The Poison Lab

In this episode of toxicologist vs the internet Ryan Is joined by special guest Dr. Justin Corcoran, MD an emergency medicine physician and medical toxicologist. They take turns answering questions from reddit.com/r/askdrugs (the internet, really, really needs a toxicologist) and challenge each others toxic sleuthing by presenting cases of poisoning and allowing the other to determine the toxin responsible.

"Toxicologist vs the internet" segment

• Everythingisosm.com (Blog post)
• Biased Mu Receptor ligands
• Oliceridine mouse studies
• Opioid hearing loss (Blog post)
• Opioid hearing loss review
• Tox pupils (Blog post)
• Why tramadol is awful (Blog post)

Additional information on toxins from Fatal poisoning cases

• Toxin 1
• Toxin 2
• Toxin 3
• Toxin 4

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• Full book reading (6 minutes!)

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Ryan and Toxo dive in to Delta 8 THC, a new (maybe?) legal drug sweeping the U.S.

• Comprehensive article on Delta-8 THC, its growing popularity, and concerns: https://www.nytimes.com/2021/02/27/health/marijuana-hemp-delta-8-thc.html

1. Systematic Review:
2. Summarizes findings from a single key study on Delta-8 THC. https://pubmed.ncbi.nlm.nih.gov/29385080/
3. Original Study (may not be accessible):
4. Investigates Delta-8 THC effects in humans.
5. https://www.karger.com/Article/Abstract/136375

• HPLC-MS/MS Strategies:
• Analytical methods for testing Delta-8 THC.
• https://academic.oup.com/jat/advance-article-abstract/doi/10.1093/jat/bkaa184/6018445?redirectedFrom=fulltext

• Mechanism of Action:
• Study exploring how Delta-8 THC binds to cannabinoid receptors.
• https://pubmed.ncbi.nlm.nih.gov/27398024/

If you’re interested in learning more or exploring the impact of Delta-8 THC, these resources provide a great starting point. Thank you for listening!

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Case from the show

• https://pubmed.ncbi.nlm.nih.gov/22163140/

Mithradates

• https://www.wemjournal.org/article/S1080-6032(11)00043-3/pdf

Case series on mad honey effects

• https://pubmed.ncbi.nlm.nih.gov/20575670/

Blog post on sodium channel openers

• https://emcrit.org/toxhound/ff-plant-sodium-channel-openers/

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In this second rendition of toxicologist vs the internet Ryan Is joined by special guest Dr. Jillian Theobald, MD, PHD an emergency medicine physician and medical toxicologist. They take turns answering questions from reddit.com/r/askdrugs (the internet, really, really needs a toxicologist) and challenge each others toxic sleuthing by presenting cases of poisoning and allowing the other to determine the toxin responsible. Listen in to hear about the clinical effects of benzodiazepine on TV watching, the patient side of ketamine, cocaine chest pain, heavy metals, flower petals and much much more!

• Patient Experience Blog:
• "30 Years of Depression Gone"
• https://humanparts.medium.com/30-years-of-depression-gone-3dffafabc7cf?fbclid=IwAR1gh08Kn3uSczlKbvMH54yjkWILzyA_6O3Y82q4hVqcAr3shozxwegCnmg

• Study on Cognitive Enhancers:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770454/#CR14

1. Hepatic Injury Risk:https://pubmed.ncbi.nlm.nih.gov/15114493/
2. Anti-Anxiety Effects:https://pubmed.ncbi.nlm.nih.gov/33207379/

1. Propranolol Effects on Coronary Constriction:https://pubmed.ncbi.nlm.nih.gov/1971166/
2. Labetalol Effects on Coronary Constriction:https://pubmed.ncbi.nlm.nih.gov/8506886/

• Clinical guidance for toxicity management:
• https://pubmed.ncbi.nlm.nih.gov/25724076/

• https://pubmed.ncbi.nlm.nih.gov/18802411/

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• Chloroquine: >5 g is associated with severe toxicity (though toxicity can occur at lower doses).
• Hydroxychloroquine (HCQ): Toxic dose is less well-defined.

• Seizures: Due to sodium channel blockade.
• Arrhythmias: Resulting from sodium channel blockade.
• Hypotension: Caused by alpha-adrenergic blockade.
• Hypokalemia: Often a notable feature.

1. Decontamination:

• Administer activated charcoal if the patient is awake, alert, and has no risk of emesis.

1. Supportive Care:

• High-dose epinephrine:
• Recommended dose: 0.25 mcg/kg/min.
• Based on retrospective case-control series: https://www.nejm.org/doi/full/10.1056/NEJM198801073180101
• Diazepam:
• Administer 1–2 mg/kg over 30 minutes, followed by 1–2 mg/kg over 24 hours.
• Prevents seizures and may provide cardioprotective effects.

1. Airway Management:

• Consider early intubation to secure the airway in deteriorating cases.

1. Expert Consultation:

• Contact a poison center for guidance: 1-800-222-1222.

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In this episode Ryan and Toxo discuss some potential toxic spices and break down the toxicity and treatment of a once well known medicine

• Use of Cinchona Bark Powder for Malaria:
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973170/
• Evolutionary Pressure of Malaria on Sickle Cell Traits:
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499995/

• Definition: Classic toxicities caused by ingestion of quinoline derivatives from cinchona bark.
• Brief Review:
• https://pubmed.ncbi.nlm.nih.gov/32644745/

• Sources:
• Powdered cinchona bark: Used in tonic water, to treat restless legs, or as a remedy for certain viruses.
• Prescription quinoline derivatives:
• Quinine
• Quinidine
• Hydroxychloroquine
• Chloroquine

• Symptoms:
• Dizziness, flushing, headache, tinnitus.
• Potential for vision loss.
• Laboratory Abnormalities:
• Hypoglycemia, hypokalemia, long QRS.

Supportive Care:

• Manage airway, breathing, and circulation (ABCs).
• Early use of epinephrine as a preferred pressor based on animal and chloroquine data.

Correct Endocrine/Metabolic Abnormalities:

• Hypertonic Sodium: For wide QRS (use cautiously to avoid worsening hypokalemia).

Decontamination:

• Consider multi-dose activated charcoal for significant ingestions.

• Key Findings:
• Ocular toxicity is often delayed but can become permanent.
• Quinine levels >15 are associated with increased ocular toxicity.
• Quinine-induced blindness: https://pubmed.ncbi.nlm.nih.gov/3983356/
• Hall AP, et al. Quinine-induced blindness. Br J Ophthalmol. 1997. doi:10.1136/bjo.81.12.1029
• Recovery:
• Vision may recover centrally first, then peripherally.
• Hyperbaric oxygen therapy (HBO) is often used but remains debated.

• Mechanism:
• Tinnitus caused by microstructural changes in the outer hair cells of the cochlea and organ of Corti.
• Vasoconstriction and prostaglandin inhibition contribute to decreased hearing.
• Studies:
• Jastreboff PJ, et al. Quinine-induced tinnitus in rats. Arch Otolaryngol Head Neck Surg. 1991. doi:10.1001/archotol.1991.01870220110020
• Roche RJ, et al. Quinine induces reversible high-tone hearing loss. Br J Clin Pharmacol. 1990. doi:10.1111/j.1365-2125.1990.tb03704.x

1. Cardiac Arrhythmias in Patients Taking Quinine Alone:Padmaja UK, Adhikari P, Periera P. Experience with quinine in falciparum malaria. Indian J Med Sci. 1999. PMID: 10695226.
2. Negative Inotropic Effects of Quinidine:Hoffmeister HM, et al. Negative inotropic effect of class-I antiarrhythmic drugs. Eur Heart J. 1987. doi:10.1093/oxfordjournals.eurheartj.a062178.
3. Tinnitus and Hearing Effects: Jarboe JK, Hallworth R. The effect of quinine on outer hair cell shape, compliance and force. Hear Res. 1999. doi:10.1016/s0378-5955(99)00031-3.

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In this episode Ryan Is joined by a special guest Dr. Matthew Stanton PharmD, BCPS, DABAT, an emergency medicine pharmacist and clinical toxicologist. Ryan and Matt take turns answering questions from reddit.com/r/askdrugs (the internet, really, really needs a toxicologist) and finally they challenge each others toxic sleuthing by presenting some cases of poisoning and allowing the other to try to determine the toxin responsible.

• Potential Toxicity of Vitamin E Acetate in THC Vape Cartridges
• Authored by Ryan and Matt:
• Study 1
• Study 2
• Related News:
• Article covering the arrest of a man selling vape cartridges—incident occurred one floor below our host. Co-author of the above papers is quoted.
• Read the full article

• False Positive for Fentanyl
• Review Article

• Comprehensive Review
• Understanding Serotonin Syndrome
• LSD and 5-HT2A Partial Agonism
• Mechanistic Insights
• Binding Affinity of Psychoactive Compounds
• Review Article
• Cases of LSD-Related Deaths
• Discussion and Review
• Serotonin Syndrome with Stimulant Compounds
• Risk Review
• Methamphetamine-Induced Serotonin Syndrome
• Case Report

• Case 1: Toxicity Review
• Detailed Analysis
• Case 2: Methemoglobinemia
• Comprehensive Review
• Case 3: Toxicity Insights
• In-depth Review
• Case 4: Poisoning Case Report
• Case Discussion

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Ryan and Toxo go in depth on an old substance that has begun to resurface with new toxicity due to users taking massive amounts. Loperamide. Dive into the regulatory history, mechanisms of its toxic cardiac effects, and a brief discussion of treatment in episode 4.

Buying as much loperamide as you possibly can

1. 1969: Synthesized. (1)
2. 1976: FDA Approved as Schedule V. (2)

• "IMODIUM FDA Application No.(NDA) 017694". U.S. Food and Drug Administration (FDA). 1976.
• https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf

1. 1982: Descheduled. (3)

• Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN9780080861142.

1. 2010: Increasing poison center calls, arrhythmia cases, and hospitalizations. (4,5,6)

• Eggleston W, Marraffa JM, Stork CM, et al. Notes from the Field: Cardiac Dysrhythmias After Loperamide Abuse — New York, 2008–2016. MMWR Morb Mortal Wkly Rep 2016;65:1276–1277.
• http://dx.doi.org/10.15585/mmwr.mm6545a7

1. 2016: DEA denies rescheduling request. (7)

• https://www.chpa.org/PDF/09_05_17_CommentsCitizenPetitionLoperamide.aspx

1. 2019: FDA works with manufacturers to reduce package size to 48 tablets. (8)

• https://www.fda.gov/drugs/drug-safety-and-availability/fda-limits-packaging-anti-diarrhea-medicine-loperamide-imodium-encourage-safe-use
• Pharmacist Knowledge Gap: Awareness of abuse remains low.
• Feldman R, Everton E. National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected. J Am Pharm Assoc (2003). 2020. doi:10.1016/j.japh.2020.05.021
• https://pubmed.ncbi.nlm.nih.gov/32641253/

1. Inhibition of Sodium and HERG Channels:

• Kang J, Compton DR, Vaz RJ, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide. Naunyn Schmiedebergs Arch Pharmacol. 2016. doi:10.1007/s00210-016-1286-7
• https://pubmed.ncbi.nlm.nih.gov/10837556/
• IC50 for HERG Ikr ~ 40 nm/l (1908 ng/dl), inhibits as low as 10 nm/l.
• Klein MG, Haigney MCP, et al. Potent Inhibition of hERG Channels by Loperamide. JACC Clin Electrophysiol. 2016. doi:10.1016/j.jacep.2016.07.008

1. Reported Fatalities:

• Marraffa JM, Holland MG, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila). 2014. doi:10.3109/15563650.2014.969371
• https://pubmed.ncbi.nlm.nih.gov/29941678/

• Guidelines:
• Eggleston W, Palmer R, Dubé PA, et al. Loperamide toxicity: recommendations for patient monitoring and management. Clin Toxicol (Phila). 2020. doi:10.1080/15563650.2019.1681443
• https://www.sciencedirect.com/science/article/pii/S1880427611800050
• Supportive Care:
• Arrhythmia Management:
• Electrical cardioversion for torsades.
• Magnesium to prevent early after depolarizations (target Mg >2, K >4).
• Lidocaine recommended for VT (does not prolong QTc).
• Overdrive pacing (e.g., isoproterenol) if bradycardia precedes arrhythmia.
• Beta-blockers for long QT syndrome.
• Wide QRS Tachycardia: Use hypertonic sodium (1–2 amps of 8.4% Sodium Bicarbonate IV).

• Further research is needed to understand the incidence of loperamide-induced toxicity and the impact of FDA packaging changes.
• Concerned about loperamide regulation? Contact us at [email protected].

1. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf
2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guidelines for VT and Sudden Cardiac Death. J Am Coll Cardiol. 2018. doi:10.1016/j.jacc.2017.10.054

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Great review of potential torsades mechanisms based off experimental data- https://www.sciencedirect.com/science/article/pii/S1880427611800050

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• Action potential
• Sodium/Potassium ATPase pumps create more positively charged ions outside the cell than inside the cell, this creates a relative negative charge in the cell
• Phase 4- Resting (~ -90 mv)
• Phase 0- Sodium enters the cell (+10 mv)
• Phase 1- Potassium efflux from cell as now there is no negative charge holding it in (0 mv)
• Phase 2- Calcium channels open and allow calcium in, calcium triggers the ryandoine receptor and allows for calcium dependent calcium release from the sarcoplasmic reticulum occurs
• Phase 3- Potassium continues to leave the cell allowing return to -90 mv

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