The Designer Drug – What You Always Wanted to Know Steven Kipnis MD, FACP, FASAM Medical Director, NYS OASAS

Thanks to: Paul L. Cary Toxicology Laboratory University of Missouri Steve Hanson Acting Associate Commissioner - NYSOASAS

CASE A healthy 48-year-old man has a generalized convulsion after ingesting a powder he purchased through the Internet. The powder was sold with the wording “not for human consumption” listed on the packaging. The seizures continue in the pre-hospital setting, as well as in the ED, for approximately 15 minutes in total before ceasing after administration of lorazepam 4 mg IV. Initial vital signs after cessation of his seizures include a blood pressure of 140/88 mm Hg; pulse, 106 beats/min; respiratory rate, 22 breaths/min; temperature, 37.7°C. Physical examination is notable for mydriasis and diaphoresis with 5 beats of myoclonus in the bilateral lower extremities. Shortly after arrival in the ED, the patient is intubated for airway control. Finding on noncontrast CT of the brain are unremarkable, and EEG results are normal. Initial pertinent laboratory values include normal electrolyte, creatinine, and glucose levels. His creatine phosphokinase level is elevated, at 2,500 U/L. Toxicology screening does not detect acetaminophen, ethanol, or salicylates

CASE A healthy 48-year-old man has a generalized convulsion after ingesting a powder he purchased through the Internet. The powder was sold as “research grade JWH-018 – synthetic cannabinoid,” with the wording “not for human consumption” listed on the packaging. The seizures continue in the prehospital setting, as well as in the ED, for approximately 15 minutes in total before ceasing after administration of lorazepam 4 mg IV. Initial vital signs after cessation of his seizures include a blood pressure of 140/88 mm Hg; pulse, 106 beats/min; respiratory rate, 22 breaths/min; temperature, 37.7°C. Physical examination is notable for mydriasis and diaphoresis with 5 beats of myoclonus in the bilateral lower extremities. Shortly after arrival in the ED, the patient is intubated for airway control. Finding on noncontrast CT of the brain are unremarkable, and EEG results are normal. Initial pertinent laboratory values include normal electrolyte, creatinine, and glucose levels. His creatine phosphokinase level is elevated, at 2,500 U/L. Toxicology screening does not detect acetaminophen, ethanol, or salicylates

A 36-year-old male in the Netherlands became acutely agitated and enraged after ingesting mephedrone along with cocaine, and subsequently lost consciousness and died despite resuscitation efforts. A 29-year-old male found unresponsive at a nightclub died of cerebral edema and brainstem herniation. Serum sodium was noted to be 125 mmol/L, later suggested by laboratory data to have resulted from water intoxication. The first synthetic cathinone-related death in the United States, described in the scientific literature, involved a 22-year-old male who was found unresponsive and subsequently died at the receiving hospital. One case of mephedrone-related myocarditis has also been reported in the literature. A 19-year-old male presented with crushing chest pain after ingesting mephedrone sold as ‘‘not for-human-consumption’’ plant food.

Drive to Get High People will seek any means to alter their state of consciousness

The Story of Designer Drugs

Designer Drugs: Created (or reformulated, if the drug already existed) to get around existing drug laws (Controlled Substance Act), usually by modifying the molecular structures of existing drugs to varying degrees.

Designer Drugs: Second International Opium Convention in 1925 which specifically banned alternative esters of morphine 1960s - 1970s, new synthetic hallucinogens (modifications of LSD & PCP) “Designer drug” was first coined by law enforcement in the 1980s 1980s - 1990s, design of MDMA (ecstasy) & methcathinone 2000 - 2005, derivatives of psilocybin & mescaline, anabolic steroids European authorities have identified 41 new psychoactive drugs in 2010 alone

What Drives the Production Designer Drugs ? Consumer preferences Law enforcement control

An agonist is a chemical that binds to a receptor and triggers a response – often mimicking the action of a naturally occurring substance. Receptor Drug (agonist)

Why Change the Key? Prolong the effect of the drug Increase the potency of the drug “Select” the desired effect Make the drug more difficult to detect Avoid patent infringement Make an illegal drug “legal” Drug

Spice/K2 and Synthetic Cannabinoids (HMA – Herbal Marijuana Alternatives)

No! We’re not talking about this!

We’re talking about this! There are hundreds of synthetic cannabinoids.

Brand Names of Common HMA’s Spice K2 Tai Fun (Blackberry, Vanilla, Orange) Exclusive (Original, Mint, Cherry) Chill Zone (Berry, Mint, Original) Chill Out (Cherry, Mint, Original) Sensation (Vanilla, Orange, Bkberry) Chaos (Mint, Original, Cherry) Zen Zen Ultra

What’s in these “incense” products?

“Listed” Ingredients in Spice Canavalia rosea: beach bean or bay bean Nymphaea caerulea: Blue Egyptian water lily Scutellaria nana: Dwarf skullcap Pedicularis densiflora: Indian warrior Leonotis leonurus: Lion's Tail and Wild Dagga Cannabis – like effect Zornia latifolia: is a perennial herb Nelumbo nucifera: Lotus Leonurus sibiricus: Honeyweed or Siberian motherwort Vanilla Honey

Preparation of the “incense”: Botanicals (vegetable matter) are sprayed with liquid preparations of: HU-210 HU-211 CP 47,497 JWH-018 JWH-073

Origins of Synthetic Cannabinoids CP 47,497 - developed by Pfizer in 1980 as an analgesic HU-210 & HU-211 - synthesized at Hebrew University, Israel in 1988. HU-210 is an anti-inflammatory; HU-211 as an anesthetic JWH-018 & JWH-073 - synthesize by a researcher at Clemson (1995) for use in THC receptor research - John W. Huffman more than 100 different synthetic cannabinoids have been created

Usage Very little known about the extent of use 2009 Survey in Frankfurt Surveyed 1463 students aged between 15 and 18 at schools providing general and vocational training. Prevalence of use was 6% of respondents reported using Spice at least once National Poison Data System in 2010 (Aurora, CO) During the 9 month study period, there were 1898 exposures reported with a mean age of 22.5 years old Most cases reported were in men. Community Epidemiologic Work Group (CEWG) noted K2 epidemic in Midwest US in 2010 Appears to be shifting from marijuana to synthetics

Usage Mode of use: Smoked Drink as an infusion/herbal tea

Availability Sold in metal-foil sachets Sold in: Typically contain 3 g of smoking mixture sufficient for 8 joints Typical cost is 20 – 60 dollars per pack Sold in: Internet sites Tobacco stores Head shops Some gas stations Often sold as “incense” labeled with disclaimer: not for human consumption

Smoking Cannabinoids What does CB1 receptor control? Basal Ganglia: motor control, learning Hippocampus: memory, spatial navigation Cerebrum: cognitive functions - attention, language, emotions *CB2 found in blood cells, immune tissue and spleen. ? in CNS

Dual effects: Herbs (very little medical literature of effects) Synthetic cannabinoid

Pharmacological Effects of Synthetic Cannabinoids are Similar to THC Mental (these affects predominate): Altered state of consciousness Mild euphoria and relaxation Perceptual alterations (time distortion) Intensification of sensory experiences Pronounced cognitive effects Impaired short-term memory Anxiety Paranoia Avoidant eye contact Agitation Delusions (paranoid, grandiose) Psychosis

Pharmacological Effects of Synthetic Cannabinoids are Similar to THC Physical: Increase heart rate & blood pressure Dry eyes Diaphoresis Mild decrease in potassium Seizures Reduction in motor skill acuity Increase in reaction times

Dependence Syndrome Similar to Marijuana Withdrawal: “Inner unrest” Drug craving Nightmares Profuse sweating Nausea Tremor Headache Hypertension Increased HR

Reported Effects of Synthetic Cannabinoids are Different Than THC Production inconsistencies Herbal incense blends are harsher to inhale Effect on appetite is non-existent Increased restlessness & aggressive behavior Herbal incense produces a shorter “high” (perceptual alterations & sensory effects are limited) Doesn’t mix well with alcohol (hangovers) Incense costs more than marijuana

Synthetic Cannabinoid Data

Percentage of U.S. 12th Grade Students Reporting Past Year Use of Drugs* Other Than Alcohol and Tobacco, 2011 (N=approximately 14,900) Marijuana and synthetic marijuana are the most prevalent illicit drugs used by 12th graders, according to recent data from the 2011 Monitoring the Future (MTF) survey. Slightly more than one-third (36.4%) of high school seniors reported using marijuana in the past year, including 11.4% who reported using synthetic marijuana, compared with less than 10% for all other illicit drugs.

Legal Status of Synthetic Cannabinoids (DEA) March 1, 2011, the DEA, issued final notice to temporarily place five synthetic cannabinoids into the Controlled Substances Act (CSA) for at least one year Synthetic cannabinoids treated as Schedule 1 drugs A drug that has a high potential for abuse A drug that has no currently accepted medical use in treatment in the United States There is a lack of accepted safety for use of the drug under medical supervision

Legal Status of Synthetic Cannabinoids (DEA) DEA took action - imminent hazard to the public safety Imposes criminal sanctions and regulatory controls of Schedule I substances under the CSA Covers the manufacture, distribution, possession, importation, and exportation US Senate considering a bill permanently banning these drugs

State Laws Some states have passed their own laws banning the substance New York has pending legislation

Synthetic Cannabinoids “Banned” by the (DEA) Synthetic cannabinoids covered under the DEA’s new rule includes the following: JWH-018 * JWH-073 * JWH-200 CP-47,497 CP-47,497 (C-8 homologue)

Can synthetic THC chemicals be detected by drug testing?

Drug Testing: New on-site, rapid, instant tests Numerous laboratories employing LC/MS/MS technology $$$ per sample Many unknowns regarding this testing

While parent drugs are detectable, metabolites of synthetic cannabinoids may be the only detectable compounds found Can use blood and urine as sample

Unresolved Issues of Concern: What synthetic compounds (or metabolites) are being tested by these laboratories? No standardized urine cutoff levels No standardized methods (LC/MS/MS) Tests detect metabolites No independent quality control materials No proficiency testing Detection window unknown May be 48 – 72 hours

What to test for ? ? ?

More dangerous than we first thought?

Management No pharmacolgically specific antidote Supportive care Benzodiazepines for agitation and anxiety Intubation in one case for decreased respiratory rate Duration of effects???

Bath Salts

Bath Salts: Ivory Wave Ivory Pure Ivory Coast Purple Wave Vanilla Sky

Appealing Product?

Not talking about this:

What’s in Bath Salts Cathinone Known for centuries Active metabolite is cathine Found in leaves and twigs of Khat plant (Catha edulis) Original synthetic cathinone is methcathinone Produced in 1928 Public Health hazard as per League of Nations in 1933 Schedule I drug in 1993

Mephedrone Reformulation of cathinone is a chemical found in the khat plant of Eastern Africa Khat existence traced to 15th C. Ethiopia Grown in Somalia, Yemen, Kenya, Ethiopia Khat is banned in the U.S.

Methylmethcathinone (Mephedrone) Designer drug chemically similar to cathinone First synthesized in 1929 Amphetamine-like properties Powerful synthetic stimulant “Rediscovered” by synthetic chemists in 2003 Widespread in Europe, Australia, US

What’s in Bath Salts: Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties which acts as both a norepinephrine-dopamine reuptake inhibitor (NDRI). MDPV has four times the potency of Ritalin MDPV - no history of FDA approved medical use Sold since 2007 as a research chemical September 2011 – DEA Schedule I (mephedrone, methylone and MDPV)

MDPV: Currently popular in Europe, UK & Australia Is usually snorted - similar to cocaine Considered extremely addictive MDPV was “legal” – now Schedule I Adverse medical/psychiatric ramifications No on-site or screening drug tests

4-methylethcathinine (4-MEC) Found commonly used as the active ingredient in "Ecstasy" pills in some countries such as New Zealand Referred to as “Molly”

Usage UK online study of club-goers reported: 41% tried methedrone 10% tried methylone 33% used in the last month 14% used it weekly Blood samples from Finland were taken from 3000 drivers suspected to be under the influence 286 (8.6%) had positive for bath salts

Administration – white/brown powder; capsules and tablets also available Oral (mouth, “bombing”) Intranasal (snorting, “keying”) Intramuscular Intravenous Rectal Gingival Inhalation via smoking

Onset and Duration of Action Mephedrone 30-45 min Methylone 30 – 45 min MDPV 15 – 30 min Duration Mephedrone 2 – 5 hrs Methylone 2 – 5 hrs MDPV 2 – 7 hrs

Inhibitor of reuptake of dopamine, serotonin and NE Increased presynaptic release of same monoamines though less effect than number 1

Pharmacological Effects of “Bath Salts”: Physical: Increase heart rate & blood pressure Pupil dilation Dizziness Nausea Breathing difficulties Headache Chest pain Bruxism Tremors Insomnia Myocardial infarction

Pharmacological Effects of “Bath Salts”: Mental: Hyperactivity, arousal & over stimulation Increased energy & motivation Euphoria - agitation Diminished perception of the requirement for food and sleep Talkativeness Increases sexual arousal Crave to redose frequently

Health Hazard?

Health Hazard? Bizarre behavior Phenomenal physical strength Self mutilation Suicide Persistent paranoid psychosis Persistent symptoms of paresthesias and mood changes for days to weeks after using

?

Dependence Like amphetamines – induce tolerance and dependency in at least 30 percent of users with craving and impaired control

Long Term Effects Little is know as relatively recent use Potential neurotoxicity with decrease dopamine transporter activity in the basal ganglia leading to a parkinson’s like disorder

Detection Not detected in routine urine Elisa testing May cause false positive methamphetamine screen GC-MS test available for mephedrone, MDPV, methylone

Management No specific antidote exists Supportive care Aggressive sedation with benzodiazepines for increased heart rate, seizures, agitation and hypertension Avoid beta blockade due to potential exacerbation of hypertension due to unopposed alpha-adrenergic stimulation Hyperthermia may require cooling If severe (persistent vital sign elevation, neuro and psychiatric abnormalities), all patients should be admitted and have: EKG Serial temperature checks CPK Lytes Renal/liver functions

On September 8, 2011, the Drug Enforcement Administration (DEA) published a Notice of Intent to place three synthetic cathinones into Schedule I of the Controlled Substances Act (CSA) mephedrone, 3,4 methylenedioxypyrovalerone (MDPV) methylone

New York

Bath Salt Data

The Next Wave (or a repeat of an old wave repackaged)?

Kratom Legal plant product – Mitragyna speciosa Korth South Eastern Asia tree Used to treat opioid withdrawal Access via internet without prescription Dual properties of stimulation and analgesia

M. Speciosa Korth Plant with greater than 25 alkaloids Mitragynine responsible for opioid effect Works at the mu and delta supraspinal opioid receptors, serotonin and noradrenergic pathways in spinal cord

Mitragynine 13 times more potent than morphine Powder, leaves, gum Smoked or tea

Reported Benefits Analgesic Anti-inflammatory Anti-pyretic Anti-tussive Antihypertensive Local anesthetic Hypoglycemia Antidiarrheal Anti-malarial

Clinical Effects 5 – 10 minutes after consumption effects start Last about one hour Low dose – stimulant effect High dose – opioid effect Seizures can be seen

Detection Liquid chromatography/MS

Management Supportive Airway management

The New “Designer Drugs” Hallucinogens - This class has many different compounds that can be used for this purpose. These include: Salvinorin A (Salvia divinorum) Lysergic Acid Amide Leunorine (Lion’s Ear) Tropane Alkaloids (atropine, scopolamine) Datura stramonium Atropa Belladonna Psilocybin Muscarine N,N-Dimethyltryptamine

The New “Designer Drugs” Hallucinogens Salvinorin A: Street names include: Magic Mint, Seer’s Sage, Lady SD, and Sally D. used for centuries by the Mazatec shamans in Oaxaca Mexico for spiritual healing used by chewing the fresh leaves, ingesting a tincture or juice from the leaf, or smoking dried leaves The psychoactive component is neoclerodane diterpene Salvinorin A. It is the most potent of all naturally occurring hallucinogens and is equal to LSD. Unlike LSD which acts on the serotonin receptors, this works at the Kappa Opioid receptor as an agonist. There is rapid onset when smoking (one minute) to ten minutes seen with buccal (oral) absorption. It has a short half-life as the effect usually lasts 20 minutes

The New “Designer Drugs” Hallucinogens Salvinorin A: Users state that they “enter another reality”, have improved mood, are calm, have increased insight and have a floating feeling. There are visual and auditory hallucinations that occur with use. Adverse effects have included: Sweats mind racing Yawning anxiety irritability insomnia dizziness fatigue loss of coordination mental slowness

Detection High performance liquid chromatography MS

Management Supportive No antidote ?? if naloxone can reverse effects

The New “Designer Drugs” Hallucinogens Lysergic Acid Amide (LSA): ergot and fungi infected plants and produce ten times less potent than LSD (Lysergic Acid Diethylamide) Seeds are crushed and eaten or soaked in water or alcohol and eaten. The effects last four to eight hours and can include: auditory and visual hallucinations; elevated blood pressure and heart rate; memory loss; anxiety; panic attacks; acute psychosis; and suicidal thoughts.

DESIGNER DRUGS MDMA (ECSTASY) PMA (CARDIO AND NEUROTOXIC) PMMA PCP PCC(DEATH)

Molly Hallucinogenic amphetamine Similar effects to MDMA and methamphetamines $50 - $100 per gram

2C-E Nicknamed "Europa" synthesized in 1970’s -1980’s psychedelic phenethylamine taken orally powerful hallucinogenic effects high can last 6- 12 hours sold through European sources one death reported in MN on March 11, 2011

2C-E Nicknamed "Europa" synthesized by Alexander Shulgin popularized MDMA (Ecstasy) 2C-I another phenethylamine available 2C-E is chemically related to other 2C phenethylamines exact legal status is unclear - 2C-B banned under CSA

Methoxetamine Access via the internet “Legal ketamine” – ketamine analog Discovered in 2010

Piperazine Derivatives Amphetamine like – originally developed as an antihelminthic BZP, TMFPP – “legal ecstasy” Schedule I in 2004

BZP Antidepressant Inhibits serotonin transporter Pills/powder Effect lasts 6 – 8 hours Takes 2 hours to get first effect Management: Benzodiazepines Fluids Cooling EKG

“Krokodil” Desomorphine (Dihydrodesoxymorphine) is an opiate analogue invented in 1932 in the United States that is a derivative of morphine Desomorphine has attracted attention in Russia due to its simple production, utilizing codeine, iodine, gasoline, paint thinner, hydrochloric acid, lighter fluid and red phosphorus. The street name in Russia for home-made Desomorphine made in this way is "krokodil" (crocodile), reportedly due to the scale-like appearance of skin of its users Since the mix is routinely injected immediately with little or no further purification, "Krokodil" has become notorious for producing severe tissue damage including injury to the veins (phlebitis) and gangrene. Other consequences of use have included severe withdrawal, spread of HIV through the use of contaminated needles and death.

Pump-it! Powder: Methylhexanamine Source - found naturally in the geranium plant It is not scheduled by the DEA - legal Banned in athletics Stimulant Not widely studied

Wet Marijuana Embalming Fluid-Soaked Marijuana: The trend of smoking marijuana soaked in embalming fluid is gaining popularity throughout the United States.  The syndrome of intoxication looks nearly identical to that seen following phencyclidine (PCP) use, with agitation, disorganized speech and thoughts, and diminished attention.   The authors believe that this new trend in drug use involving marijuana also presents a resurgence in PCP use. Soaked in water – uneven burn Mixed with THC: wet, fry, crystal joint, supergrass

“Jenkem”: Fermentation of human waste Feces and urine stored in tight container for several days Reaction produces methane gas Methane major component of natural gas “Huffed” by users producing anoxia

Growth of Designer Drugs What’s different today then in the 1970’s when the drug Ecstasy (MDMA) was popularized? What has changed to fuel the rapid development and distribution of designer drugs?

Internet!

over 800 million users over 2 billion over 100 million

What does the Internet offer? Improved accessibility Increased affordability Enhanced anonymity

Unfortunate Truisms: Legal controls that prohibit designer drugs will always lag behind their production Drug detection methods for the identification of designer drugs may also not be available when these compounds become popular

Erowid

Designer Drugs: Designer drugs are here to stay Rapid evolving landscape Testing will nearly always lag behind Legal controls with be challenging and delayed Growing evidence of adverse effects Some become fads, others stay around (MDMA)

A Final Note New legislation

Legislation 2012 The Synthetic Drug Control Act of 2012 (US Senate .3189) amends the Control Substance Act to add two classes of substances to schedule 1 – most addictive and most restrictive use with the highest legal implications if found to be using or selling: Cannabimimetic substances and analogs- all analogs of cannabinoid receptor agonists (CB1). This is the class of THC which stimulates the cannabinoid type 1 receptors in the brain Stimulants (bath salts are in this class) and all the isomers and analogs: Methedrone MDPV Methylone Naphyrone Flephedrone Ethcathinone Butylone Alpha-PPP MOPPP MDPPP Alpha-PVP MDAI MPBP

Legislation 2012 FDA Safety and Innovation Act (Reauthorization Bill)will change emergency scheduling of drugs from one year with a possible 6 month extension to 2 years with a possible 1 year extension. All future analogs of synthetic drugs (structure and/or function) will be schedule 1 if the bill is signed by the President.

ONDCP will be unveiling a Synthetic Drug Prevention Toolkit, which we hope will serve as a resource for communities dealing with this issue. 

Governor Cuomo Announces State Makes it Illegal to Sell or Possess Bath Salts or Synthetic Drugs (August 7, 2012) Governor Andrew M. Cuomo today announced that the New York State Department of Health (DOH) has issued new regulations to crack down on the increasingly widespread use of bath salts and other synthetic drugs. The new regulations, issued today by DOH and approved by the Public Health and Health Planning Council, will expand the existing list of prohibited drugs and chemicals to include dozens more substances that are now used to make synthetic drugs, better ensuring that distributors can no longer skirt the law by simply modifying the drug's ingredients. In addition, the regulations will allow for the first time an owner of an establishment and/or an employee selling synthetic drugs to be charged with possession of an illicit substance. Further, to support enforcement, the regulations will increase the criminal penalties for those who violate the rules. Violators will face fines up to $500 and potentially up to 15 days in jail. The Governor also announced a new toll-free hotline 1-888-99SALTS (1-888-997-2587). Individuals with information about illegal distribution of bath salts or synthetic drugs are encouraged to call this hotline.

Resources Synthetic Cannabinoids 1. http://www.redwoodtoxicology.com/resources/drug_info/synthetic_cannabinoids.html 2. http://www.ncsl.org/issues-research/justice/synthetic-cannabinoids-enactments.aspx 3. http://www.justice.gov/dea/pubs/abuse/drug_data_sheets/K2_Spice.pdf 4. http://www.drugfreeinfo.org/PDFs/Synthetic%20Marijuana%20Fact%20Sheet.pdf 5. http://www.drugfreeinfo.org  

Resources Bath Salts: 1. http://www.webmd.com/mental-health/features/bath-salts-drug-dangers 2. http://www.drugabuse.gov/about-nida/directors-page/messages-director/2011/02/bath-salts-emerging-dangerous-products 3. http://www.iowa.gov/odcp/docs/BathSaltsAlert.pdf 4. http://www.iowa.gov/odcp/docs/IAPoisonhotlineBathSalts.pdf 5. http://www.drugfreeinfo.org  

stevenkipnis@oasas.ny.gov www.oasas.ny.gov/admed/ www.askdoctorsteve.com