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Emerging Substances of Abuse

James R. Latronica, D.O.Addiction Medicine Fellow

Penn State Health Hershey Medical Center

Associate Editor

Journal of Addictive Diseases

©2020 by James Latronica

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Conflicts of Interest

▪ None to disclose

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Learning Objectives

▪ Identify “atypical” and emerging substances of abuse/use

▪ Describe availability and regulation

▪ Describe toxidromes

▪ Describe dependence/withdrawal where applicable

▪ Describe regulation where applicable

▪ Describe current or potential treatments

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▪ Common Threads

– Often younger user population

– Legal or unregulated

– Toxicology/Testing rare and/or specialized

– Mixed modality = ↑ Danger

“Atypical” Substances of Abuse

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Kratom

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▪ Mitragyna speciosa

– “mitre” or “Mithraic”

▪ Names: kratom, thang, kakuam, thom, ketum, biak

▪ Native to SE Asia

– used in ceremonies/“traditional medicine”

Kratom

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Kratom | Pharmacology

▪ Over 40 similar alkaloids

– Mitragynine is most prevalent

▪ μ and κ opioid receptor agonism1

– κ activity may explain use as agonist/”replacement” therapy

▪ Also: dopamine, serotonin, GABA, adrenergic2

Mixed modality = ↑ Danger

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Kratom | Effects

Low Dose Stimulatory/Dissociative

High Dose

Sedative/Euphoric

(typical opioid)3

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Kratom | Use

▪ “Eaters”

– 3-10 uses per day

– 1-3 leaves per chew

– 3-30 leaves per day

▪ “Dosing” Leaves

– 20 dry leaves = 17 mg of mitragynine4

– Not dissimilar from tobacco/nicotine use Photo Credit: deserthopetreatment.com

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Kratom | Use

Table courtesy of: erowid.org

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Kratom | Toxidrome

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Kratom | Toxidrome

▪ Overall → very similar to opioids

▪ Reversal?

– Other active alkaloids not inhibited by naloxone in animal studies5

Mixed modality = ↑ Danger

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Kratom | Regulation

▪ DEA (2013): “No known medical use”6

– 2016: Schedule I status → failed after public backlash7

▪ FDA: “No FDA-approved uses”8

– 2018: dangerous drug “with opioid properties”9

▪ “No-Man’s Land”

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Kratom | Regulation

▪ Often sold as unregulated “supplement”

▪ Online, “head shops”, gas stations

▪ Often also simply sold openly

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▪ Data largely from case reports and case series

– MOUD becoming common

▪ Journal of Addiction Medicine10

– 52F taking 1 Tbsp. 4-6 times per day (~80-120g)

– Induced with buprenorphine/naloxone

– Stable and abstinent x several months

– UTox: +7-hydroxymitraginine 48 days after discharge

Kratom | Treatment

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Phenibut

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Phenibut

▪ β‐phenyl‐γ‐aminobutyric acid HCl

– derivative of baclofen

▪ Discovered and used clinically in USSR in 1960s

– anxiolytic/nootropic

– Used by Soviet cosmonauts11

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Phenibut | Pharmacology

▪ GABA-mimetic

– GABAB > GABAA

▪ Dopaminergic

– differs from benzos

▪ Phenyl ring allows crossing of BBB

▪ β‐phenethylamine

(PEA) antagonist

– endogenous anxiogenic

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▪ Most primary sources are in Russian

▪ Anxiolytic w/o sedation

▪ ↑ memory/intellectual function12

– 0.25g-0.5g TID x 1-2 weeks

– Only known RCT

Phenibut | Effects

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Phenibut | Effects

▪ Neuroprotection?

▪ Pharmacological Research (2016)13

– Mouse model

– MCAO occlusion

– 10 or 50mg/kg x 2 wks

– ↑ histological picture

– ↑ brain volume sparing

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▪ High Doses

– similar to benzos

– sedation, disinhibition, anxiolytic effects

▪ Extended Use

– craving, tolerance, increased frequency of use

Phenibut | Toxidrome

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Phenibut | Regulation

▪ FDA: “Phenibut does not meet the definition of a dietary ingredient Under the Federal Food, Drug, and Cosmetic Act (FD&C Act)”14

▪ Controlled Substance: only in Australia, Hungary, and Lithuania

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▪ Similar to benzos

– Anxiety, diaphoresis, insomnia

▪ Severe cases

– Hallucinations, psychosis, HTN/HOTN, respiratory depression requiring IMV

Mixed modality = ↑ Danger

Phenibut | Withdrawal/Treatment

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▪ Barbiturates

▪ Benzos

▪ Baclofen

▪ Antipsychotics

▪ Phenibut Taper

– would not recommend

– variable dosing, contaminants, mixed-modality effects

Phenibut | Withdrawal/Treatment

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Dextromethorphan (DXM)

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Dextromethorphan (DXM)

▪ Medullary cough center suppressant

– OTC (“behind-the-counter” in U.S.)

▪ Other mechanisms

– NMDA antagonist

– SNRI

– nAch modulator

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▪ Also a ligand of:

– 5HT1B/1D

– H1

– α2-adrenergic

– mAch

Mixed modality = ↑ Danger

Dextromethorphan (DXM)

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DXM | Effects

Typical Dosing

-Cough suppression

-Mild stimulation

High Dose (>2mg/kg)

-Dissociation

• NMDA activity

-Euphoria

-Hallucinations

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DXM | Use

▪ Pop culture influence

▪ Cough syrup-based drinks (+/- DXM)

– “Robo-trippin’”

– “Sizzurp”

– “Lean”

▪ Younger Users

– “It’s legal!”

– “It’s medicine, it’s safe!”

– UDS: “no codeine, no problem”

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DXM | Use

▪ Pseudobulbar Affect (PBA)

– DXM/quinidine

– Nuedexta

▪ MDD/Alzheimer’s

– DXM/bupropion

– “AXS-05”

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DXM | Toxidrome

▪ Vomiting, nystagmus, xerostomia, agitation, ataxia, convulsions, dissociation…

– Very long list!

▪ Rapid tachyphylaxis15

– increased addiction potential

▪ SSRI and MAOI can worsen symptoms16

Mixed modality = ↑ Danger

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DXM | Regulation▪ FDA

– multiple approvals

– OTC (often behind-the-counter)

▪ DEA

– 2018: “Drug of Concern”17

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▪ Naloxone?

– Mixed results19

▪ Benzos?

▪ EtOH abstinence meds?

DXM | Treatment

▪ Mainly supportive18

▪ Symptoms-based

– Hydration

– De-escalation

– Comfort meds

– Psychosocial

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Synthetic Cannabinoids

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Synthetic Cannabinoids

▪ CB1/CB2 agonists

– not actually cannabinoids

▪ Names

– K2/Spice

– other local brand names

▪ Origin

– Research tool

– Cannabis prohibition

▪ Sold

– Gas stations, “head shops,” internet

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Synthetic Cannabinoids | Pharmacology

▪ CB1/CB2 agonists

– Most plentiful receptor in human body

– Higher potency/binding affinity than THC20

▪ Extremely variable end-user effects

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▪ Generally used like cannabis

– Smoked via combustion

▪ Inexpensive

▪ Widely available (previously)

▪ “Blinded” to UDS (previously)

Synthetic Cannabinoids | Use

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▪ Highly variable

– Similar to previous “designer drugs”

▪ Serious

– Renal failure, cardiotoxicity, stroke, seizure, rhabdomyolysis

▪ “Zombie Outbreak”

– 2016: Brooklyn, NY

Mixed modality = ↑ Danger

Synthetic Cannabinoids | Toxidrome

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Synthetic Cannabinoids | Regulation

▪ Many warnings from various bodies

▪ Illegal in various states

▪ Several compounds now Schedule I

▪ Regulation is always lagging

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Synthetic Cannabinoids | Regulation

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▪ Mainly supportive

▪ Symptoms-based

▪ UDS (including POC) now available

– Only for specific few compounds

Synthetic Cannabinoids | Treatment

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Works Cited

1.) A.-C. Stolt, H. Schroder, H. Neurath et al., “Behavioral and ¨ neurochemical characterization of kratom (Mitragyna speciosa) extract,” Psychopharmacology, vol. 231, no. 1, pp. 13–25, 2014

2.) I. Ujvary, “Psychoactive natural products: overview of recent ´ developments,” Annali dell’Istituto Superiore di Sanita, vol. 50, no. 1, pp. 12–27, 2014.

3.) W. C. Prozialeck, J. K. Jivan, and S. V. Andurkar, “Pharmacology of Kratom: an emerging botanical agent with stimulant,

analgesic and opioid-like effects,” Journal of the American

Osteopathic Association, vol. 112, no. 12, pp. 792–799, 2012

4.) T. Amattayakul, “The kraton leaves,” Journal of the Department of Medical Sciences, Thailand, vol. 2, no. 2, pp. 104–106, 1960

5.) J. M. Holler, S. P. Vorce, P. C. McDonough-Bender, J. Magluilo Jr., C. J. Solomon, and B. Levine, “A drug toxicity death involving propylhexedrine and mitragynine,” Journal of Analytical Toxicology, vol. 35, no. 1,

pp. 54–59, 2011.

6.) "Kratom (Mitragyna speciosa korth)" (PDF). U.S. Drug Enforcement Administration. January 2013. Archived from the original(PDF) on 11 June 2016.

7.) 1.Connecticut, G. G., PhD, JD Associate Professor of Pharmacology University of Connecticut School of Pharmacy Storrs. The DEA Changes Its Mind on Kratom. https://www.uspharmacist.com/article/the-dea-

changes-its-mind-on-kratom.

8.) Commissioner, O. of the. FDA and Kratom. FDA (2019). https://www.fda.gov/news-events/public-health-focus/fda-and-kratom

9.) FDA Declares Kratom an Opioid. We’re Here to Explain What It Does. The Scientist Magazine® https://www.the-scientist.com/news-analysis/fda-declares-kratom-an-opioid-were-here-to-explain-what-it-does-

30306.

10.) Khazaeli, A., Jerry, J. M. & Vazirian, M. Treatment of Kratom Withdrawal and Addiction With Buprenorphine. Journal of Addiction Medicine 12, 493–495 (2018).

11.) 1.The cosmonaut drug that may have caused a school overdose. https://www.abc.net.au/news/2018-02-23/what-is-phenibut-the-drug-suspected-in-school-overdose/9475814 (2018).

12.) 1.Brunner, E. & Levy, R. Case Report of Physiologic Phenibut Dependence Treated With a Phenobarbital Taper in a Patient Being Treated With Buprenorphine. Journal of Addiction Medicine 11, 239–240 (2017).

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Works Cited

13.) Vavers, E. et al. The neuroprotective effects of R-phenibut after focal cerebral ischemia. Pharmacological Research 113, 796–801 (2016).

14.) 1.Nutrition, C. for F. S. and A. FDA Acts on Dietary Supplements Containing DMHA and Phenibut. FDA (2020).

15.) 1.Boyer, E. W. Dextromethorphan Abuse. Pediatric Emergency Care 20, 858–863 (2004).

16.)Chyka, P. A. et al. Dextromethorphan poisoning: An evidence-based consensus guideline for out-of-hospital management. Clinical Toxicology 45, 662–677 (2007).

17.) Drugs of Concern | DEA. https://www.dea.gov/taxonomy/term/311.

18.) MD, S. C. A., MD, J. L. H. & MD, M. F. B. Dextromethorphan Abuse and Dependence in Adolescents. Journal of Dual Diagnosis 6, 266–278 (2010).

19.) Cranston, J. W. & Yoast, R. Abuse of Dextromethorphan. Archives of Family Medicine 8, 99 (1999).

20.) Law R, Schier J, Martin C, Chang A, Wolkin A (June 2015). "Notes from the Field: Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use - United States, January-May 2015". MMWR.

Morbidity and Mortality Weekly Report. 64 (22): 618–9. PMC 4584925. PMID 26068566.