Dextromethorphan AbuseDrs. Heather Bell & Kurt DeVine

Family & Addiction MedicineJuly 15, 2020

Disclosure

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

History of Dextromethorphan

• 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, antihistamines• ~1million US youth and young adults (age 12-25) misuse these products every year

Mechanism of Action

• Produced from a derivative of morphine:• D-isomer of Levomethorphan (an opioid)• Not an opiate• Different mechanism than opioids• Does not bind mu or delta opioid receptors

• Therapeutic doses:• Acts at Sigma [opioid] receptors• Anti-tussive effects

• High-doses:• Metabolized to dextrorphan• Active metabolite • Antagonist at NMDA receptors

• Similar to PCP and Ketamine

Mechanism of Action

• Sertonergic:• Binds to serotonin receptors• May result in serotonin syndrome*

• Blocks reuptake of peripheral adrenergic neurotransmitters resulting in:

• Hypertension, tachycardia, mydriasis, 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

Pharmacokinetics

• T1/2: • ~3 hours in rapid metabolizers• ~30 hours in slow metabolizers

• Liver metabolism• CYP2D6

• ~85% US population have high CYP2D6 activity• Rapidly high dextrorphan levels after overdose

• Meds that inhibit this (MAOi, fluoxetine, paroxetine, haloperidol)

• 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• Psychosis• Hyperthermia• 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 hallucinations and euphoria• 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, hallucination, dissociative effects,

paranoia• Dissociative effects: feel they are leaving their bodies or

things around them are not real

• “Extreme” doses:• Extreme sedation, respiratory depression, 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 physical dependence• Often co-ingested with : alcohol,

marijuana, opioids, benzodiazepines, stimulants

• *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 doxylamine

• “Crystal Dex”

Trends:

• Multi-factoral• OTC, legally sold• Often already in households• Inexpensive• False perceptions of “low risk”• Online access- “encouraging”• 1 package has enough DXM to produce euphoric and

hallucinatory effects• “Gateway Drug”- youth that misuse DXM also misuse:

• Marijuana: 82%• Inhalants: 49%• Hallucinogens (LSD, PCP, MDMA): 44%

Availability

• “Over-taken codeine 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• Candy • DXM• Dex• Drex• Red Devils• Poor mans PCP

• Skittles• Robo• Rojo• Tussin• Velvet• Vitamin D

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->80.9Related 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• Hypoxia• 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 hepatotoxicity 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 Toxidrome from DXM

• DXM hydrobromide• Symptoms:

• Fatigue• Ataxia• Headache• Memory loss

• Serum chloride: rises significantly• Negative anion gap• Treatment: saline hydration and diuretic 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 blood pressure, elevated heart

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:• Severe vomiting• Myalgias• Diarrhea

• ~3 more weeks:• Night sweats• Insomnia• Anxiety• Cold intolerance

• Other “long-term”• Nightmares• Panic attacks• Memory issues• Intense cravings• Flashbacks • Toxic psychosis• “Permanent psychological issues”

Treatment

• Supportive care• +/- involve medical toxicologist (Dr Beth Bilden?!)• Quiet, calm room• Meds (if needed)

• +/- sedation• +/- restraints• Benzos (short acting)• Low-dose antipsychotics• +/- 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 (diphenhydramine)” - Shadkam

Psilocybin vs DXM (2018 study)

• 20 hallucinogen 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 caffeine)• 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 perception

Psilocybin vs DXM (2018 study)

Psilocybin• Classic psychedelic: serotonin

2A receptor agonist• LSD• DMT

• T1/2: 3 hours

DXM• Dissociative hallucinogen (NMDA

receptor antagonist)• Ketamine• PCP

• T1/2: 2 hours

Psilocybin vs DXM (2018 study)

Psilocybin• Known:

• Acutely disrupt visual perception, attention and special working memory

• Neuroimaging studies: modulate memory, inhibitory, processing, visual processing

DXM• Known:

• Episodic memory, psychomotor function, attention, vigilance, continuous performance, executive function, meta-cognitive visual perceptive tasks

• Ketamine: shift brain functional connectivity 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• Orderly and dose dependent

effects:• Psychomotor performance, working

memory, episodic memory, associative learning, visual perception

Greater effects on working memory

DXM• Effects on psychomotor performance, visual

perception and associative learning• Range of effects dose dependent

Greater effects on balance*, episodic memory, response inhibition, executive control Less psychological insight, lower ratings of

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. Psychopharmacology. 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 ExpToxicol. 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 andtheir parents. J Altern Complement Med. 2010 Jul;16(7):787-93.

• UpToDate: Dextromethorphan abuse and poisoning: Clinical features and diagnosis.