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

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

3. 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

4. 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

5. 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.

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

8. The Story of Designer Drugs

9. 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.

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

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

12. 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)

13. 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

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

15. No! We’re not talking about this!

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

17. 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

20. What’s in these “incense” products?

21. “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

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

23. Origins of Synthetic Cannabinoids
CP 47,497 - developed by Pfizer in 1980 as an analgesic
HU-210 & HU synthesized at Hebrew University, Israel in HU-210 is an anti-inflammatory; HU-211 as an anesthetic
JWH-018 & JWH 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

24. 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

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

26. 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

27. 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

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

29. 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

30. 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

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

32. 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

33. Synthetic Cannabinoid Data

34. 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.

35. 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

36. 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

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

38. 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)

40. Can synthetic THC chemicals be detected by drug testing?

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

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

43. 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

44. What to test for ? ? ?

45. More dangerous than we first thought?

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

47. Bath Salts

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

49. Appealing Product?

50. Not talking about this:

54. 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

55. 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.

56. 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

57. 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)

58. 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

59. 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”

60. 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

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

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

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

64. 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

65. 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

66. Health Hazard?

67. 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

68. ?

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

70. 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

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

72. 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

73. 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

74. New York

75. Bath Salt Data

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

77. 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

78. 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

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

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

81. 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

82. Detection
Liquid chromatography/MS

83. Management
Supportive
Airway management

84. 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

85. 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

86. 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

87. Detection
High performance liquid chromatography MS

88. Management
Supportive
No antidote
?? if naloxone can reverse effects

89. 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.

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

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

92. 2C-E Nicknamed "Europa" synthesized in 1970’s -1980’s
psychedelic phenethylamine
taken orally
powerful hallucinogenic effects
high can last hours
sold through European sources
one death reported in MN on March 11, 2011

93. 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

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

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

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

97. “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.

98. 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

99. 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

101. “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

102. 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?

103. Internet!

104. over 800 million users
over 2 billion
over 100 million

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

108. 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

109. Erowid

110. 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)

111. A Final Note
New legislation

112. 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

113. 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.

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

115. 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 SALTS ( ). Individuals with information about illegal distribution of bath salts or synthetic drugs are encouraged to call this hotline.

116. Resources Synthetic Cannabinoids
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117. Resources
Bath Salts:
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