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Dextromethorphan Abuse

Drs. Heather Bell & Kurt DeVine Family & Medicine July 15, 2020 Disclosure

• Neither Dr Heather Bell nor Dr Kurt DeVine have any financial relationships or disclosures History of

• FDA approval: 1958 • Initially marketed as Romilar • Dextromethrophan was the sole active ingredient • Removed from the market in 1973 due to “abuse” • Redesigned • Liquid formulation • Unpleasant taste • ~1 bottle to achieve euphoric effect • Gel-tabs then developed History

• Currently in >140 over the counter cough preparations • Coricidin • Robitussin • Nyquil • Delsym • Formulations: • Syrups • Suspensions (sustained release syrup) • Capsules • Strips • Lozenges • Often combined with: pseudoephedrine, acetaminophen, • ~1million US youth and young adults (age 12-25) misuse these products every year

• Produced from a derivative of : • D-isomer of (an ) • Not an opiate • Different mechanism than • Does not bind mu or delta opioid receptors • Therapeutic doses: • Acts at Sigma [opioid] receptors • Anti-tussive effects • High-doses: • Metabolized to • Active metabolite • Antagonist at NMDA receptors • Similar to PCP and Mechanism of Action

• Sertonergic: • Binds to receptors • May result in * • Blocks reuptake of peripheral adrenergic resulting in: • Hypertension, , , diaphoresis • Metabolized by CYP2D6: • Fast metabolizers (~85% of the US population) • More susceptible to abuse • UDAS: • Not on a typical UDAS • High doses can create false-positive PCP

• T1/2: • ~3 hours in rapid metabolizers • ~30 hours in slow metabolizers • • CYP2D6 • ~85% US population have high CYP2D6 activity • Rapidly high dextrorphan levels after overdose • Meds that inhibit this (MAOi, , , ) • Increase dextromethorphan levels • Decrease dextrophan levels • Dampen associated neurobehavioral effects • To dextrorphan and 3-methoxymorphinan • Renally excreted • Peak concentration @2.5 hrs Side-Effects

• Therapeutic doses: • Nausea • Myalgias • Constipation • Drowsiness • Mild HA • Supratherapeutic doses: • Tachycardia • Hypertension • Agitation • Ataxia • • • Cardiac/respiratory arrest Dosing (therapeutic)

• Standard release (IR): • 5mg -> 30mg per dose • Max: 120mg/24 hours • Extended release: • 60mg dosing • Max: 120mg/24 hrs Dosing (Abuse)

• Dose dependent: • Effects typically begin at 30-60min • Persist for up to 6 hours • 1st plateau: • 100-200mg/dose • Feelings of stimulation • MDMA like • 2nd plateau: • 200-400mg/dose • Visual and • Etoh and Marijuana like Dosing (Abuse)

• 3rd plateau: • 300-600mg/dose • Hallucinations, euphoria, significant perceptual distortions of objects in the visual field, significantly impaired motor functioning and coordination • 4th plateau: • >600mg/dose • Extreme sedation, , effects, paranoia • Dissociative effects: feel they are leaving their bodies or things around them are not real • “Extreme” doses: • Extreme sedation, respiratory , potential MI High-Dose: Other Ill Effects:

• Risk for harm: • Poor judgment • Impulsive behavior • Perceptual disturbances • MVA • Impulsive-violent acts: • Assault, suicide, homicide High-Dose: Other Ill Effects:

• Individuals develop tolerance • Habitual use • Cravings • Do not develop • Often co-ingested with : , marijuana, opioids, , • *Serotonin Syndrome Extraction:

• “Agent Lemon” • 2 phase acid extraction using: • Lemon juice • Ammonia • Lighter fluid • Reduces amount of acetaminophen and pseudoephedrine • More concentrated dextromethorphan and • “Crystal Dex” Trends:

• Multi-factoral • OTC, legally sold • Often already in households • Inexpensive • False of “low risk” • Online access- “encouraging” • 1 package has enough DXM to produce euphoric and hallucinatory effects • “Gateway ”- youth that misuse DXM also misuse: • Marijuana: 82% • : 49% • (LSD, PCP, MDMA): 44% Availability

• “Over-taken due to availability, efficacy and safety profile at directed doses” • Oral strips, lozenges, liquids or capsules • “Poor-Man’s” PCP • Several states including: California, North Dakota, Texas, New York have restricted sale to minors DXM Abuse:

•Known as: •Going pharming •Dexing •Robodosing •Robotripping Street Names:

• CCC/Triple C • Skittles • Candy • Robo • DXM • Rojo • Dex • Tussin • Drex • Velvet • Red Devils • D • Poor mans PCP Data:

• Rates of ED visits for DXM ingestions- SAMHSA: • 2004: 2420 • 2005: 2570 • 2006: 3174 • 2007: 3074 • 2008: 3580 • 2009: 3911 • 2010: 4140 • 2011: 4449 • Gender distribution: • In 12-17 yo: female > male • In >18yo: male>female Data:

• National Poison Data System (NPDS) maintained by the American Association of Poison Control Centers (AAPCC) • Annual rate of single-substance DXM intentional abuse calls tripled from 2000-2006: • Plateau: 2006-2015 • Peak: 2006 34,755 • Highest in 14-17 yo: • 1761 calls/year • 10 calls per million population • 2006-2015: • Rates decreased by 56.3%: 143.8->80.9 Related to growing public health efforts to curtail OTC DXM California Poison Control System study: 2006

• 1382 cases • 10 fold increase in DXM abuse cases • 1999-2004 • 0.23/1000 calls -> 2.15/1000 calls • 74.5% age 9-17yo • Highest in 15 & 16yo • Primarily Coricidin HBP Cough and Cold tabs NIDA

• National Institute on Drug Abuse (NIDA) statement: • Recognizes DXM use and abuse • Builds up acids in body fluids • Liver damage if co-ingestion with acetaminophen • • Respiratory issues: chronic decreased RR • Transition to other substance use disorders Acetaminophen Co-ingestion

• Intoxication of DXM peaks/presents to ED around 6-8 hours • Acetaminophen does not show signs of toxicity until around 10 hours • At this point may occur • Often unrecognized by medical providers • Unrecognized co-ingestion by user: • Of 26 pts with elevated APAP levels: • Only 16 even reported they had taken APAP • 16 needed N-Acetylcysteine (NAC) for APAP • 7 had elevated transaminases Bromism: Elusive from DXM

• DXM hydrobromide • Symptoms: • Fatigue • Ataxia • Headache • Memory loss • Serum chloride: rises significantly • Negative anion gap • Treatment: saline hydration and treatment • Mental status changes- slow resolution Chronic Use

• “Subjective” need to increase dose • Rapidly progressive tolerance develops • Dependence does not develop • Toxic psychosis • Cognitive deterioration Patient Presentation

• H & P: • Often unable to hx secondary to altered mental status • GEN: hyperthermic, diaphoretic, AMS, inappropriate laughing • HEENT: mydriasis, nystagmus • CV: elevated pressure, elevated rate • RESP: depression • Neuro: mild ->severe agitation, confusion, hallucination, (“zombie like”) ataxia, muscle rigidity, seizures, coma Patient Presentation

•H & P: • Identify he likelihood of trauma and rape • Up to 14% of DXM OD seen in the ED are part of a suicide attempt Labs:

• DXM: +/- availability- typically reserved for forensic or nonclinical • BMP • CBC • LFT • CK • Acetaminophen • Salicylate • Ethanol • EKG • UDAS • +/- pregnancy test • +/- imaging if trauma Typical Findings:

• Hyperthermia • Metabolic acidosis • Rhabdomyolysis Withdrawal

• First week: • Other “long-term” • Severe • Nightmares • Myalgias • Panic attacks • Diarrhea • Memory issues • ~3 more weeks: • Intense cravings Flashbacks • Night sweats • Toxic psychosis • Insomnia • “Permanent psychological issues” • • • Cold intolerance Treatment

• Supportive care • +/- involve medical toxicologist (Dr Beth Bilden?!) • Quiet, calm room • Meds (if needed) • +/- sedation • +/- restraints • Benzos (short acting) • Low-dose • +/- olanzapine • Narcan if respiratory depression • Activated charcoal if within the hour • Cooling • Treat rhabdomyolysis • Treat serotonin syndrome Treatment

•Inpatient •Outpatient •12-step Long-Term

• Neurodevelopment • DXM containing syrups lead to differences in cortical thickness and subcortical gray matter • Earlier initiation shows more significant findings • Several specific brain areas: • Bilateral precuneus (PreC) • L dorsal lateral prefrontal cortex (DLPFC L) • L inferior parietal lobe (IPL L) • R precentral gyrus (PreCG R) • R lateral occipital cortex (LOC R) • R inferior temporal cortex (ITC R) • R lateral orbitofrontal cortex (LOFC R) • R transverse temporal gyrus (TTG R) • Earlier age brain areas • L dorsal lateral prefrontal cortex (DLPFC L) • R precentral gyrus (PreCG R) • Impulsive behavior in patients: • L dorsal lateral prefrontal cortex (DLPFC L) Ms. J

• “Loved it from the first try” • “Brought me closer to God” • “I dreamt my mother ripped my face off with her fingernails, cut some of my fingers and toes off and ripped my arm off” • “Dirty High” = Etoh + DXM Case Report- 1994

• 39 yo insurance salesman • Hospital: acute mania (lengthy stay) • 1 year of deterioration- quit job • Depression during hospital/suicidal • Not delusional when depressed • Moods were varied with occasional mania associated with delusional ideas Case Report- 1994

• Clinical behavior and informal assessment suggested some degree of cognitive impairment • Formal cognitive assessment obtained: • IQ: 89 • Verbal: 94 • Performance: 84 • Poor functional abilities (drawing and so on) Case Report- 1994

• CT head: • Month after admission • Normal • Spect scan: (single-photon emission computerized tomography) • Analyzes function of specific areas • Suggest widespread dysfunction • EEG: • No seizure • Some suggestion of possible temporal lobe epilepsy in view of his religiosity/hypergraphia • Deterioration continued after carbamazepam Case Report- 1994

• Continued to consume cough syrup bottle per week for many months • Continued to deteriorate • Included mania, delusion, slurred speech, confusion, visual hallucinations and so on • Drug screen negative: except for DXM

• No information on final disposition Case Report- 1994

• Discussion: • Deterioration in cognitive state even in periods of abstinence • (No other case reports similar) • DXM: typically short term cases of cognitive changes • This case: prolonged But How To Treat Cough?

• “Most prescribed and over-the-counter preparations for cough in children are not effective and might carry the risk of adverse events”- Goldman

• “The result of the study demonstrated that receiving a 2.5mL dose of honey before sleep has a more alleviating effect on URIs-induced cough compared with DM (dextromethorphan) and DPH ()” - Shadkam vs DXM (2018 study)

• 20 users • 11 women, 9 men • Mean age: 28.5 (22-43) • All had history of use of both substances • 5 blinded drug administration sessions • Double blind-placebo controlled • Exclusion: • Current or history of SUD (excluding ) • Personal or family history of psychosis or bipolar • Pregnant or nursing Psilocybin vs DXM (2018 study)

• Assessments done in controlled environment with supervising volunteer (for safety) • Assessments on: • Gross motor • Strength of the drug (subjective) • Neurocognitive • Emotional/conflict • Psychomotor • Memory • Executive function and overall cognitive impairment • Visual Psilocybin vs DXM (2018 study)

Psilocybin DXM • Classic psychedelic: serotonin • Dissociative hallucinogen (NMDA 2A receptor ) • LSD • Ketamine • DMT • PCP • T1/2: 3 hours • T1/2: 2 hours Psilocybin vs DXM (2018 study)

Psilocybin DXM • Known: • Known: • Acutely disrupt , • Episodic memory, psychomotor function, attention and special working attention, vigilance, continuous performance, memory executive function, meta-cognitive visual • Neuroimaging studies: modulate perceptive tasks memory, inhibitory, processing, • Ketamine: shift brain functional connectivity visual processing from hubs in centered cortical regions to those primarily centered in subcortical regions • Alter brain activity in vision, verbal fluency, memory, executive function

?: underlying interactions between sertonergic & glutamatergic systems - Both substances have a similar subjective profile Psilocybin vs DXM (2018 study)- findings

Psilocybin DXM • Orderly and dose dependent • Effects on psychomotor performance, visual effects: perception and associative learning • Psychomotor performance, working • Range of effects dose dependent memory, episodic memory, associative learning, visual perception  Greater effects on balance*, episodic memory, response inhibition, executive control  Greater effects on working  Less psychological insight, lower ratings of memory personal meaningfulness and spiritual significance

*: Balance effects= greater risk in uncontrolled settings Sources

• Barrett FS et al. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: Effects on cognition. . 2018 October; 235(10):2915-2927. • Bryner, JK et al. Dextromethorphan Abuse in Adolescence. Arch Pediatr Adolesc Med. 2006 December; 160(12): 1217-1222. • Dextromethorphan (DXM) Abuse and Addiction: Treatment, Symptoms, and Signs. American Addiction Centers. 2019. • Goldman. Honey for the treatment of cough in children. Can Fam Physician. 2014 Dec; 60(2):1107-1110. • Hinsberger, MD et al. Cognitive Deterioration from Long-Term Abuse of Dextromethorpan: A Case Report. J Psychiatr Neurosci, Vol. 19, No. 5, 1994. • Hung et al. Bromide Intoxication by the Combination of Bromide-Containing Over-The-Counter Drug and Dextromethorphan Hydrobromide. Hum Exp Toxicol. 2003 Aug;22(8):459-61. • Journey, JD et al. Dextromethorphan Toxicity. NCBI Bookshelf. National Library of Medicine, National Institutes of Health. 2019. • Karami et al. Trends in dextromethorphan cough and products: 2000-2015 National Poison System intentional abuse exposure. Clinical Toxicology. Vol. 56(7), 2018. • Martinak B, et al. Dextromethorphan in Cough Syrup: The Poor Man’s Psychosis. Psychopharmacology Bulletin. 2017;47(4):59-63. • Monks, Sarah et al. Bromism: An overlooked and elusive toxidrome from chronic dextromethorphan abuse. American Journal of Emergency Medicine. 1999. • Olives TD Et al. Ten Years of Robotripping: Evidence of Tolerance to Dextromethorphan Hydrobromide in a Long-Term User. Journal of Medical Toxicology 15, 192-197 (2019) • Qui et al. Potential gray matter unpruned in adolescents and young adults dependent on dextromethorphan-containing cough syrups: evidence from cortical and subcortical study. Brain Imagin Behav. 2017 Oct;11(5):1470-1478. • Shadkam et al. A comparison of the effect of honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in children and their parents. J Altern Complement Med. 2010 Jul;16(7):787-93. • UpToDate: Dextromethorphan abuse and poisoning: Clinical features and diagnosis.