What Happens When Adam, Molly, and Spice Walk into a Psych Ward?

A discussion on (some of the) the latest drugs of abuse

Leigh Anne Bressler, DOPGY4

OSHU Psychiatry Residency Program

February 23, 2016

With Special Thanks to:

•Veena Raju, PGY4, superb Co-senior Resident, soon to be Child and Adolescent Fellow in Boston, MA•Jessica Myers, PGY3, outstanding soon-to-be 4th year OHSU Resident

Objectives:

1. Introduce a range of newer substances abused in the community and their corresponding terminologies.

2. Identify substances which are prevalent and more commonly abused in Oregon.

3. Recognize intoxication and withdrawal syndromes of select substances.

4. Evaluate the therapeutic potential of particular substances of abuse.

Synthetics and

SerotoninPhenylethylamines

MDMA: where it all began• First produced by Merck in 1912 • 1965: chemist Alexander Shulgin synthesizes while working

at Dow• In 1960/70s, “Adam” gained popularity among the

psychotherapy community• DEA classified as Schedule I drug in 1985 (no therapeutic

value)• 1991, Shulgin published PiHKAL

MDMA Pharmacology3,4 methylenedioxymethamphetamine

• 5-HT2a receptor agonist, also acts as stimulant, releasing NE• Typical dose 1-2 mg/kg (60-120mg)• Onset: 30 to 60 minutes• Duration of Intoxication: 4 to 6 hours• Formulation: Tabs, Capsules, Powder, Liquid• Route: PO, insufflation• UDS + for amphetamines and methamphetamines• Common Adulterants: DXM, ephedrine, cocaine, caffeine

The Ecstasy Revolution

Ecstasy, XTC, Adam, Molly, E, Xempathogens designer amphetamines

euphoria, heightened awareness of senses, stimulantWhen intoxicated, known as “rolling”

Recent use/trends:•https://www.drugabuse.gov/drugs-abuse/mdma-ecstasymolly

• More than 20 percent of U.S. respondents reported using MDMA in the past year (Global Drug Survey 2015)

• Oregon Student Wellness Survey 2014

Cautionary Tales2004 to 2011, MDMA-associated ED visits increased by

120%

New York City 2013

2 deaths +MDMA 3rd day of festival canceled

Los Angeles 2010

18 MDMA-related ED cases3 hospitalizations

1 ICU admit

Serotonin Syndrome

Treatment: • Supportive care in hospital setting• Benzodiazepines to address sympathomimetic symptoms

Harm Reduction EcstasyData.org

The “2Cs”: phenethylamines 2.0•One of many “designer drug” or “research chemical” classes •2C=acronym•methoxy groups at the 2 and 5 positions on the ring, and a hydrophobic substitute at position 4•Currently considered “drugs of concern” by the DEA; schedule I or II under the CSA or being considered for such status.

(4-bromo-2,5-dimethoxyphenethylamine)

1974 Fast forward to 2003

Ralf Heim synthesized 25I NBOMe (2C-I-NBOMe)

2C Series Initial claim to fame

Shulgin synthesized 2C-B

2C-X-NBOMe Pharmacology

25I-NBOMe; 25C-NBOMe; 25B-NBOMe 2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl) ethanamine• Attached ring-shaped sugar molecule “HPBCD” increases GI absorption--sometimes

added• Onset: 1 hr • Duration of intoxication: up to 15 hrs• Formulations: liquid, powder, capsules, blotter• Routes: IV, PO, insufflation, buccal• Bitter/metallic taste • Metabolites excreted through the kidney

High affinity and efficacy as a 5-HT2a receptor agonist

Potent!

25I NBOMeIntoxication: 0.5 mg to 0.75 mg POToxicity: above 1.5 mg PO

2C-BIntoxication: 12 to 60 mg PO

2011 internet drug forums began buzzing about N-Bombs

25I, Smiles, Solaris, Cimbi-5, Foxy methoxy

marketed and sold as “LSD”

LSD

Desired effects:

Visual Hallucinations

Euphoria

Aphrodisiac

Prevalence

Significant medical consequences: DeliriumSeizures Multi-organ failure

N-BOMe Lives in Infamy

“Texas synthetic drug ringleader sentenced to 246 months for his role in the deaths of 2 North Dakota teens.”

-ICE Newsroom, 2014

“New LSD-like drug 25I, or N-bomb, caused seizures in Sherwood, deaths around nation.”

-Oregonian, 2014

Everything old is new again:

Novel uses of cannabis and codeine

Old plant, new highs...● Chinese Emperor Shen Nung: 2727 BC● Used by ancient Greeks and Romans.● 1840’s: Dr. W.B. O’Shaughnessy introduces to

West● 2014 survey: 22.2 million current users (NSDUH)● A significant proportion of those who use regularly reported

that their primary motive was medicinal.

Oregon Stats: Cannabis● “Current” use (in past 30 days) is highests in 18-25 year olds, followed by 12-17

year olds.● The 2013 Oregon Healthy Teens survey found current use among 8th graders to

be 10% and among 11th graders 20%● Oregon’s Medical Marijuana Program is administered

by the Public Health Division; 77,000+ people hold an Oregon medical marijuana card as of January 1, 2016.

● As of January 9, there are 368 registered dispensariesin Oregon (Oregon.gov).

Oregon Health Teen Survey 2015

Medical Cannabis:● Marijuana plant: not approved by the FDA● Dronabinol (Marinol) and Nabilone (Cesamet):

approved for chemo-associated nausea and AIDS-related cachexia.

● Primary conditions for current card-holders...● Proliferation of medical dispensaries/recent legal changes regarding recreational

use--> increased methods for the administration:vaporizers, edibles, tinctures, patches, and capsules are now common.

Pharmacology, in (very) brief:● Two psychoactive species: c. indica and c. sativa● More than 460 compounds, 80 of which are cannabinoids.● THC, or tetrahydrocannabinol (delta-9-tetrahydrocannabinol) is the most

psychoactive, and associated with some of the pharmacological effects.● Other cannabinoids include delta-8-tetrahydrocannabinol, cannabidiol (CBD),

cannabinol (CBN), cannabicyclol (CBL), cannabichromene (CBC) and cannabigerol(CBG); they have less psychotropic effects than THC, but may play a role in the medically beneficial effects of cannabis.

THC intoxication/overdose:● THC can reduce anxiety, produce relaxation, and induce euphoria.● It can alter sensory perception, decrease coordination, and slow reaction

time.● In some people, and in overdose, it can cause acute dysphoria, paranoia, and

hallucinations.● Use is associated with short-term memory loss.● Withdrawal syndrom is possible

Dabs, the basics:● AKA: BHO (butane hash oil), honey oil, wax,

shatter, amber, hash-oil● It is a clear, golden-brown cannabis derivative

with little smell.● Extraction method is considered “extremely dangerous”● The resultant, concentrated hash oil, can reach from 15-90+%(!!) THC

Dabs, a rapid emergence:● February, 2013 issue of High Times: “we didn’t really talk about it or cover it,

because it was so rare.”● 5 months later, the July 2013 issue features “Dabs!” as the cover story.

Dabs, the dangers...● Butane, used to extract it, is highly flammable and prone to explosion.● Blowtorch is used in the process of “dabbing” ● Very high concentrations of THC can lead to intoxication/overdose syndromes.● Novel and more rapid administration method.● ED visits

Not your grandma’s Pot Brownies...● A wide variety of edible, marijuana-infused food and drink products ● There has been a spike in ED visits from people who have eaten too

many edibles, with syndromes including tachycardia, hallucinations, vomiting, paranoia

● Several studies have found an increase in pediatric MJ exposure since decriminalization/legalization laws have passed, often related to edibles.

Deliciously dangerous….● Different pharmacokinetics ● Edible products often are made with pure THC● Products can contain from 6-10 dose equivalents of THC per individual serving.● Packaging/products are visually appealing and familiar

to young consumers.

Old meds, new mixers...A brief history of codeine...

● Codeine is extracted from the opium poppy● The name is derived from the Greek word kodeia, for “poppy head.”● Medicinal and recreational use of opium peaked in the 1830s and spurred the

Opium Wars.● Codeine was first isolated by French chemist Pierre-jean Robiquet in 1832, paving

the way for the proliferation of “less addictive” and “safer” codeine- based preparations.

● Codeine is now the most widely used opiate in the world. (WHO)

Sippin’ on some sizzurp...● Abuse of codeine-based cough preparations known for decades● Prescription and OTC anti-tussives present a world-wide public health issue● In 2006, over 3 million people in the US

aged 12-25 reported using OTC cough andcold medicine to “get high”

● Since the late ‘90s, abuse of codeine-promethazine hydrochloride cough syrup (CPHCS) has become increasingly popular

Intoxication/Overdose:● Similar to other opiates● Overdose--respiratory depression, extreme somnolence progressing to

stupor or coma, bradycardia and hypotension● Promethazine intoxication/overdose ● Possible anticholinergic toxidrome may also

be seen; other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis

● Convulsions are rare but possible with both

Pharmacology, in brief...● 3-methylmorphine, a natural isomer of methylated morphine.● It acts on the mu opioid receptor● Promethazine: primarily H1 receptor antogonism and moderate

muscarinic, D2-receptor blocking activity● It is used in cough syrups for its antihistamine, antiemetic, and sedative

effects● Enzymatic induction

“Lean”, the basics:

● Sprite + Jolly Ranchers + CPHCS.● Some preparations include alcohol.● AKA purple drank, purple stuff, syrup, sizzurp, barre● Named for the posture users assume when intoxicated● Gained popularity in the Southern Rap culture● Especially popular in youth <21

Abuse in popular culture:

● DJ Screw● Jamarcus Russell● ESPN did a special report on

codeine abuse gaining popularity amongst professional athletes

● ‘Lil Wayne’s “sizzurp”overdose● Justin Bieber was reportedly

addicted to lean.

Lean, the dangers● Overdose, as described in previous slides.● A 2011 study by Hou et al● The ingredients are often found around the home.● Codeine is addictive, though less so than other opiates.● Codeine is often obtained by doctor-

shopping, forged Rx, or pharmacy theft.

“Natural” Drugs

Herbal Marijuana Alternatives (HMAs)• Herbal ingredients + synthetic cannabinoids• Popular in Europe since the early 2000s

– EMCDDA monitoring Spice products since 2008– Banned in Russia and Europe in 2010, appeared in USA around the

same time• 2011 - US DEA made many synthetic cannabinoids

schedule I–they remain available on the internet and in head shops

• Detection:– Plant material used is too varied to reliably detect– Synthetic cannabinoids do not cross-react with standard lab tests for

THC

• Variety of brand names, including K2 and Spice• Marketed as incense, potpourri, fertilizer, etc

– labelled “not for human consumption”• Compositions altered slightly • Deliberate misrepresentation?

Many listed ingredients not present Synthetic ingredients not listedAdditivesAmanita muscaria

• Synthetic cannabinoids: – Starting in the 1960s - pharmaceutical and research efforts to develop

compounds with the analgesic and anti-inflammatory effects of THC without the psychoactive effects• led to a better understanding of the endocannabinoid system

• Similar clinical effects as marijuana but not detectable by traditional screening methods

• Adolescents and young adults

Composition• Synthetic cannabinoids - 4 major groups:

– Classical cannabinoids, eg HU-210 • Dronabinol, Nabilone

– Cyclohexylphenols, or“non-classical cannabinoids”

• CP-47,497 – more potent than THC– JWH series

• JWH-018: psychoactive compound in many Spice products; also more potent than THC

– Miscellaneous compounds

PharmacologySynthetic cannabinoids:• Lack structural similarity to THC but bind to CB1 and CB2

receptors – higher affinity for receptors– higher potency– some significantly longer half-lives -> greater potential for

overdose and/or prolonged psychoactive effects• May also exert activity on other receptor families• Rapid onset, brief duration of action

– significant variability

Toxicity and additional risks• AKI (particularly related to use of XLR-11)• Seizures• JWH-018 – suspected carcinogenic potential • Possible heavy metal residues in some mixtures• Accidental overdose:

– Variable compositions

Potential therapeutic uses• Immune• Neuroprotective• Analgesia

Kratom• Derived from Mitragyna speciosa Korth tree• Used to treat opioid withdrawal and

pain for centuriesAlso called Ketum, Kakuam, Ithang and Thom

• Legal and available on the internet without a prescription– powder – leaves– gum

• Smoked or brewed in tea• Undetectable by available drug screens

Pharmacology• >25 alkaloids that vary based on location• Mitragynine: most abundant alkaloid

– Thought primarily responsible for opioid-like effects– Structurally similar to yohimbine and different from opiates – Acts at supraspinal μ and δ opioid receptors– Additionally:

• Serotonergic and noradrenergic pathways in the spinal cord• May stimulate post-synaptic α2 receptors• May block stimulation of 5-HT2A receptors

Clinical effectsOnset 5-15 minutes, duration of action up to 5 hoursDose-dependent effects

• Analgesia, anti-inflammatory, antipyretic, antitussive, antimalarial, antihypertensive, local anesthetic, hypoglycemic, antidiarrheal

• Prolonging sexual intercourse• Mild visual effects • Chronic use:

Anorexia, weight loss, hyperpigmentation, and psychosis• Tolerance, dependence, and withdrawal

Toxicity and Management• Seizures not responsive to benzos • No reported cases of death in the US• Krypton--contained tramadol and caffeine

• Seek immediate medical attention for suspected toxicity

• Increased risk of opioid-related death • Hypoventilation: airway management + opioid

antagonism • Seizures: airway management + benzo titration

I SWEAR IT HELPS, DOC:JCP September 2015: MJ Use Is Associated With Worse Outcomes in Symptom Severity and Violent Behavior in Patients with PTSD.

-at least 9 states have approved medical MJ for use in PTSD.-lots of our patients claim that it helps them in a variety of ways, but the

study suggests it may actually worsen symptoms and violent behavior.-in this observational study, n=2,276 vets, mostly male, white. Prevalent

comorbid disorders. Admitted to specialized VA treatment programs over a 20 year period.

-4 groups: never used, stopped upon entering study, started after entering study, and continued to use during study.

-assessed at intake and 4 months after d/c.-MJ use, especially when initiated after the study was significantly

associated with worse outcomes in PTSD symptom severity, violent behavior, and measures of etoh and drug use.

MDMA vs. PTSD:• A very “hot topic” in research right now.• http://www.mdmaptsd.org/research-category.html

References• Agnich, Laura E., John M. Stogner, Bryan Lee Miller, and Catherine D. Marcum. "Purple Drank Prevalence and Characteristics of Misusers of Codeine Cough Syrup

Mixtures." Addictive Behaviors 38.9 (2013): 2445-449. Web.• Babu, Kavita M., Christopher R. Mccurdy, and Edward W. Boyer. "Opioid Receptors and Legal Highs: Salvia Divinorum and Kratom." Clinical Toxicology 46 (2008): 146-52.

Web.• Berger, Eric. "Legal Marijuana and Pediatric Exposure." Annals of Emergency Medicine 64.4 (2014): A19-21. Web.• Boyer, E.W., Shannon, M. (2005). The Serotonin Syndrome. New England Journal of Medicine. 352, 1112-1120. DOI: 10.1056/NEJMra041867• CDC. (2010). Ecstasy overdoses at a New Year's Eve rave—Los Angeles, California, 2010. Morbidity and Mortality Weekly Report. 59, 677–81. • The Center for Behavioral Health Statistics and Quality (CBHSQ) in the Substance Abuse and Mental Health Services Administration (SAMHSA). National Survey on Drug

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References• Slide 10: Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2011• National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13-4760,• DAWN Series D-39. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.• Clin Toxicol (Phila). 2013 Jul;51(6):487-92. doi: 10.3109/15563650.2013.802795. Epub 2013 Jun 4.• Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: case series.• Hill SL1, Doris T, Gurung S, Katebe S, Lomas A, Dunn M, Blain P, Thomas SH.• http://www.nejm.org/doi/full/10.1056/NEJMra041867The Serotonin Syndrome• Edward W. Boyer, M.D., Ph.D., and Michael Shannon, M.D., M.P.H.• N Engl J Med 2005; 352:1112-1120March 17, 2005DOI: 10.1056/NEJMra041867• http://www.sciencedirect.com/science/article/pii/S0165614708001545#

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