Rießelmann B., Buschmann C.T. & Tsokos M. (2010). Death due to ingestion of nicotine-containing solution: case report and review of the literature. Forensic Science International, 195, 19-22. doi:10.1016/j.forsciint.2009.11.00
  16. Sutfin E.L., McCoyb T.P., Morrell H.E., Hoeppner B.B. & Wolfson M. (2013). Electronic cigarette use by college students. Drug and Alcohol Dependence, 131, 214–221.
  17. Thornton S., Oller L., & Sawyer T. (2013). Fatal intravenous injection of electronic cigarette “eLiquid” solution. Clinical Toxicology, 51, 683.
  18. Retrieved from www.myfreedomsmokes.com
  19. Valento M. (2013). Nicotine poisoning following ingestion of e-Liquid. Clinical Toxicology, 51,683-684.
  20. Bullen C, Howe C, Laugesen M, et al (2013). Electronic cigarettes for smoking cessation: a randomized controlled trial. Lancet, 382, 1629–37
  21. Chatham-Stephens K, MD1, Law R, Taylor E, et al (2014). Notes from the Field: Calls to Poison Centers for Exposures to Electronic Cigarettes — United States, September 2010–February 2014 Weekly. 63(13); 292-293. (Accessed on 05/06/2014)
  22. Herzog B,  Gerberi J, (2013). Equity Research. E-Cigs Revolutionizing The Tobacco Industry. Wells Fargo securities.(Accessed on 05/08/2014)
  23. Library of Congress. S.2047 – 113th Congress (2013-2014): Protecting Children from Electronic Cigarette Advertising Act of 2014. (Accessed on 05/13/2014)
Edited by Alex Koyfman

Synthetic Cannabinoids



  • Synthetic cannabinoids were first designed after the structure of the primary psychoactive compound in marijuana, 9-tetrahydrocannabinol (9-THC), was figured out in the 1960s.
  • Synthetic cannabinoids have been used as a tool to study endocannabinoid biochemistry and also to design cannabinoid derivatives for medicinal use, for example in appetite stimulants and pain medications.
  • In the late 1990s, The John W. Huffman research group at Clemson University began to synthesize over 450 cannabinoids. JWH-018 was one such synthetic cannabinoid that his group created for research purposes but in 2004 it first appeared in Europe in recreational smoke blends under the marketed name “Spice” or “K2.”


Synthetic Cannabinoid Types

  • There are many types of synthetic cannabinoids. More and more continue to be created to either produce a “better high” or evade detection in drug screens. Each has their own distinct binding affinity to the cannabinoid receptor subtypes (CB1 and CB2).
  • For example, HU210 is reported to bind to the CB1 and CB2 receptors with 100 times the affinity of 9-THC.
  • Blends of K2 contain JWH-018 (a full agonist at the CB1 and CB2 receptor), JWH-073 (somewhat selective for CB1), and JWH-250 (CB1 and CB2 agonist).
  • First generation synthetic cannabinoids are believed to be more benign than the newer generation cannabinoids, which are more likely to cause cardiotoxicity and neurotoxicity. One such newer generation synthetic cannabinoid is ADB-PINACA (N-[1-amino-3,3-dimethy-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide), the compound identified in the recent Colorado outbreak known locally as Black Mamba.


Street Names

  • K2, Spice, Black Mamba, Blaze, Bliss, Bombay Blue, Fake Weed, Genie, Moon Rocks, Mr. Nice Guy, Skunk, Yucatan Fire and Zohai.

Legal Status

  • In July 2012, the Synthetic Drug Abuse Prevention Act of 2012 was signed into law, which banned 26 substances commonly found in synthetic marijuana, placing them under Schedule I of the Controlled Substances Act.
  • Despite legislation banning its use, synthetic cannabinoid use is becoming increasingly popular and is still readily available. Synthetic cannabinoids have been found in smoke shops, gas stations, and can be found for sale on the internet. They can be found in legal retail stores and packaged as incense or potpourri and may be labeled “not for human consumption.”

Growing Popularity and Media Attention

  • In 2010, the DEA reported that 30–35% of specimens submitted by juvenile probation departments tested positive for synthetic cannabinoids.
  • According to the 2011 National Institutes of Drug Abuse (NIDA)-sponsored Monitoring the Future survey, 11% of high school seniors reported smoking synthetic marijuana, making it one of the most commonly abused drugs in this population — second only to marijuana.
  • 4.5% of urine specimens collected from 5,956 U.S. athletes tested positive for synthetic cannabinoids, the highest of all drug classes detected.
  • A recent NEJM letter to the editor described an outbreak in Colorado where a total of 263 cases of possible synthetic cannabinoid exposure were identified during August 21-September 19 2013, however only 15 of these cases were reported to the state poison control center. Of the 263 cases, 76 sought medical attention in emergency departments and 7 were admitted to intensive care units. Colorado health officials identified a novel synthetic cannabinoid, ADB-PINACA, which was associated with neurotoxicity and cardiotoxicity.

Clinical Highlights

Route of Ingestion

  • Synthetic cannabinoids can be smoked, insufflated, or orally ingested.


  • The psychoactive effects are similar to 9-THC and include altered time perception, anxiety, changes in mood, confusion, hallucinations, and psychomotor agitation. There have been case reports of induced psychoses, unmasking of underlying psychiatric disease, and suicidal attempts especially in individuals with a personal or family history of psychiatric conditions. Additional undesirable effects include dry mouth, nausea, vomiting, tachycardia, palpitations.
  • Life-threatening neurotoxic effects, like seizures or ischemic stroke, and cardiotoxic effects, like arrhythmia or acute coronary syndrome / myocardial infarction, rarely occur with synthetic cannabinoid intoxication and likely occur more often with the newer synthetic cannabinoids presumably due increased potency to the cannabinoid receptors.


  • Similar to marijuana intoxication, patients typically do not need measures other than symptomatic or supportive treatment. No antidote exists for synthetic cannabinoid poisoning. Seizure control and agitation can be treated with benzodiazepines. Gastrointestinal decontamination typically has no role in patients using synthetic cannabinoids, but it may be considered in large-quantity ingestions.
  • For severe intoxication, especially with the newer generation synthetic cannabinoids, intensive care monitoring and management for seizures, ischemic stroke, and possible cardiotoxicity may be required. Death due to neurotoxicity or cardiotoxicity as well as suicidality has been reported with synthetic cannabinoid use.


  • Synthetic cannabinoids do not show up in the standard urine drug screens available in most hospitals, which test for Tetrahydrocannabinol. The best methods for detecting synthetic cannabinoids are liquid chromatography / tandem mass spectrometry (LC-MS/MS) and gas chromatography / mass spectrometry (GC/MS) and are only available in select laboratories.
  • The inability to detect synthetic cannabinoids using standard urine drug screens adds to its growing popularity.

Bottom Line

  • Suspect synthetic cannabinoids in your patients who present with marijuana-like symptoms but screen negative for cannabis using standard urine drug screens. Most patients require symptomatic support as you would normally do for your patient presenting with marijuana intoxication.
  • However, there have been a growing number of cases associated with life-threatening neurotoxic effects (seizures, strokes) and cardiotoxic effects (arrhythmia, acute coronary syndrome / myocardial infarction), presumably due to increased potency to the cannabinoid receptors in the newer synthetic cannabinoids.

Further Reading

Edited by Alex Koyfman, MD

Alternative “Legal” Highs: Kratom, Salvia Divinorum, Methoxetamine

General Info / Intro

  • Mitragyna speciosa Korth; leafy tree indigenous to SE Asia / Thailand
  • Alternative medicine for diarrhea, cough, opioid addiction, HTN, MSK pain, fatigue
  • Distributed in smart-shops and on Internet; growing interest in Western countries
  • Hallucinogenic herb (Diviner’s Sage, La Pastora, Yerba Maria); small region of Mexico
  • Used for spiritual healing and divination
  • Alternative to LSD and marijuana; distributed as above
  • “Legal and bladder-friendly ketamine” (MXE, Mexxy, m-ket, Special M)
  • First detected in UK in 2010 and banned in 2012

Clinical Highlights

  • Ingested or inhaled usually
  • Active ingredients = mitragynine, 7-hydroxymitragynine
  • Stimulant (dopamine, serotonin) / opioid-like effects (mu / kappa receptors) => used for chronic pain management and opioid withdrawal
  • Supportive Tx
  • Smoked or chewed usually
  • Active ingredient: salvinorin A
  • Binds kappa opioid receptor
  • Tachycardia (CV), euphoria / AMS / hallucinations / memory impairment (Neuro), n/v (GI)
  • Supportive Tx
  • Oral or intranasal usually; slower onset and longer duration than ketamine
  • Dissociative anesthetic / NMDA antagonist / dopamine agonist
  • Tachy / htn / agitation / hyperthermia (sympathomimetic), hallucinations / derealization / depersonalization (dissociative), truncal ataxia / dysarthria (cerebellar), mood disturbance / suicide attempt (behavioral health issues)
  • Supportive Tx

Bottom Line

Think about the aforementioned substances in a patient with either an opioid, sympathomimetic, or hallucinogenic toxidrome.



Salvia Divinorum



Images from Journal of Forensic Sciences, January 2013

Further Reading

Discussion Questions/Future Exploration

  • “Legal highs” come and go; which will stay / what are the most dangerous to our pts
  • How does the market adapt to state / federal bans