Drug Abuse & Society (RX 462) Presentations-Spring 2014

RX462 Drug Abuse & Society
Presentations: Spring 2014
Brian J. Piper, Ph.D., M.S.
Department of Basic Pharmaceutical
Sciences, psy391@gmail.com or
piperbj@husson.edu

Contents
Drug Author Classification Page
psilocybin J. Graffam Hallucinogen 4-44
JWB-018 Matthew Rodney Hallucinogen 45-63
ayahuasca James Barbour Hallucinogen 64-80
mephedrone Anonymous #1* Stimulant 81-105
MDA Anonymous #2* Stimulant/
Hallucinogen
106-121
crack cocaine Joshua Prue Stimulant 122-143
Catha edulis Anonymous #3* Stimulant 144-164
areca nut Anna Levesque Stimulant 165-184
* name removed per student request

Contents (continued)
Drug Author Classification Pages
Kava kava Anan Hussein depressant 184-214
“krokodil” Alyssa Duron depressant 215-233
valerian Dale Stewart depressant 234-245
fenfluramine Anonymous #4* anorectic 246-264
* name removed per student request
Each presenter was encouraged to include information about:
-History
-Epidemiology
-Pharmacokinetics
-Pharmacodynamics
-Toxicology
Disclaimer: All information is for educational purposes only. These presentations are not
intended to encourage/discourage use.

Psilocybin/Psilocin
J. Graffam

Psilocybin/ Psilocin
“Magic Mushrooms”
Hallucinogens
Psychedelic
Entheogen
Psychotomimetic
http://proudestjunkie.blogspot.com/2011/10/benefits-of-magic-mushrooms.html

Long ago….1,2
Earliest believed use- 7000 years ago
Northern Algeria
Shamanistic Mushroom Men

Not as long ago...1
~400 years ago
Aztecs used Teonanácatl for spiritual rituals
Europeans ruined that
http://www.fs.fed.us/wildflowers/ethnobotany/Mind_and_Spirit/teona
nacatl.shtml

19551,3
R. Gordon Wasson
1st outsider to participate in
a mexican ritual
Life magazine article
brought mushrooms to
America http://www.gnosticmedia.com/SecretHistoryMagicMushroomsProject

19561,2,3
Roger Heim identified the mushroom as the
Psilocybe genus

19571,2,3
Albert Hoffman identified the psychoactive
ingredient
Psilocybin and its metabolite Psilocin

19582,3
Hoffman synthesized Psilocybin
Sandoz Labs sold the drug as
Indocybin

1960s2
Indocybin used for research into the mind
Schizophrenia model
American’s hippy movement was coming to life

Epidemiology3,4
No one is really sure
Psychedelic use- ~20%
PLoS One published 2013-
130,152 responders
14,413 mushroom users

How it supplied
It’s illegal to own mushrooms….
But not the spores…

Typical oral doses2
Psychedelic effects- 15mg
High dose- >25mg
2 grams of dried
shrooms is a good dose

Intravenous2
1-2mg IV
Really for research uses only

Kinetics- Oral2,4
Intestinal phosphatases cleave off phosphate
Effects start 20-40 minutes
Effects peak 80-90 minutes
Aiming for psilocin levels 4-6ng/mL
Effects last 4-6 hours

Kinetics IV2
Tissue phosphatases activate drug
Effects start- 1-2 minutes
Peak in 5 minutes
Only last 20 minutes however

Kinetics2,4
t1/2- 2.5 hours
Most excretion in first 4 hours
Totally excreted in 24 hours

Pharmacodynamics2,4
Very selective
Ki
5-HT2A= 6 nM
5-HT1A= 190 nM
5-HT2C= 410 nM
No dopamine (Well very little)

5-HT2A Signaling1,6
But lets see why this induces a psychedelic trip

“Opening the thalamic filter”1,6
“It becomes easier to notice things that would
normally not reach your awareness, for all
senses.”

5-HT2A isn’t the whole story7
5-HT2A-mGluR2/3 Heterodimers

5-HT2A-mGluR2/38
Other hallucinogens but same receptor

Hallucinogen specific gene expression8
Early growth response elements

Induced by hallucinogens4,8
c-fos, BDNF, egr-1 and -2, arc
Synaptic firing
Gliogenesis
Neurogenesis
Plasticity
Learning/memory

Other neurotransmitters2
5-HT increase in dopamine- decreased
raclopride binding
Haloperidol- Decreased psychotomimetic
effects, but not visual effects
Ketanserin/Risperidone- Block effects
Sooo… Other NTs matter, but 5-HT2A mediates it all

“Set and Setting”9
The most important factors for a good trip!!!

Effects of Psilocybin2,4,9,10
Enhanced perception
Altered self-perception; depersonalization
Derealization- Dream like state
Hallucinations
Anxiety

Toxicities2,4,10,11
No organ toxicities
No changes in lab values (small elevation in prolactin)
LD50 rats- 280mg/kg
1 death- psilocin blood levels of 4µg
Another death from Wolfe-Parkinsons White
Syndrome- MI

Toxicities2,4,5,10
Long term psychological problems- Anxiety,
depression, depersonalization, HPPD- very
very small chance-
Healthy pt risk- 0.08%
Pt with psychiatric disorder- 0.18%
PLoSONE- no increased risk of psychiatric disorder
Anxiety, Panic attacks, hypertension, renal
failure

Hypertension10
Not exactly hypertensive
crisis, but something
to worry about

Lets take a look at the WPWS...11
Yeah the kid died
but…
Renal failure…? never heard of that one before.
Lets investigate.

Therapeutic uses11
OCD- Kinda; worked extremely well during the
trip and for some time after

Therapeutic uses
Smoking for nicotine addiction
In progress- check out John-Hopkins stuff
High long term success rate
Using the psychedelic nature of the drug for
mental empowerment to quit
https://www.youtube.com/watch?v=RHc60goAxv8

Abuse2,13
Not an issue really at all
monkey models show there is no seeking of the
drug
Tolerance is rapid!- 38% decrease in 5-HT2Ain
just a couple doses

Citations
1. Gadiot C. Cognitive mechanisms of psilocybin: Review and theoretical framework for future research. [Honor’s Thesis]. Middelburg, Netherlands:
Roosevelt Academy; 2010.
2. Filip T, Tomáš P, Jiří H. Psilocybin – Summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342-356.
3. Hoffman A. Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico. Bulletin on narcotics. 1971;1:3-14.
4. Jerome L. Psilocybin: Investigator’s Brochure. Multidisciplinary Association of Psychedelic Sciences. 2007. Available at
http://www.maps.org/research/psilo/psilo_ib.pdf.
5. Krebs TS, Johansen P-Ø. Psychedelics and mental health: A population study. PLoS ONE. 2013;8(8):e63972.
6.Vollenweider FX. Brain mechanisms of hallucinogens and entactogens. Dialogues Clin Neurosci. 2001;3(4):265–279.
7. Gonzalez-Maeso J. GPCR oligomers in pharmacology and signaling. Molecular Brain. 2011;4:20.
8. Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and
behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493:76–79.
9. Studerus E, Gamma A, Kometer M, Vollenweider FX. Prediction of psilocybin response in healthy volunteers. PLoS One. 2012; 7(2): e30800.
10. Griffiths RR, Johnson MW, Richards WA, McCann I, Jesse R. Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related
effects. Psychopharmacology (Berl). 2011;218:649–665.
11. Borowiak KS, Ciechanowsld K, Waloszczyk P. Psilocybin mushroom (Psilocybe
seilanceaïa) intoxication with myocardial infarction. Clinical Toxicology. 1998;36:47-49.
12. Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin
Psychiatry. 2006;67:11.
13. Buckholtz NS, Zhou D, Freedman DX, Potter WZ. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat
brain. Neuropsychopharm. 1990;3:137-148.

JWH-018
Presented by
Matthew Rodney
https://recovergateway.files.wordpress.com/2012/09/k2.jpg
http://yourteenmag.com/wp-content/uploads/2012/02/spice.jpg

Introduction1
• JWH-018 is one member of a growing class of powerful
synthetic cannabinoids often marketed in a
combination known as “spice” or “K2”
• Sold as herbs and spices laced with chemicals and
typically smoked
• Until 2011, a “legal high”
• Similar psychotropic effects to Δ-9-
tetrahydrocannabinol (THC), the primary active
component of marijuana, but MUCH more potent
• MUCH more serious adverse effects; life-threatening
http://countyourculture.com/wp-content/uploads/2010/12/jwh-018-napsubs.png

History1
• In the 1960s, Israeli medicinal chemist at
Hebrew University Raphael Mechoulam
isolated THC from marijuana and
elucidated the inner workings of the
endocannabinoid system
• Research on THC continued for the ensuing
decades to further understand the
endocannabionoid system and discover
medical applications of the drug
http://www.arizonamedicalmarijuanablog.com/wp-content/uploads/2012/09/drmechoulam1.jpg

John W. Huffman (hence “JWH”)1
• In the early 1990’s, medicinal chemist John W. Huffman
of Clemson University received a grant from the National
Institute of Drug Abuse (NIDA) to study cannabinoids
• Together with his team, he developed hundreds of
cannabinoid mimetic chemicals, including JWH-018 and
JWH-073
• The distinguishing feature of most of the drugs in this
class is that they are full CB1 agonists, where the
naturally occurring THC is a partial CB1 agonist
• Within a few years, street chemists synthesized these
drugs and mass marketed them as “herbal incense”
under generic trade names “Spice” and “K2”
http://www.ces.clemson.edu/earnest/fall_wint_05/facStaff/images/Huffman.gif

From “legal high” to Schedule I1,2
• Synthetic cannabinoids were initially unregulated and could be
bought online or in smoke shops
• JWH-018 one of the most popular since it’s relatively easy to
synthesize and potent
• Cases of serious toxicity began appearing in the news and
became widely circulated
• Government got involved to crack down on usage
• Five common synthetic cannabinoids including JWH-018
temporarily criminalized in U.S. in 2011by emergency powers
• Formally classified as Schedule I in 2012 by Synthetic Drug
Abuse Prevention Act
• Street chemists avoid prosecution by developing new slightly
modified synthetic cannabinoids that haven’t yet been
criminalized and can’t be detected in drug tests

Spice/K21
• Sold as various inert herbs which physically
resemble marijuana laced with synthetic
chemicals
• Primarily smoked, though sometimes also
ingested orally. No reports of snorting or
injecting
• Rarely sold on the street as a pure chemical
– Many unknown chemicals sold together
– Synergy increases potency and adverse effects
• Pure powder form formerly available online
“Bonsai Fertilizer”
http://www.adsinusa.com/adphotos.htm?id=3826o4302

Can you tell marijuana apart from
spice?
http://seminolepreventioncoalition.org/_images/k2-spice-image1.jpg
http://nocamels.com/wp-content/uploads/2013/09/bigstock-Medical-Marijuana-48404087.jpg

“Spiced Out” by PippUK3
• “I imagined some chemistry boffin tinkering slightly with the
proposed structure of a hypothetical THC analogue, a la
Shulgin or Nichols. Except this guy just happened to have
successfully suppressed all known euphoric properties of the
original, and even intensified the dysphoric.”
• “But, here is this cannabinoid and its given me a dose of
paranoia, and my mouth is as dry as the inside of Ghandi's
flip flop. As I laid there in bed I went on to have a full on panic
attack, the like of which I have never had before.”
• “The paranoid thoughts reached a crescendo of pointless
gnashing of 'what if's and other self loathing nonsense that
seemed to suddenly embody themselves in my minds eye, and
my breathing became shallow and fast.”

PippUK continued3
• “…my heart beat began to ramp up
frighteningly and I could feel the very sudden
strong jerks of that poor muscle in my chest.
And I felt that each breath was scarcely
enough to deliver the oxygen I needed. I was
really quite scared at that point.”
• “… this JWH-018, if it is the active compound
in Spice, did well and truly whupp this
hardened weedsmoker most surprisingly.”

Structure
http://www.emcdda.europa.eu/attachements.cfm/att_90881_EN_JWH-018.gif
JWH-018
http://www.godandscience.org/images/thc.gif
http://lipidlibrary.aocs.org/Lipids/amides/Figure1.png

Pharmacodynamics1,4
• JWH-018 is a full agonist of CB1 receptors in CNS
– CB1 receptors found on GABA-ergic and glutaminergic
neuron axons.
– THC is a partial CB1 agonist
• In vivo mouse studies show that JHW-018 has MUCH
higher affinity for CB1 receptor than THC (10 times
higher) with many active metabolites that retain
affinity equal to or greater than that of THC
– A 3 mg injection of JWH-018 showed as much of a
reduction on mouse exploratory behavior over 10 hours
as 30 mg of THC
• Synthetic cannabinoids often come in unknown
combinations with synergistic effects

Effects1
• CNS
– Deficits in
working memory
– Euphoria
– Sedation
– Anxiety
– Irritability
– Confusion
– Psychosis
– Seizure
Physical
Nausea
Diaphoresis
Mydriasis
Xerostomia
Palpitations
Tachycardia
Convulsions
http://www.anylabtest-san-antonio.com/wp-content/themes/lab/images/k2-drug-test.jpg

Toxicity1,5,6,7
• JWH-018 causes profound toxicity not seen with
marijuana
• Multiple case reports of acute myocardial infarction in
healthy teenagers after use
• Case report of seizure within as little as 30 minutes after
use of pure JWH-018
• Psychotic symptoms with long term use in those
exhibiting no symptoms before
• Exacerbation and reemergence of psychotic symptoms in
those predisposed to it
• Some of the synthetic cannabinoids besides JWH-018
sometimes sold in spice (JWH-015 , JWH-133) can
suppress immune function by agonism of CB2 receptors

Huffman says…8,9
• "Apparently somebody picked it up, I think in
Europe, on the idea of doping this incense
mixture with the compound and smoking it."
• "You can get very high on it. It's about 10 times
more active than THC."
• "It's like playing Russian roulette. You don't know
what it's going to do to you."
• "You're a potential winner of a Darwin award.“
• “People who use it are idiots.”
http://a.abcnews.go.com/images/Blotter/ht_john_huffman_jef_110606_wmain.jpg

Pharmacokinetics1,10
• Pharmacokinetic profile not well
understood
– No in-depth studies done in humans
• Involves CYP450 enzymes
– CYP2C9 and CYP1A2 especially
• Phase 2 enzymes involved in elimination,
namely glucoronidases
• Eliminated primarily in urine
• Highly fat soluble (like THC)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936256/figure/F2/

Epidemiology1,11,12
• According to a recent “Monitoring the Future”
internet survey, 11% of high school seniors admitted
to using spice
• 8% of college students admitted use in another
survey in Miami, Florida
• Males use it more often than females
• 3 types of users identified
– Regular weed smokers
– Occasional drug users trying to avoid prosecution
– Curious experimenters trying out drugs
• Very often used along with marijuana (surprise!) and
other drugs such as alcohol and cigarettes

Conclusion
• Legal efforts to prevent use of synthetic
cannabinoids continue due to progressive
development of new entities
• Highly dangerous designer drug
• Not a substitute for weed!
• Don’t try this at home…or anywhere!
http://img.wikinut.com/img/1.txrs6m86_kfzkj/jpeg/724x5000/Hippie-hair.jpeg
http://www.rsc.org/images/C0AY00200c-300-FOR-TRIDION_tcm18-181877.jpg
http://skullappreciationsociety.com/wp-content/uploads/2012/05/joe_king_skull_2.jpg

Citations
• 1. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the
pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry.
2012;39(2):234-43. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936256/
• 2. Palmer K, Houck L. Citing Imminent Hazard to Public Safety, DEA Temporarily Places Synthetic Cannabinoids
Into Schedule. http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2011/03/citing-imminent-hazard-to-
public-safety-dea-temporarily-places-synthetic-cannabinoids-into-schedule-.html. March 2, 2011
• 3. PippUK. "Spiced Out: An Experience with Spice Products (Various) (ID 76319)". Erowid.org. Jan 25, 2009.
erowid.org/exp/76319
• 4. Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, Prather PL. Phase I hydroxylated
metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity
and activity. PLoS ONE. 2011;6(7):e21917.
• 5. Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2.
Pediatrics. 2011;128(6):e1622-7.
• 6. Lapoint J, James LP, Moran CL, Nelson LS, Hoffman RS, Moran JH. Severe toxicity following synthetic
cannabinoid ingestion. Clin Toxicol (Phila). 2011;49(8):760-4.
• 7. Hurst D, Loeffler G, McLay R. Psychosis Associated With Synthetic Cannabinoid Agonists: A Case Series. Am J
Psychiatry 2011;168:1119-1119.
• 8. Fake Pot that Acts Real Stymies Law Enforcement. http://www.nbcnews.com/id/35444158#.U2G1xPldW0M.
February 2, 2011.
• 9. Bryner J. Fake Weed, Real Drug: K2 Causing Hallucinations in Teens. http://www.livescience.com/6149-fake-
weed-real-drug-k2-causing-hallucinations-teens.html. March 03, 2010
• 10. 4. Chimalakonda KC, Seely KA, Bratton SM, et al. Cytochrome P450-mediated oxidative metabolism of abused
synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab
Dispos. 2012;40(11):2174-84.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477201/
• 11. Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of Spice products (synthetic
cannabinoids). Drug Alcohol Depend. 2012;120(1-3):238-41.
• 12. Castellanos D, Singh S, Thornton G, Avila M, Moreno A. Synthetic cannabinoid use: a case series of
adolescents. J Adolesc Health. 2011;49(4):347-9.

DMT
• N,N-Dimethyltryptamine
• Psychedelic Hallucinogen
• Tryptamine
– Monoamine Alkaloid
DMT
5-HT
4-PO-DMT

Psychedelic Effects
• Experience is recognized as a ‘trip’
– Dissimilar from LSD, Psilocybin, and other psychedelics
• Has been described as a link between ‘our reality’
and a ‘spiritual reality’
• Time perception severely altered
• 5-HT2A Agonism: MOA for hallucinations
• Oddly similar consistencies in ‘trip’
– Sounds
– Entities
– Environment

Subjective Interpretations of ‘Trip’
“The first thing I noticed was a burning in the
back of my neck. Then there was this loud
intense hum. It was like the fan at first, but
separate. It began engulfing me. I let go into it
and then . . . WHAM!”
“DMT has shown me the reality that there is
infinite variation on reality. There is the real
possibility of adjacent dimensions… It's not a
hallucination, but an observation. When I'm
there, I'm not intoxicated. I'm lucid and sober."

Common ‘Trip’ Features
“There was the usual sound: pleasant, a roar, a sort of an
internal hum.”
“There is a sound, a bzzzz. It started off (subtly) and got
louder and louder and faster and faster."
“It started with a sound. It was high-pitched like a tightly taut
wire."
“There was the sound of the entire universe, more like a hum.
It was pervasive, overwhelming."
SOUNDS

“That was real strange. There were a lot of elves. They
were prankish...”
"There were lots of beings. They were talking to me but
they weren't making a sound."
“They were reptilian and humanoid, trying to make me
understand, not with words, but with gestures.”
“Then I felt like I was suddenly in the presence of an alien or
of aliens, vaguely humanoid."
"They were like clowns or jokers or jesters or imps. There
were just so many of them doing their funny little thing.”
ENTITIES OBSERVED

“It's a different world. Amazing instruments.
Machine-type things. There was one person
operating some of this stuff. I was in a big room;
he was in another part of it.”
“There was a movement of color. The colors were
words. I heard what the colors were saying to
me."
ENVIRONMENT

DMT Biological Distribution
• Proposed existence in a variety
of plants and animals
– Mammals (Humans, Rats, Rabbits)
– Many plants (Psychotria viridis)
• L-Tryptophan metabolite
• Biological importance unclear
but often theorized
– Dreams
– Birth/Death

DMT in Mammals
• Pineal Gland
– Theorized ‘storage compartment’
– Hypothesized release upon entrance/exit of life
• Monoamine Oxidase
– Blocks DMT from being orally active via First-Pass
Metabolism
– Removes active DMT from synaptic cleft by
enzymatic degradation
• Limits duration of ‘trip’ to roughly 10-15 minutes

AYAHUASCA
+
=
Psychotria viridis
(DMT containing plant)
Ayahuasca (B. Caapi)
Contains Harmaline
MAO-I (RIMA)
AYAHUASCA
DECOCTION

General Properties
• Extended DMT ‘trip’
– Roughly 3-5 hours depending on dose
• Delayed Onset
– Tmax peak: 110 minutes +/- 30 minutes
• Enhanced control/grasp of ‘trip’
“I think that the shamans in South America use
other plants to fill out and make the DMT more
reasonable. Pure DMT seems empty or hollow."

History
• Napo Province of Ecuador
– Estimated use began around
1500-2000 B.C.
– Shamanistic rituals
• Expansion to urban Brazil
(1500s)
– Santo Daime (1930s)
– Uniao do Vegetal (UDV, 1961)
• Research scientists introduced
ayahuasca to western
civilizations

Use and Potential Abuse
• Use of DMT has grown in recent history
• Global Drug Survey 2010 (22,289
respondents)
– Lifetime prevalence = 8.9%
– Past year prevalence = 5.0%
– 472 ‘last new drug used for first time’
– New users = 24%
• Low abuse potential due to low urge to use
more (although effects seen as desirable)

Legislative Regulations
• DMT is a Schedule I Controlled Substance in
it’s pure form (i.e. solution, crystallized, etc.)
• Plants used in the brewing of Ayahuasca are
not regulated. However, there are legal issues
surrounding their use in brewing of decoction
• Religious groups have protested for use
ceremonially
– UDV
– Santo Daime

Toxicology
• Not thoroughly investigated
• Self-limiting (by person)
• Possible Serotonin Syndrome (20x avg. dose)
• Naïve exposure to DMT
– Effects on physiology markedly increased
• Serum ACTH, BP, HR, etc.
• Chronic exposure to DMT
– Effects on physiology become less dramatic
– No impact on dose dependent hallucinations

“Spiritual Enlightenment”
“I was trying to look out, but they were saying,
'Go in.' I was looking for God outside. They said,
'God is in every cell of your body.’ And I was
feeling it, totally open to it, and I kept opening to
it more, and I just took it in…That God is in
everything and that we are all connected, and
that God dances in every cell of life, and that
every cell of life dances in God."

Death and Dying
“Everyone should try a high dose of DMT once.
I don't know if the beings today were saying
"Try death once" or "Try life once." That place
is so full and so complete that the idea of this
place is to try and be as complete as possible.
Yet when I came back into my body it was so
heavy and so confining. Also, time here seems
so strange. Eternity is an attribute of the
place. It would have to be."

History 2,8
http://www.thenakedscientists.com/HTML/uploads/RTEm
agicC_Gatecrasher.jpg.jpg
• First Synthesized by Saem de Burnaga Sanchez
in 1929
• Rediscovered in Early 2000
• Became Popular among UK clubbers 2007
• Spread Through Europe then the US
• Had many Street Names
• Meow
• Miaow Miaw
• Bubbles (mixed w/methylone)
• Meph
• …
Saem de Burnaga Sanchez,
http://cannabisymas.com/

• Popularity boomed exponentially
– ‘Legal High’
• Less legal complications
– Easy access
• Local Stores / Mom and Pop shops
• Internet
– Cheaper then its alternatives
History 2,8

Mephedrone suspected deaths
in the UK – May 2010 2

MDMA, Piperzine, Cathinone Derivatives Seizure
records Jul 2005 – Mar 2010
Europe2

Legal Status2,8,9
• Uncontrolled until 2008
– Sweden first country to outlaw Mephedrone
– Denmark Followed
– 2009 Estonia
– 2010: Germany, Netherlands, UK …

USA9
• Component of Bath Salts
– Marketed as not for human consumption
– Legal for a period of time
• 2011 made Schedule 1 drug under Title
21 FDA, designation number 1248
(temporary scheduling).
usamania.wikispaces.com

Dosage Form & Administration2,8
• Mephedrone comes in many different forms:
– Capsules
– Tablets
– White Powder
• Administration
– Intranasally
– Orally
– Smoke
– Inject
– Rectally

Pharmacological Effects10
• Euphoria
• Energy
• Empathy (feeling of closeness)
• Visual and auditory hallucinations
• Paranoia
• Anxiety
Mark Dominique, PharmD, LCSW
Husson UniversityApril 10, 2014
news.vanderbilt.edu

Side Effects2,4,6,8
 Delirium
 Aggression
 Agitation
 Tachycardia
 Anxiety
 Panic attacks
 Paranoia
 Hyperthermia
 Excessive Sweating
 Stroke
 Hyperthermia
 Hallucination
 Seizures
 Elevated CK, LFT
 Suicidality
 Cerebral edema
 Insomnia
 Myocardial infarction
 SVT
 Vasoconstriction
 Hypertension
 Rhabdomyolysis
 Cyanosis
 Arrhythmias
 Metabolic acidosis
Mark Dominique, PharmD, LCSW
Husson UniversityApril 10, 2014

Self-Reported Side Effects of
Mephedrone users in the UK Club
Scene (Online Survey, N = 947)8

Bath Salts Toxicity Tx10
• Supportive
– Fluid
– Cooling
– Vitals
– Electrolytes
• Agitation
– Lorazepam 2 mg PO or IM
– Antipsychotics 2nd line
starcasm.net

Mephedrone vs Cocaine
A Better High?8

4-methylmethcathinone
Cathinone

Structural Comparison with other
Psychoactive Agents
MDMA Methamphetamine
Cocaine
Tertiary Amine
Secondary Amine

Synthesis7
Stereoselective Synthesis
*** Don’t try at Home

Metabolism6
N-Demethylation
1. Mephedrone
2. Nor-mephedrone
3. Nor-dihydro-mephedrone
4. Nor-dihydromephedrone
5. Carboxytolyl-mephedrone
6. Nor-OH-tolyl-mephedrone
7. HO-tolyl Mephedrone
Oxydation
Reduction
Can be detected in Urine!!!

Effects of Mephedrone on DA & 5HT3
• Sprague-Dawley rats (290-400g)
• Binge injected with mephedrone,
– 4X 10 or 25 mg/kg s.c. every 2h.
• MDMA, Cocaine and Methamphetamine
groups also injected
• Control group injected with Saline
• Rats sacrificed 1 h after last dose
• Self administration models for mephedrone
and methamphetamine also conducted for
8 days

Dopamine Nerve Ending
Neurotoxicity1
• Female C57BL/6 mice (20-25g).
• Injected with 20 or 40 mg/kg of mephedrone q2h X 4
• Regimen is known to cause neurotoxicity with
methamphetamine
• Control group treated with saline.
• The mice were sacrificed at 2 or 7 days and analyzed
for nerve damage.
• Day 2 & 7 mephedrone did not change the striatal DA
content
• tyrosine hydroxylase and dopamine transporter
(indicators of drug induced nerve damage) were also
not affected.
• Activation of microglia and astrocytes (regional
indicators of striatal damage) was also not present

Conclusion
• Mephedrone has a short history as a recreational
drug.
• It is currently Controlled in most of the western
hemisphere
• It increases dopamine and 5HT levels
• Does not appear to cause dopamine nerve
damage
• Has high potential for abuse
• Has a variety of serious side effects
– May cause Death
• Further studies needed

Reference
1. Angoa-Pérez M, Kane MJ, Francescutti DM, et al. Mephedrone, an abused psychoactive
component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to
dopamine nerve endings of the striatum. J Neurochem. 2012 Mar; ;120(6):1097-107.
2. Europol–EMCDDA Joint Report on a new psychoactive substance: 4-methylmethcathinone
(mephedrone)". European Monitoring Centre for Drugs and Drug Addiction. 2010
3. Hadlock GC, Webb KM, McFadden LM, et al. 4-Methylmethcathinone (mephedrone):
neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther. 2011;
Nov;339(2):530-6
4. Martínez-Clemente J, López-Arnau R, Carbó M, Pubill D, et al. Mephedrone pharmacokinetics
after intravenous and oral administration in rats: relation to pharmacodynamics.
Psychopharmacology. 2013; 229(2):295-306.
5. Meyer MR. Metabolism and pharmacokinetics of designer cathinones. Biological Psychiatry.
Conference: 67th Annual Scientific Convention and Meeting of the Society of Biological
Psychiatry Philadelphia, PA United States. Conference Start: 20120503 Conference End:
20120505. Conference Publication: (var.pagings). 2012.

Reference cont.
6. Ribeiro E, Magalhaes T, Dinis-Oliveira RJ. Mephedrone, the new designer drug of
abuse: Pharmacokinetics, pharmacodynamics and clinical and forensic issues. Acta
Medica Portuguesa. 25 (2) (pp 111-117), 2012.
7. Schifano F, Albanese A, Fergus S, et al. Mephedrone (4-methylmethcathinone; 'meow
meow'): chemical, pharmacological and clinical issues. Psychopharmacology (Berl).
2011 Apr;214(3):593-602.
8. Winstock AR, Mitcheson LR, Deluca P, et al. Mephedrone, new kid for the chop?
Addiction. 2011;106(1):154-61
9. 2009 National Report (2008 data) To the EMCDDA by the Reitox National Focal Point –
Denmark . 2009
10. Mark Dominique, PharmD, LCSW Husson University, April 10, 2014

3,4-Methylenedioxyamphetamine
(MDA)
Anonymous #2
Drug Abuse
April 8, 2014

Also Known As
• Love Drug
• Love Pill
• Sass
• Sass-a-frass
• Not to be confused
with:
– MDMA
– Ecstasy
wikipedia.org

Other Information
• Systematic (IUPAC) name
– (R) 1-(benzo[1,3]dioxol-5-yl)propan-2-amine
• Clinical data
– Legal status
• Schedule I (US)
• Schedule III (CA), Class A (UK), Prohibited (S9) (AU),
– Routes of Administration
• Oral
• Sublingual
• Intranasal
• Intravenously
• Rectally

MDA History
• Synthetic Amphetamine Derivative
• Metabolite of MDMA
– Pheylethylamine Hallucinogen
• First synthesized in 1910
– G. Mannish & W. Jacobson
– Smith Kline & French licensed in 1930
• Parkinson’s disease
• Antidepressant and/or anorectic
– Truth Drug
– Cough Suppressant in 1958 by H.D. Brown
• Designer club drug in the 60’s
– Used by young adults
– Use associated with raves and dance clubs

PD
• Causes an increase in the release
– Serotonin
– Dopamine
– Norepinephrine

PK
• Largely unknown
• Duration of effects
– ~ 8 - 12 hours
– Some effects can last ~48 hours
• Absorption
– Readily absorbed in the GI tract

Online User Account
• “With 100 mg, the coming on was gradual and pleasant,
taking from about 1-1 ½ hours to do so. The trip was
intense….One thing that impressed itself upon me was the
feeling I got of seeing the play of events, of what I thought
to be significance of certain people coming into my life, and
why my ‘dance’ is unique.”
• “After taking 140 mg, I vomited quite abruptly, and then
everything was OK….The tactile sense is beautiful, but there
seems to be some numbness as well, and I feel that nothing
erotic would be doable. Intimacy, yes, but no performance
I’m pretty sure. I saw the experience start drifting away
only four hours into it and I was sad to see it go. I was an
all-around delightful day.”

MDA Effects
• Positive Effects
– Elevated mood
– Stimulation
– Feelings of comfort and
acceptance
– Feelings of love and empathy
– Increased musical
appreciation
– Increased sensory awareness
• Neutral Effects
– Visual distortions
– Mild visual hallucinations
– nystagmus
• Negative Effects
– Elevated heart rate
– Elevated blood pressure
– Restlessness
– Anxiety
– Changes in body temperature
regulation
– Excessive teeth grinding
– Difficulty concentrating
– Muscle tension
– Erectile dysfunction
– N & V

Long Term Negative Effects
• Psychological
– Depression, severe anxiety, paranoia sleep disturbances
• Physical
– Muscle tension, teeth clenching, nausea, blurred vision,
rapid eye movements, chills, faintness
• High doses
– Sharp increase in body temp, muscle breakdown, kidney &
cardiovascular system failure***
• Long-Term use
– Liver damage, brain damage
• Brain damage is due to the destruction of serotonin producing
neurons which leads to problems regulating mood, pain, sleep,
and aggression

MDMA vs. MDA
• Frontal Cortex
– 2 weeks after receiving 8 doses (20 mg/kg) of MDMA or MDA
– Control group saline only

References
• Buchanan JF, Brown CR. 'Designer drugs'. A problem in clinical toxicology. MedTox Adverse Drug Exp 1988; 3:1.
• Colado MI, Williams JL, Green AR,. The hyperthermic and neurotoxic effects of Ectasy (MDMA) and 3,4 Methylenedioxyamphetamine
(MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype. BJ Pharm. 1995; 118:1281-9.
• Hensley D, Cody JT,. Simultaneous Determination of Amphetamine, Methamphetamine, Methylenedioxyamphetamine (MDA),
Methylenedioxymethamphetamine (MDMA), and Methylenedioxyethylamphetamine (MDEA) Enantiomers by GC-MS. J An Tox. 1999;
23: 1-6.
• Liu RH, Liu HC, Lin DL. Distribution of Methylenedioxymethamphetamine (MDMA) and Methylenedioxyamphetamine (MDA) in
Postmortem and Antemortem Specimens. J An Tox 2006; 30: 545-550.
• Maurer HH, Kraemer T, Springer D, Staack RF. Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the
amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis.Ther Drug Monit 2004; 26:127.
• Noogle FT, DeRuiter J, Coker ST, Clark CR,. Synthesis, Identification, and Acute Toxicity of some N-Alkyl Derivatives of 3,4-
Methylenedioxyamphetamine. 1987. 70(6):981-6.
• O’Heam E, Battaglia G, De Souza EB, Kuhar MJ, Molliver. Methylenedioxyamphetamine (MDA) and Methylenedioxymethamphetamine
(MDMA) Cause Selective Ablation of Serotonergic Axon Terminals in Forebrain; Immunocytochemical Evidence for Neurotoxicity. J
NeuroSci 1988; 8:2788-2803.
• Poklis A, Mackell MA, Drake WK. Fatal intoxication from 3,4-methylenedioxyamphetamine. J Forensic Sci 1979; 24:70.
• DeLetter EA, Espeel MF, Marijke EC, et. al., Immunohistochemical demonstration of the amphetamine derivatives 3,4-
methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in human post-mortem brain tissues and the
pituitary gland. Int J Legal Med. 2003; 117:2-9.
• Stout PR, Horn CK, Klette KL,. Rapid Simultaneous Determination of Amphetamine, Methamphetamine, 3,4-
Methylenedioxyamphetamine, 3,4.Methylenedioxymethamphetamine, and 3,4-Methylenedioxyethylamphetamine in Urine by Solid-
Phase Extraction and GC-MS: A Method Optimized for High-Volume Laboratories. J Analy Tox 2002; 26:1-9.
• Todd G, Noyes C, Flavel SC, et. al., Illicit Stimulant use Is Associated with Abnormal Substantia Nigra Morphology in Humans. PLoS ONE.
2013; 8:1-8

Objectives
- Differentiate between cocaine and crack cocaine
- Know the different routes of administration and
pharmacokinetics of cocaine
- Know which receptors crack works on
- Explore patterns of use throughout the United States

Cocaine1,2
- Cocaine refers to the powdered form of
the drug, cocaine hydrochloride.
- Common street names include: blow,
coke, dust.
- Most commonly snorted, but can also
be dissolved in water and injected
intravenously.
- Obtained from the leaves of the coca
plant.
http://moroccantimes.com/wp-content/uploads/2014/03/cocaine.jpg

Crack Cocaine1,2
- Most commonly called crack.
- Cocaine HCl must be
converted into its base
form, crack, in order to be
smoked.
- Widely considered the most
addictive form of cocaine.

History of Crack1,2,3
- Crack use was first observed in
the mid 1980s.
- Primarily seen in the projects of
Miami, New York, and Los
Angeles.
- Created as a means to get a
stronger high off less drug.
- Associated with low
socioeconomic status.

Epidemiology2
-Most common in:
-Males
- 20s
- Unemployed
- Urban areas
http://1.bp.blogspot.com/-D4-VcT-tdyU/T6nfkqfzPNI/AAAAAAAABp8/1rhDqieTh94/s1600/Tyrone2.jpg

Smoking Crack1,2
- Cocaine base has a melting
point of 98oC.
- Vaporized at a lower
temperature, which destroys
little of the product.
- Cocaine HCl melts at 195oC. At
this temperature, much of the
drug is destroyed before
vaporization occurs.
http://i.huffpost.com/gen/1143888/thumbs/s-BUY-ROB-FORD-CRACK-VIDEO-large.jpg?6

Pharmacokinetics2,4
Cocaine
- After nasal insufflation, cocaine is absorbed through the
vasculature in the nasal mucosa.
- Absorption is self-limiting due to its vasoconstrictive properties.
- Peak ‘high’ occurs 30-60 minutes after insufflation
-Effects last nearly 30 minutes

Pharmacokinetics1,2,4,5
Crack
- When smoked, drug is absorbed through the alveoli directly
into circulation.
- Effects are seen within seconds.
- ‘High’ is more intense and comes on much more quickly.
- Lasts roughly 5-10 minutes.

Neurotransmitter Effects1,2,4,5,6
- Cocaine is a CNS stimulant that causes a large release of
dopamine within the brain.
- Cocaine also binds the dopamine transporter, inhibiting the
reuptake of dopamine from the synapse.
- Higher concentrations of dopamine in the synapse leads to
increased binding of the postsynaptic dopamine receptors.
- Cocaine also interferes with the reuptake of norepinephrine,
causing sympathomimetic effects.

Psychological Effects1,5
-Delirium
-Psychosis
-Paranoia
-Dependence
-Addiction
-Depression

Addiction to Crack1,2,4,5,6
- Snorting cocaine takes longer
to get into the system and to
the brain than crack does based
on sites of administration and
ease of absorption.
- Faster effects after
administration coupled with a
stronger high lead to addiction
more quickly.

Addiction5
- The subject develops rapid tolerance, requiring
more and more each time to get the desired
effect.
- Withdrawal symptoms can commence soon
after first dose wears off.

Withdrawal2
Symptoms generally onset quickly:
-Extreme fatigue
-Intense cravings
-Irritability
-Sweating
-Psychosis
-Depression
-Anhedonia
http://www.brighteyecounselling.co.uk/images/alcohol-withdrawal.gif

Physiological
effects
http://drugabuse.com/wp-content/uploads/crack_cocaine_main_physiological_effects_image-279x300.png
Physiological effects of crack

Effects of Prolonged Use5
-Tolerance
-Mood disturbances
-Aggression
-Delirium
-Psychosis
-Heart attack
-Heart disease
-Stroke
-Respiratory failure
-Brain seizures
-Sexual dysfunction
-Death
http://www.drugabuse.gov/publications/research-reports/cocaine/what-are-long-term-effects-cocaine-use

Stroke in “Crackheads”7
-Study included ONLY african americans.
-Observational study to compare variables of crack smoking and
non-crack smoking individuals suffering strokes.
-Found that the stroke victims with a past history of crack use
were younger, had fewer risk factors, and were predominantly
male.

Monitoring the Future8
- Use (last 12 months) among
adolescents is at record lows.
- Less than 2%
-More than half of adolescents believe
crack poses a risk for significant harm
to the user, even if only once.
- Nearly 90% of adolescents disapprove
of the use of crack.
http://www.home.isr.umich.edu/wp-content/uploads/2012/12/MTF-logo-high-res-300x194.jpg

Cocaine Usage in the U.S.9
- In 2008, approximately 1.9
million Americans were
cocaine users.
- 359,000 (18.9%) of these
were crack users.
- Out of the 2 million drug-
related emergency room
visits, 482,188 were related
to cocaine.
http://www.crainsnewyork.com/apps/pbcsi.dll/storyimage/CN/20100727/FREE/100729851/AR/0/Emergency-Room-sign.jpg?q=100

References
1. Morton WA. Cocaine and Psychiatric Symptoms. Prim Care Companion J Clin Psychiatry. 1999;1(4):109-113. (Accessed on April 14, 2014)
2. Gorelic, DA. Cocaine use disorder in adults: Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis. In:
UpToDate, Saxon AJ (Ed), UpToDate, Waltham, MA. (Accessed on April 14. 2014.)
3. Reinarman C, Levine HG. Crack in America, Demon Drugs and Social Justice. Univ of California Press; 1997. (Accessed on April 14, 2014)
4. Gold Standard, Inc. Cocaine. Clinical Pharmacology. Updated October 13, 2009. Available at:http://www.clinicalpharmacology-
ip.com.husson.idm.oclc.org/Forms/Monograph/monograph.aspx?cpnum=145&sec=mondesc&t=0. Accessed: April 13, 2014.
5. Crack cocaine. University of Maryland Center for Substance Abuse Research. Updated October 29, 2013. Available
athttp://www.cesar.umd.edu/cesar/drugs/crack.asp#brain. Accessed April 13, 2014.
6. National Institute on Drug Abuse. The neurobiology of drug addiction: section IV, the action of cocaine. Revised January 2007. Available at:
http://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iv-action-cocaine. Accessed April 13, 2014.

References
7. Leece P, Rajaram N, Woolhouse S, Millson M. Acute and chronic respiratory symptoms among primary care patients who smoke crack cocaine. J Urban
Health. 2013;90(3):542-51. (Accessed April 13, 2014)
8. Johnston, LD. O’Malley, PM. Miech, RA. Bachman, JG. Schulenberg, JE. Monitoring the future: 2013 Overview. Available at:
http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2013.pdf. (Accessed April 13, 2014)
9. National Institute of Drug Abuse. Cocaine. May 1999. Available at: http://www.drugabuse.gov/sites/default/files/cocainerrs.pdf. (Accessed April 13,
2014)

Catha edulis
By: Anonymous #3
http://www.forestryimages.org/browse/detail.cfm?i
mgnum=5359745

• A seedless flowering plant from an evergreen tree
or large shrub
• Grown and harvested in a variety of climates year
round
• Other names
– Qat: Yemen and Saudi Arabia
– Khat: Ethiopia
– Mirra: Kenya
– Qaad: Somalia
– Jaad: Somalia
General1
http://www.bluelight.org/vb/content/84-UK-Herbal-Stimulant-Khat-to-be-Banned

How and Why2,3,4
• Leaves, shoots and stalks are chewed into a ball
and parked in the cheek.
• Juices are swallowed with saliva and absorbed
into the blood stream.
• Provides a natural stimulation.
• Leaves have a aromatic odor and a slightly sweet
and astringent taste.
• Other user routes of administration:
– Smoking
– Making a drink from the dried leaves

Chemical2
• Ingredients in the juices of the plant:
– More than 40 alkaloids
• Phenylalkylamines and Cathedulins (major alkaloids)
• Cathinone and Cathine (stimulating alkaloids)
– Flavonoids
– Sterols
– Amino acids
– Terpenoids
– Glycosides
– Tannins
– Vitamins
– Minerals
https://www.caymanchem.com/app/template/Articl
e.vm/article/2164

History5,6
• Origin: Eastern Africa and the Arabian Peninsula.
– From Ethiopia to Yemen before 6th Century A.D.
• Became popular in the Islamic community
– Conflicting evidence about acceptance
• Quran: no consumption of intoxicating substances
• Some believe Mohammad “specifically encouraged” its use
• Arabian Community
– Sexual depressant given to men who guarded the virginity
of young women before their contract marriages.
– Social lubricant and used to help employees stay awake at
work.
• Cash crop in Yemen

http://maps-africa.blogspot.com/2012/05/east-africa-map-pictures.html

Epidemiology7
• An observational cross-sectional survey in Jazan (Gizan)
in Saudi Arabia
• Distributed to a intermediate and upper secondary
schools
– 72 schools participated, 3,923 students
• 56.3% male
• 43.7% female
– Academic year 2011-2012
– Full time students, ages 13-21
• Conclusion:
– 20.5% chewed khat with the number of males significantly
higher than females

Popularity4,8
• Yemen
– In the capital, it is estimated that 80% of the males, 50% of the
women, and 15-20% of children under 12 use Khat daily
• East Africa and the Arabian Peninsula countries
– In the 1990s, ~10 million people use Khat daily
• Ethiopia
– About 50% of the men use Khat daily
– 5:1 male to female use ratio
• Immigrants to Europe and North America
– Use Khat more in their new countries compared to their home
countries.
• Worldwide
– Use has increased and become almost equal in both genders

http://www.dailymail.co.uk/news/article-
2357420/Journey-khat-fields-Kenya-produced-streets
UK.html
http://arij.net/en/khat-sends-secondary-students-
psychiatric-clinics-and-liver-treatment-centres
http://darmuseum.org.kw/dai/home/special-
event-activities/event-trips/yemen/

Causes2
• Different geographical locations, climate, and
environment determines what compounds are
found in the leaves and what effects they may
have on the GI and nervous system.
• Cathinone and cathine are held responsible for
the effects on the central nervous system.
– Increased alertness, arousal, euphoria and elation,
tolerance, and dependence (CNS)
– Constipation, acute cardiovascular effects, and urine
retention (PNS)
• Urine retention is thought to be caused by the cathinone
compound stimulating the alpha1- adrenergic receptors

Effects2,8
• Cathinone’s effects occur in about 15 minutes
• A period of a talkative and excited mood with an inability to
concentrate occurs first
• Within 15-45 minutes of Khat chewing, the cathinone
released can cause a minor and temporary rise in blood
pressure and heart rate.
• Oral administration half life: 3 hours
• Max plasma concentration in 1-2 hours
• Near the end of the effects, the user may feel depressed,
irritable, difficulty sleeping, and a loss in appetite.
• The sluggish and drowsy effects can be felt the following
morning.

Khat vs. amphetamine8
• Cathinone is structurally similar to
amphetamine
• Cathinone’s effects occur in 15 min compared
to amphetamine’s 30 min.
• Amphetamine is twice as potent as cathinone
and 7-10 times more potent than cathine.
http://www.bluelight.org/vb/archive/index.php/t-559984.html

Toxicology2,3,4
• Negative side effects: increased blood pressure, tachycardia,
anorexia, gastric disorders, constipation, depression, irritability,
migraines, insomnia, and liver damage.
• Contrary to historical use as a sexual depressant, many regular
users state that they feel an increased libido and use it to augment
their sexual experiences
• Oral lesions such as hyperkerotosis and oral cancer can be caused
by chewing Khat.
• A study has suggested within 1 hour of exposure, Khat increased
the cytosolic reactive oxygen species (ROS) and decreased the
levels of intracellular glutathione (GSH).
• Insufficient amount of research completed to definitively describe
the mechanism that Khat uses to produce it’s toxic effects in the
human body.

Social4,5,6,8
• Acceptance of Khat chewing is varied among cultures
• Saudi Arabia
– Khat chewing is illegal but many chew anyway because it is deeply
rooted in their culture.
• Yemen
– An important cash crop and a large part of their economy
• Con: a large amount of time is spent buying and chewing Khat. A khat chewing
gathering can last from 3-7 hours
– ~40% of all drinkable water is used to help grow Khat
– Khat use has been associated with use of other drugs, alcohol, tobacco
smoking, and risky sexual behaviors
• Internationally
– Cathinone (C1) and Cathine (C3) are scheduled substances
– Catha edulis is not controlled so it is hard to control its growth and
development

Khat and other substances8
• Khat and Tobacco
– Not enough studies to say with definitive conclusion but it is
believed that Khat and tobacco use has a larger effect on
cognitive functions and the regulation of emotions than using
Khat alone.
• Khat and Alcohol
– Unsure of effects in the body but users claim that the alcohol
helps calm them down from the stimulating effects of Khat.
• Khat and Withdrawal
– Not enough studies to prove withdrawal symptoms occur but
there is some evidence of a low tolerance level and withdrawal
syndrome occurring
• Symptoms: inertia, trembling, sedation, depression, nightmares, and
hypotension

http://download.thelancet.com/pdfs/journ
als/lancet/PIIS0140673607604644.pdf?id=
qaaJDqNwuzIZOcWSeNRwu

http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673607604644.pdf?id=qaaJDqNwuzIZOcWSeNRwu

References
1. Alsanosy RM, Mahfouz MS, Gaffar AM. Khat chewing habit among school students of Jazan region, Saudi Arabia.
PLOS One. 2013; 8(6): e65504. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679146/pdf/pone.0065504.pdf.
Accessed April 8, 2014.
2. Wabe NT. Chemistry, pharmacology, and toxicology of Khat (Catha edulis Forsk): A review. Addict Health. 2011; 3(3-
4): 137-149. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905534/. Accessed April 8, 2014.
3. Lukandu OM, Costea DE, Neppelberg E, et.al. Khat (Catha edulis) induces reactive oxygen species and apoptosis in
normal human oral keratinocytes and fibroblasts. Toxicol Sci. 2008; 103(2): 311-324.
http://www.ncbi.nlm.nih.gov/pubmed/?term=Khat+(Catha+edulis)+induces+reactive+oxygen+species+and+apoptosi
s+in+normal+human+oral+keratinocytes+and+fibroblasts. Accessed April 8, 2014.
4. Wedegaertner F, al-Warith H, Hillemacher T, et.al. Motives for khat use and abstinence in Yemen- a gender
perspective. BMC Public Health. 2010; 10: 735. http://www.biomedcentral.com/1471-2458/10/735. Accessed April 8,
2014.
5. Reda AA, Moges A, Biadgilign S, Wondmagegn BY. Prevalence and determinants of Khat (Catha edulis) chewing
among high school students in Eastern Ethiopia: A cross-sectional study. PLOS One. 2012; 7(3): e33946.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316517/pdf/pone.0033946.pdf. Accessed April 8, 2014.
6. Saeed A. Catha Edulis (Khat), A sex depressant, euphoriant in history. Anc Sci Life. 1986; 45-48.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331378/pdf/ASL-7-45.pdf. Accessed April 8, 2014.
7. Mahfouz MS, Alsanosy RM, Gaffar AM. The role of family background on adolescent khat chewing behavior in Jazan
region.Ann Gen Psychiatry. 2013; 12:16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679779/. Accessed April 8,
2014.
8. Hoffman R and al'Absi M. Khat use and neurobehavioral functions: Suggestions for future studies. J Ethnopharmacol.
2010; 132(3): 554-563. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976806/. Accessed April 8, 2014.

Areca Nut
Anna Levesque
Drug Abuse and Society
April 08, 2014
http://onlinelibrary.wiley.com

General Overview1,2
• Common names
– Areca catechu
– Areca Nut
– Betel Nut
– Paan
– Paan-gutkha pinglang
– Supari
– Tamol (fermented)
• NOT A NUT – drupe
• Larger than an olive
• Grows on areca palm tree in
tropical and subtropical areas
www.andamanplantations.com

General Overview1,2
• Primary ingredient in Betel Quid
– Betel leaf
– Areca nut
– Slacked lime (calcium hydroxide)
– (Tobacco)
– Preparation varies greatly
• Green unripe
• Raw ripe
• Baked
• Roasted
• Boiled
• Fermented
scatterolight.blogspot.com
screening.iarc.fr

History & Epidemiology1,2,3,4
• Ancient practice in many parts of Asia
– South/Southeast Asia
• Pakistan, Sri Lanka, Bangladesh, Thailand,
Cambodia, Malaysia, Indonesia, China,
Papua New Guinea
– Asia Pacific Islands
– Use dates back 8776 years ago in Western Thailand
– Tun-huang manuscripts: used as medicine in China a
century ago
• More recent use in Africa, Europe, North America
– South/East Africa, the UK, Australia
– Migrated communities
• 200-400 million users worldwide
• 10-20% of people in the world are potential users
www.artsconnected.org

History & Epidemiology1,2,3,4
• Popular among both men and women
• Generally more common among elderly
• Often used by children
• Became available commercially in the last two
decades
• Industry worth about $500 million USD (India)
• May be more commonly used by people of
lower socioeconomic status, less education
www.freeenterprise.commedical-dictionary.thefreedictionary.com

Reasons for Use2,3,5
Backed By Scientific Evidence
• Euphoria/antidepressant
• Salivation/thirst quenching
• Strengthens gums/fortifies
teeth
• Aid cognitive
performance/alertness
• Antihelminthic
• Analgesic/sedative
Lacking Scientific Evidence
• Reduced salivation
• Stimulates appetite
• Suppresses hunger
• Aid digestion
• Dispel nausea
• Anti-diarrheal
• Morning sickness
Stimulant (arecoline) AND
a relaxant (arecaidine and
guvacine)
www.indiamart.com

Pharmacokinetics2,6
• Usually chewed
• Some reports of being smoked
• Roasted, flavored, and served to guests after
meals
• Dose-response relationship for each effect is
not completely understood
• Interactions:
DRUG RESULT
Flupenthixol and
procyclidine
Rigidity, bradykinesia, jaw
tremor
Fluphenazine Tremor, stiffness, agitation
Prednisone and salbutanol Inadequate control of
asthma

Pharmacodynamics3,5,6
• Main neuroactive alkaloid: Arecoline
– Resembles muscarine and pilocarpine
– Potent muscarinic agonist at M1,2,3
– Weak ganglionic nicotinic agonist at acetylcholine
receptors
• Arecaidine is most potent at M2
• Work together to increase the release of
catecholamines from chromaffin cells
www.indiamart.com www.medicalisotopes.com
Arecoline Arecaidine

Pharmacodynamics3,5,6
• Causes central cholinergic stimulation
• Sympathetic activation caused by increased plasma
concentrations of norepinephrine and epinephrine
• Effects are dose-dependent
• Addiction and withdrawal seen in heavy users
• Can cause cholinergic toxicity, toxic psychosis, and other
neurologic issues
www.nlm.nih.govpetedharane.com

Toxicology3,5,6
• Acute significant toxicity is rare; likely underreported
• 42,000 patients called Taiwan Poison Control Center
– 17 possible betel quid cases (most consumed 1-6 nuts)
• 15 recreational
• 1 attempted suicide
• 1 medicinal
– 11 experienced nausea, vomiting, dizziness, tachycardia, and/or
palpitations
– 6 experienced coma, respiratory failure, and/or myocardial
infarctions
– 1 died (previously healthy 44 year-old male; chewed one betel
quid)
• Other adverse events: hypotension, sweating, chest discomfort,
abdominal colic, numbness, death, exacerbation of
extrapyramidal effects
www.cia.gov

Toxicology3,5,6
• Treatment of overdose is usually
symptomatic
• May be treated with stomach lavage,
activated charcoal, IV fluid, and electrolyte
replacement therapy
• Atropine not recommended but may be
used if severe acute cholinergic crisis
• Recovery typically in 24 hours
en.wikipedia.org

Toxicology7
Rat Study:
• Healthy male and female Wistar albino rats, 10-12 weeks old
• Fasted overnight, administered raw areca nut extract
• Male LD50: 2321.96 mg/kg
• Female LD50: 2257.52 mg/kg
• Signs of toxicity
– Depression
– Profuse salivation
– Tremors
– Burrowing
– Hunched back
– Muscular incoordination
– Weakness
– Altered gait
– Convulsions
– Writhing movement of the neck
– Severe diarrhea
– Labored breathing/gasping
– Death
www.junsungls.com

Society’s Perspective2,8
• Fourth most commonly used psychoactive substance in the
world
– Right after caffeine, nicotine, and alcohol
• Completely socially acceptable in many countries
• Use ceremonially in courtship, weddings
• Offered when greeting or leaving as a gesture of relaxation
• Available on the internet
http://www.ebay.com/sch/i.html?_trksid=p2050601.m570.l1313&_nkw=areca+nut&_sacat=0&_from=R40

Effect on Health8,9,10
• Strong association with major oral health issues
• Main factor in Oral Submucosal Fibrosis (OSF)
– Arecoline upregulates αVβ6 integrins and causes activation of TGF-β
pathway, which increases collagen production
• Submucosal fibrosis is highly precancerous
• Areca nut extract (ANE) increases reactive oxygen species, which
initiates pyknotic necrosis, which is exacerbated by inhibition of
GSK3-β by SB216763
• ANE is cytotoxic, causes formation of vacuoles
• Arecoline is genotoxic and causes DNA damage and downregulates
cyclin-dependent kinase inhibitors p21 and p27
• Causes many problems in the oral cavity including ulcers, thickened
epithelium, brownish discoloration, submucosal fibrosis,
pseudomembranous wrinkle alteration
• In the cells, causes ballooning, epithelial hyperplasia, massive
inflammatory infiltration, basal nuclei hyperkeratosis, pyknosis, and
dysplasia
www.oralsubmucousfibrosis.com

Effects on Health11,12
• Linked to oral and esophageal cancer, hepatocellular
carcinoma, liver cirrhosis, obesity, type II diabetes,
hypertension, hyperlipidemia, metabolic syndrome,
chronic kidney disease
• Strongly associated with cancer
• Difficult to determine pathway in carcinogenesis due
to compounding factors
• Study showed that raw areca nut (RAN) induced
stomach cancer in mice
• Increases levels of p53, Bax, Securin, and p65 in
esophageal and stomach cells
• Downregulates mitotic checkpoint proteins
• More likely to produce reactive oxygen species when
used in betel quid because the lime makes saliva
alkaline; develop cancer earlier
www.darshanenterprise.com

Future Expectations8
• Will be banned in many states and countries

Case Report5
• Newborn of a healthy, 38-year old woman who was a
chronic areca nut user
• Born after 38 weeks (9.5 months) gestation; normal
weight and length
• Presented with irritability and hypertension 48 hours
after normal delivery
• Normal serum chemistry and electrolytes
• Negative for HIV, hepatitis C, hepatitis B, toxoplasma,
rubella, syphilis
• Negative for opiates, cocaine, cannabis,
amphetamines, benzodiazepines, barbiturates, ethanol
Lopez Lopez

Case Report5,13
• At 3 days old, Finnegan scores were >8
• Started on phenobarbital 15 mg/kg IM
followed by 8 mg/kg per day orally
• Withdrawal improved after 5 days of
treatment
Lopez Lopez

References
1. Gupta PC, Ray CS. Epidemiology of Betel Quid usage. Ann Acad Med Singapore. 2004;33:31-36.
2. Strickland SS. Anthropological perspectives on use of the Areca Nut. Addict Biol. 2002;7(1):85-97.
3. Deng JF, Ger J, Tsai WJ, et al. Acute toxicities of Betel Nut: Rare but probably overlooked events. J Toxicol Clin Toxicol. 2001;39(4):355-60.
4. Ji WT, Lee CI, Chen JYF, et al. Areca Nut extract induces pyknotic necrosis in serum-starved oral cells via increasing reactive oxygen
species and inhibiting GSK3-beta: An implication for cytopathic effects in Betel Quid chewers. PLoS One. 2013;8(5):1-10.
5. Lopez-Vilchez MA, Seidel V, Farre M, et al. Areca-Nut abuse and neonatal withdrawal syndrome. Pediatrics. 2006;117(1):129-31.
6. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355(9198):134-8.
7. Lohith TS, Shridar NB, Jayakumar K, et al. Acute oral toxicity of raw Areca Nut extract in rats. Indian J. Anim. Res. 2013;47(5):431-434.
8. Gupta PC, Ray CS. Epidemiology of Betel Quid usage. Ann Acad Med Singapore. 2004;33:31-36.
9. Khan I, Kumar N, Pant I, et al. Activation of TGF-beta pathway by Areca Nut constituents: A possible cause of oral submucosal fibrosis.
PLoS One. 2012;7(12):1-12.
10. Ji WT, Lee CI, Chen JYF, et al. Areca Nut extract induces pyknotic necrosis in serum-starved oral cells via increasing reactive oxygen species
and inhibiting GSK3-beta: An implication for cytopathic effects in Betel Quid chewers. PLoS One. 2013;8(5):1-10.
11. Kurkalang A, Banerjee A, Ghoshal N, et al. Induction of chromosome instability and stomach cancer by altering the expression pattern of
mitotic checkpoint genes in mice exposed to Areca-Nut. BMC Cancer. 2013;13:315.
12. Lin WY, Chiu TY, Lee LT, et al. Betel Nut chewing is associated with increased risk of cardiovascular disease and all-cause mortality in
Taiwanese men. Am J Clin Nutr. 2008;87(5):1204-11.
13. Klein J. Identifying neonatal abstinence syndrome (NAS) and treatment guidelines. University of Iowa Children’s Hospital. Published
February 11, 2013.

Kava [1]
• Piper methysticum.
• The many names of Kava
– Awa
– Ava
– Gea kavain
– Maluk
– Sakau
– Yagona
http://www.kratom-
k.com/product_images/t/793/Kava_Root__17445_zoo
m.jpg

History[2]
• Originated in South Pacific Islands
• Introduced to the West by Capt. Cook
• Widespread use in Australia, Europe, and
America.

http://3.bp.blogspot.com/-
9MGUQRhJcVg/ULJ_dWaN21I/AAAAAAAAAAY/X_DypYrA0NU/s1600/map.gif

Kava Uses [3]
Beverage used traditionally in ceremonies. The
Review of Nature Products states that Kava
“produces mild euphoric changes, characterized
by feeling of happiness,
fluent and lively speech,
and increased
sensitivity to sounds.”
http://www.hollyanissa.com/wp-content/uploads
/2012/07/Week30.jpg

Kava in the West [2]
• In western countries kava used medicinally.
• Know for its psychoactive effects
– Anxiety
– Insomnia
https://encrypted-
tbn2.gstatic.com/images?q=tbn:ANd9GcQpOnqTkho9pC3ElvvEQwa7ERjwodKBap0E8wU0
LF-Wzi1T_m8JVg

Kava preparation [4]
• So how is kava prepared ?
http://3.bp.blogspot.com/_6i2sW4aFUeE/TG4FYbA9-
aI/AAAAAAAAAEs/6_Qvok9yWmU/s1600/IMG_0457.jpg

http://api.ning.com/files/0N4byQT3Y2JD-ZpmjVZ55-
GYnW8Xr-ZAfaEO7h5grQA_/kavaceremonywakaya.jpg

Economics of Kava [1]
• Kava is not only the traditional drink for many
villages, but it is considered a significant cash
crop in some islands.
• Kava also produces a major cash yield in Tonga,
Samoa, and Vanuatu.
• In Hawaii kava is used for medicinal and religious
purposes, the “kahunas” (medical people whom
communicate with God) used kava to cure many
disease and ailments, such as chills and colds,
general debility, sharp headaches, weary muscles,
and displacement of the womb.

http://informedfarmers.com/wp-content/uploads/2010/10/crops.jpg

MOA [5,6]
• MOA not clear
• One theory is that Kava exert some effect on
GABA-A binding sites, and an inhibitory effects
on dopamine and norepinephrine.
• In vitro study by Mathews done on human
liver showed different kavalactones from Kava
extract inhibiting CYP enzymes including CYP
2C9, 2C19, 2D6, 3A4, and 1A2.

Kava interactions [6]
• Kava and alcohol
– cause an increase in toxicity of kava and/or
alcohol
• Kava and benzodiazepines
– increase the effects of benzos
• Kava and levodopa
– reduces the effects of levodopa

PK/PD [2,7]
• A study on kawain found Peak levels at 1-2
hours.
• Distribution half life of 50 minutes.
• Elimination half-life of 9 hours.
• Metabolites and kavalactones such as Kawain
are excreted renally mostly in human urine,
and some excreted in feces.

Safety/Toxicity [2]
• There is a widespread concern regarding
hepatotoxicity with Kava use. Reports of liver
damage, cirrhosis, hepatitis, and liver failure
have been documented in Western countries
including Switzerland, and Germany.
http://www.mimscience.org/mims/wp-
content/uploads/2012/02/liver.png

Reports of toxicity [8]
• Pipermethysticine (PM) present in Kava leaves
and stems is a potential cause of
hepatotoxicity.
• In Fischer trial 334 rats were given 10 mg/kg
PM daily demonstrated oxidative stress
changes in two weeks. The oxidative stress
was shown to increase cytosolic superoxide
dismutase enzymes and hepatic glutathione.

And more [8]
• Kavalactone Flavokavin B is a cytotoxic agent
present in Kava root. Flavokavin B causes
hepatocellular toxicity through mitogen-
activated protein Kinase (MAPK) signaling
pathway which leads to oxidative stress and
results in apoptosis of the cell.

Pause !!
• Kava toxicity
• Always present or a creation of the West?

Side effects [2,8]
• In general well tolerated
• Kava Dermopathy
– dry, scaly skin with yellow pigmentation on the
hands and feet.
https://encrypted-
tbn2.gstatic.com/images?q=tbn:ANd9GcTIY83_n
7JkhrrmLZs6y3R9c808UCefvgsdhSQTlJn5shwm3
xVM

Act of Vanuatu [9,10]
• Nov. 7 of 2002
• States that only noble kava cultivars with a
long history of safe traditional and medicinal
use must be met before export from Vanuatu.
• Also, according to the Act, 2 day cultivars and
Wichmanni (wild kava) do not satisfy the
appropriate legislation for desired kava effect
and are prohibited for export.

Noble Kava Cultivars of Vanuatu [9]
Noble cultivar Origin
Ahouia Tanna
Asiyai Aneityum
Biyai Aneityum
Borogoru Maewo
Gegusug Gaua
Kelai Epi
Leay Tanna
Melomelo Ambae
Palasa Santo

Regulation Globally [11]
• Australia - Kava is legal to possess & sell, but it is illegal
to import into Australia without a license, since it’s
listed as a “Schedule IV”.
• Germany - Germany is where the original Kava ban
that sparked worldwide banning of Kava originated.
Germany moved to lift its ban in 2007 after almost
everyone else in the world did.
• Canada - may export Kava to Canada, as long as it’s to
individuals who are using it for personal consumption,
and NOT to any businesses.
• Banned in some other countries like Britain, and
France.

How about U.S [2]
• Kava is not approved by the FDA, but has not
been taken off the market in the U.S either
despite health concerns about its safety.

Kava abuse !! [12]
• Duke University Medical Center states Kava
doesn’t have any dependence or withdrawal
effects.
• In clinical settings, 280 mg/day of
kavalactones were given, and a follow up data
for 4 weeks showed no effect on heart rate,
blood pressure, or sexual dysfunction. No
differences between kava and placebo were
found.

Kava Addiction [12,13]
• Pilot study and a survey were done to
determine if kavalactones decrease the
craving associated with drug abuse. The
substances used included alcohol, cocaine,
tobacco, and heroin.
• The findings suggest that kava may reduce the
craving associated with the aforementioned
substances, which makes kava a great future
candidate to help with addiction.

• Kava is used medicinally for which of the
following:
a) Depression
b) Anxiety
c) Erectile dysfunction
d) PMS

Quiz
• True or False
• Kava is banned from many countries due to its
addictive properties.
• Kavas’ toxicities are most likely due to:
a) Its ingredients
b) Its preparation
c) Because Caucasians cant tolerate drugs the way
islanders do.
d) I don’t know because I wasn't paying attention

References
1. Davis R.I, Brown J.F. Kava (Piper methysticum) in the South Pacific: its importance, methods of
cultivation, cultivars, diseases and pests. Australian Centre for International Agricultural
Research. 1999; No. 46, 32.
http://ageconsearch.umn.edu/bitstream/113917/2/tr046_pdf_19769.pdf. Published 1999.
Accessed Apr 20, 2014.
2. Basch E, Basch S, Bent S, Boon H, Bryan K, Cost D, Ernst E, Isaac R, Rogers A, Rourk E, Schadde S,
Shkayeva M, Sollars D, Strominger Z, Tanguay-Colucci S, Tsourounis C, Ulbricht C, Varghes M,
Weissner W, Woods J. Kava (Piper methysticum). Natural Standard.
http://husson.naturalstandard.com.husson.idm.oclc.org/databases/herbssupplements/kava.asp
Updated 4.8.2014. Accessed Mar 15, 2014.
3. Pepping J. Kava: Piper methysticum. AJHP. 1999; vol(56):957.
file:///C:/Users/Anan/Downloads/36023842%20(3).pdf. Published May 1999. Accessed Apr 15,
2014.
4. Singh Y. Kava: an overview. Journal of Ethnopharmocology. 37 (1992);13-45.
file:///C:/Users/Anan/Downloads/36023308%20(1).pdf. Published 1992. Accessed Apr 20, 2014.
5. Abadi S, Papoushek C, Evans M. Is kava extract effective for treating anxiety? Canadian Family
Physician. 2000;20:84-9. http://www-ncbi-nlm-nih-
gov.husson.idm.oclc.org/pmc/articles/PMC2018572/pdf/11570299.pdf Published Sep, 2001.
Accessed Mar 15, 2014

6. Ankea J, Ramzana I. Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper
methysticum Forst. f). J Ethnopharmacol. 2004 Aug;93(2-3):153-60.
doi:10.1016/j.jep.2004.04.009.
7. Mathews J, Etheridge A, Valentine J, Black S, Coleman D, Patel P, So J, Burka L. Pharmacokinetics
and Disposition of the Kavalactone Kawain: Interaction With Kava Extract and Kavalactones in
Vivo and in Vitro. DMD. October 2005 vol. 33 no. 10 1555-1563. doi:10.1124/dmd.105.004317
8. Rowe A, Zhang L, RamzanI. Toxickinetics of Kava. Adv Pharmacol Sci. 2011; 2011:
326724. doi: 10.1155/2011/326724.
9. Teschke R. Kava and the Risk of Liver Toxicity: Past, Current, and Future. AHPA. 2011; 26:12.
http://www.ahpa.org/portals/0/pdfs/11_0303_March2011_AHPA_Report_Kava_Special_Report.
pdf Published Mar, 2011. Accessed Apr 6, 2014.
10. Teschke R, Sarris J, Glass X, Schulze J. Kava, the Anxiolytic Herb: Back to Basics to Prevent Liver
Injury?. Br J Clin Pharmacol. Mar 2011; 71(3): 445–448. doi: 10.1111/j.1365-2125.2010.03775.x
11. Makaira. Kava-Worldwide Legal Status. Kona Kava Farm.
http://www.konakavafarm.com/blog/kava-news/kava-worldwide-legal-status/ . Posted Jul 24,
2009. Accessed Apr, 2014.
12. Connor KM, Davidson JR, Churchill LE. Adverse-effect profile of Kava. CNS Spectr 2001
Oct:6(10):848, 850-3. http://www.ncbi.nlm.nih.gov/pubmed/15334034. Accessed Apr, 2014.
13. Steiner G. Kava as an anticraving agent: preliminary data. Pac Health Dialog. 2001 Sep;8(2): 335-9.
http://www.ncbi.nlm.nih.gov/pubmed/12180513?report=abstract. Accessed Apr, 2014

Krokodil: “World’s Deadliest drug”
Alyssa Duron
video.foxnews.com

Objectives
• Explain the history of Krokodil (desomorphine) and its
relation to morphine.
• Explain its proposed mechanism of action.
• Describe the reasoning behind the making of
desomorphine and the results its trials in animals and
in chemotherapy patients.
• Provide toxicology data and its reported harms and
risks.
• Define epidemiology and usage patterns in Eastern
Europe.
• Discuss the effects of Krokodil on its users.

The search for novel morphine
analogues1
• 1929: Committee on Drug Addiction (U.S.A)
• Lead by Dr. NB Eddy, Secretary of the Drug Addiction
Committee.
• Search for non-addictive, strong analgesic
• 200 analogues synthesized in first decade
• Tested some drugs in the prison population.
• Potency assessed by reversal of analgesia.
• Important findings:
• Parallel between analgesic effect and addiction liability.
• Schedule I compound since 1936 in the U.S.2

Desomorphine vs. morphine3
Desomorphine Morphine
Difference between desomorphine and morphine is the absence of the
secondary hydroxyl group and the saturated double bond.

Addiction & tolerance properties of
Desomorphine
• 8-10x more potent than morphine on a weight
basis.2
• 15x more sedating4
• 10x the analgesic effect4
• 3x more toxic4
• May have less of an effect on G.I. tract1
• LD50 in mouse is 27mg/kg IV or 104 mg/kg SQ5
• Half life is roughly 1-2 hr in comparison to
morphine at 4-5 hr.12

First experiment in dogs6
1 2
7 8
2 mg/kg
Desomorphine
5 mg/kg
Desomorphine
10 mg/kg
Morphine sulfate
50 mg/kg
Morphine sulfate
Study run from October 23 – December 28, 1933 and
given every day but Sundays. After study, observed
daily for 2 weeks for withdrawal symptoms.
Summary: Depressant effect of both desomorphine doses was >10 mg/kg
morphine dose and slightly less than the 50 mg/kg morphine dose. No
specific withdrawal symptoms observed in either group. In both groups:
moderate salivation, decrease in body temperature, decrease in RR, decrease
in weight observed.

1936: Eddy & Himmelsbach7
• Observational trial in 1936. Desomorphine was
substituted for morphine in 5 morphine addicts.
• 200 mg per day in one, and 400 mg per day in others.
• Interval was every 6 hours for 8-21 days of
substitution.
• Findings include:
• Increasing the dose of desomorphine did not compensate
for its short duration of action.
• Efficacy in comparison to morphine is likely similar.
• Abstinence symptoms from desomorphine developed
much faster than after withdrawal of morphine.
• At least equal to symptoms of morphine abstinence
syndrome but appeared sooner.

Patented in 1932 as
“permonid”
– Patented as Permonid by Hoffman-La Roche in
Switzerland.2,3
– Available as an ampulla and suppository for post-op
pain2,3:
• Fast onset of action
• Decreased tendency to cause respiratory depression and
nausea.
• Was continued in Switzerland until 1981 for one single
patient who had a rare disease who needed 0.16 g daily (80
ampules) and did not develop any somatic side effects from
this medication.3
zikkir.com

Krokodil: homemade
heroin substitute
– First publicized use in Siberia in 2002.2
– Name “krokodil” (or crocodile in English) comes from2:
• Scaly appearance of user’s skin (necrosis, gangrene) when
infection occurs.
• Name of its derivative chlorocodide.
– Made similarly to ephedrine to methamphetamine.2
– Ingredients include: codeine, iodine, red phosphorous.2
• Product has toxic by-products found inside (i.e. paint
thinner, lighter fluid, gasoline, lead, zinc, iron, HCl, iodine,
red phosphorous).2
Airspacemag.com

Constant cooking process8
• Process takes only 10-45 min
but has to be completed
throughout the day since
–Short duration of action.
• Pack of 10 codeine tabs costs
120 Rubles ($3.35) and
produces a yield equivalent to
500 Rubles of heroin.
• Production results in a liquid
drug ready for frontloading.
Animalnewyork.com
Businessweek.com

Environmental risk factors8
– Processing chemicals and codeine (could be)
purchased easily and is (was) not controlled.
• OTC sale prohibited in Russia June 1, 2012.9
– Opium poppy fields were prevalent throughout
the region, but seasonal growth.
– More control and restriction of substance abuse
in the 1970’s-80’s in the USSR.
– Closed borders lessened drug trade, particularly
Afghan heroin.
En.wikipedia.org

Reported krokodil usage patterns10
http://rospravosudie.com/society/narko

http://rospravosudie.com/society/narko
Marijuana
Heroin
Desomorphine
Hashish
Amphetamine
Codeine
Morphine
Translation: Alex Sinkov

Toxicities & effects
The life expectancy of the individual using is estimated to be
as low as 2-3 years.11
Localized4
• Thrombosis
• Open ulcers
• Phlebitis
• Gangrene
• Skin and soft
tissue
infections
• Limb
amputations
Systemic4
• Pneumonia
• Blood
poisoning
• Coronary
artery burst
• Meningitis
• Rotting gums,
nose, ears, lips
• Liver and
kidney
problems
Neurological4
• Speech
impediments
• Motor skill
impairments
• Personality
changes

Ibtimes.com
Mrconservative.com
Motherjones.com
Dailymail.co.uk

Stories of addiction12
• A user in a focus group in Odessa was asked if he was
worried about getting HIV. He replied, “No.” When asked
what he biggest worry was, he replied, “Withdrawl.” His
second biggest worry was “Police.” He said, “Police and
withdrawl are today. If I get HIV I will still live 10 more
years.”
• “I was taken to a hospital when I was fever sick with a fever
and couldn’t walk and they refused to treat me. They told
me to go buy syringes, bandages, and medications. They
asked me for money, and when I didn’t have any I was
asked to leave the clinic by the doctors.”

References
• 1. Furst S, Hosztafi S. The chemical and pharmacological importance of morphine analogues. Acta Physiologica Hungarica
2008;95(1):3-44.
• 2. National Medical Services, Inc. Analytical Specifications-DESOMORPHINE. 2012.
• 3. Gahr M, Freudenmann RW, Hiemke C, Gunst IM, Connemann BJ, Schonfeldt-Lecuona C. Desomorphine goes
“Crocodile.” J Addict Dis. 2012;31(4):407-12.
• Image: Goldfrank LR, Nelson LS, Lewin HA, Howland MA, Hoffman RS, Flomenbaum NE. Goldfrank’s Toxicologic
Emergencies, 9th ed: http://www.accessemergencymedicine.com.
• 4. Drug Enforcement Administration, Office of Diversion Control. Desomorphine: Dihydrodesoxymorphine;
dihydrodesoxymorphine-D; Street Name: Krokodil, Crocodil. Drug & Chemical Evaluation Section. 2013.
• 5. Eddy NB, Howes HA. Studies of morphine, codeine, and their derivatives: Desoxymorphine-C, Desoxycodeine-C, and
their hydrogenated derivatives. Pharmacol Exp Ther. November 1, 1935;55:257-267.
• 6. Eddy N, Himmelsbach CK. Experiments on the tolerance and addiction potentialities of dihydrodesoxymorphine-D
(“Desomorphine”). Publ. Hlth Rep., Wash. 1935;118:1260-1292.
• 7. Eddy N, Halbach H, Braenden O. Synthetic substances with morphine-like effect; clinical experience: potency, side-
effects, addiction liability. Bull Wld Hlth Org. 1957;17:569-863.
• 8. Grund J-P, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who
inject drugs in Eurasia. Int J Drug Policy. 2013;24:265-274.
• 9. Andrey Rylkov Foundation for Health and Social Justice. Over-the-counter sales of drugs that contain codeine
prohibited in Russia. June 1, 2012. http://en.rylkov-fond.org/blog/drug-policy-and-russia/drug-policy-in-russia/codeine-
prohibition/.
• 10. KOAEKC. RosPravosudie. Angel dust on the map of Russia. 2013. http://rospravosudie.com/society/narko.
• 11. Lemon TI. Homemade heroin substitute causing hallucinations. Afr J Psychiatry. 2013;16:411.
• 12. Booth RE. ‘Krokodil’ and other home-produced drugs for injection: a perspective from Ukraine. Int J of Drug Policy.
2013;24:275-280.

• Perennial flowering plant, Europe & N. Asia
– Has been introduced into other continents
• Known as baldrian, valerian, all-heal, etc.
• 1 to 2 meter single stem, white or pink bloom
• Other members of valeriana are not used
– Differing chemistry and chemical density
• Medicinal formulations from roots
– Pungent oil isolated from rhizome & root
– Various compounds with possible activity
– As oil extract or powdered radix dried at <40°C
Valeriana officinalis1

• Used as medicinal herb throughout history1
– Use varied over time, becoming more specific
• Ancient Greeks advocated use for many problems2
– “[GI distress], flatulence, nausea, liver problems,
convulsions, urinary tract disorders, poisonings… body
odor, vaginal yeast infection”
• Dioscorides mentioned as diuretic – 55AD1
• Fabio Colonna, epilepsy, phytobasanos – 15921
• Antiepileptic, sedative, and hypnotic1,2
– Tissot argued first line Tx for epilepsy in 1770’s
– Lost some credibility as antiepileptic after 18c
Historical Use

• Popular in continental Europe in 18-19c
– Used as anticonvulsant & antimigraine
• Lost favor in 20c, now an alternative medicine
– Recognized as mild sedative hypnotic in Germany
– Commonly sold OTC herbal in U.S. and Europe
• Commonly taken in tea or as capsule
• Commercial components differ (!)
– European products – valepotriates & volatile oil
• Demonstrate relaxation/sedation
• No decrease in mental concentration
– U.S. products contain little or no valepotriates
• Used for restlessness due to nervousness/anxiety
Shift Toward Modern Use2

• Clinical data supports use as sedative
– Often used as alternative to benzodiazepines
– Particularly for anxiety-induced sleep problems
– Supported by GABA binding and in vivo studies
• Some pharmacopoeias: Spasmolytic adjuvant
– Has been used with belladona, etc.
– Smooth muscle spasmolysis (eg. IBS)
• Still used as antiepileptic (no strong data)
• WHO monograph suggests limit 10g/day
• Active compound unknown – synergy?
– Many constituents are GABA binding2
Current Use3

Constituents of Valerian Products2
Spasmolytic, psychostimulant, sedative,
alcohol antagonist
Sedative, spasmolytic, muscle relaxant,
antidepressant

• Conjecture: sesqueterpine metabolite
– Ideal scenario – 0.9% of root
• Anticonvulsant, sedative, muscle relaxant
• Chemically similar to valproic acid
– Unsurprisingly, similar indications
• Strong sweat or cheese odor
– Amide derivative lacks this odor (isovaleramide)
– Use of amide has precedent – valpromide for VPA
Isovaleric Acid1

Assessment N Product Objective Results Subjective Results
improvement
of sleep quality
128 Valerian
(aqueous)
200mg
Sleep latency
decreased by 37% vs
23% placebo (p=0.01)
43% vs 25% “better
than usual” sleep
(p<0.05)
37% vs 28% report
fewer awakenings
(p<0.05)
Sedative (effect
on driving)
109 Valepotriates No impairment,
insignificant improved
stress reaction
Performance &
mood under
stress
48 Valerian 100mg No reduction in pulse
rate during stress
↓ subjective feelings
of somatic arousal
Evidence for Efficacy2
USPSTF – probably safe, probably effective as sleep aid, possibly as spasmolytic

530-1060mg qhs
145-290mg qhs
100-200mg qhs
350mg qhs
1-2g TID

Toxicity2
• Considered safe despite lack of definite evidence
• Insufficient evidence for chronic toxicity
• Side effects uncommon during trials
• Reported chronic adverse effects vary
– Headache, excitability, anxiety, cardiac disturbance
• Attempted suicide – Case for excess use
– 40-50 470mg capsules (>18g)
– Fatigue, abdominal pain, tremors, mydriasis
– Activated charcoal – full recovery <24 hours
– Unknown capacity for interaction with sedatives
• Assume interaction, use caution

• No evidence of endemic problem use
• Anecdotal evidence of excess use varied
– Generally combined with other legal herbals
– Generally sedative, occasional psychedelic reports
• ~11.2g in tea + 1tbsp in water over ~1 hour4
– “my heartbeat pounded inside my head. I struggled to put my clothes on and
then immediately laid down for a few minutes. It took about 15 before my
head stopped pounding and I stopped dripping with sweat… Still not relaxed
enough, I took a tablespoon of powdered valerian and stirred it up in a glass of
water. I chugged it down in one drink, nearly gagging from the taste… I could
hardly breathe, my lungs felt solid and my heartbeat weak.”
Illicit Use

1. Eadie M. Could valerian have been the first anticonvulsant? Epilepsia (Series 4).
2004;45(11):1338-1343. Available from: Academic Search Complete, Ipswich,
MA. Accessed April 7, 2014.
2. Caron M, Riedlinger J. Valerian: A practical review for clinicians. Nutrition In
Clinical Care.1999;2(4):250-257. Available from: Academic Search Complete,
Ipswich, MA. Accessed April 7, 2014.
3. WHO Monographs on selected medicinal plants – vol. 1. Geneva. 1999
4. Stray Tom. "In Excess: An Experience with Valerian (ID 28576)". Erowid.org. May
19, 2006. erowid.org/exp/28576
Sources

History
• Trade Names: Pondimin, Ponderax,
Adifax
• 3-trifluoromethyl-N-ethylamphetamine
• Racemic mixture of dextrofenfluramine
& levofenfluramine
• Weight loss medication introduced in
1973
• Combined with Phentermine to create
the ultimate weight loss drug Phen-Fen
• Withdrawn from US market in 1997
http://www.dailymail.co.uk/new
s/article-2543989/Not-FDA-
approvals-created-equally-Study-
reveals-medications-far-safety-
testing-others.html

Epidemiology
• “Miracle weight-loss drug”
• 1.2-4.7 million people used fenfluramine for 3-
12 months
• 1 in 3 adults are considered overweight
• Weight-loss drugs usually associated with
short-term weight loss

Social
• Appetite suppression
• Used by men and women of all ages
• C-IV medication
• Legal damages led to $13 billion to patients from
the makers
• Phen-Fen:
– Both analogues of amphetamine
– Phentermine affects dopamine
– Fenfluramine affects serotonin
– Allowed for two ways to suppress appetite
http://s3.amazonaws.co
m/answer-board-
image/933a5d06-a566-
4033-9931-
4d815a247347.jpg

Pharmacokinetics
• 20mg oral tablet
• Onset of action: 1-2 hours
• t1/2: 20 hours
• Effects last: 4-6 hours
• Dose: 1 tablet three times daily
• Max daily dose: 120mg
• Metabolism: de-ethylation to norfenfluramine
which is then deaminated and oxidized to m-
trifluoromethylbenzoic acid
• Excretion: urine

Pharmacodynamics
• Rapidly releases serotonin & inhibits serotonin
reuptake
– Serotonin involved in memory, cognition, mood,
anxiety, impulsivity, aggression, sleep, pain, and
neuroendocrine function
• Changes seen in rats, mice, guinea pigs,
squirrel & rhesus monkeys and baboons

Fenfluramine and Serotonin
• Male Sprague-Dawley Rats
• Examined relationship between drug
induced 5-HT release and long-term 5-HT
depletion in their brains
• In vivo: dFEN and mCCP elevated
extracellular 5-HT in the nucleus accumbens
• In vitro: dFEN and mCCP potent inhibitors of
5-HT uptake; High dose dFEN associated with
depletion of 5-HT levels but mCCP was not
– Different mechanisms behind 5-HT release and
depletion

Toxicity
• Led to valvular heart disease
– Prevalence: 0.1-30%
• High levels of circulating serotonin associated
with carcinoid syndrome  valvular heart
disease
• Increased exposure positively correlated with
risk of cardiac side effects

Toxicity
• ADRs: Agitation, drowsiness, confusion, fever,
flushing, tremor, hyperventilation, abdominal
pain, sweating
• <5mg/kg is toxic
• High Doses: confusion, ventricular extrastoles,
coma, ventricular fibrillation, death
• OD: dilated non-reactive pupils, normal or
elevated BP

Toxicity
• Disruption of heart valve
serotonin receptors lead
to:
– Pulmonary hypertension
and thickening of the
leaflet and cordae
tendineae
• Norfenfluramine is a 5-HT2B
receptor agonist
– High concentration in
cardiac valves
– Overstimulation or
inappropriate stimulation
of these receptors leads to
valvular cell division
– Leading to the thickening of
the leaflet
http://media.tumblr.com/tumblr_lgkwtrpVxN1qfcmjd.jp
g

Left: thickened mitral valve (MV) during diastole.
Right: demonstrates severe mitral regurgitation (MR) during systole

Prevalence of Aortic/Mitral
Regurgitation
• Variation in prevalence between studies
based on FDA criteria
• True prevalence between 2-12%

What now?
• Belgium
• Added to treatment for Dravet Syndrome
– Epilepsy resistant to many medications
• 12 patients
• 0.34 (0.12-0.90) mg/kg/day in addition to anti-
epileptic drugs
• Decrease in seizure activity in all patients
– 4 seizure free for 2 years
• No cardiac side effects to date

References
1. Jick H, Vasilakis C, Weinrauch L, et al. A population-based study of appetite-
suppressant drugs and the risk of cardiac-valve regurgitation. N Eng J Med. 1998;
339: 719-724
2. Rothman R, Ayestas M, Dersch C and Baumann M. Aminorex, fenfluramine, and
chlorphentermine are serotonin transporter substrates: implications for primary
pulmonary hypertension. Circulation. 1999; 100.
3. Cardiac Valvulopathy Associated with Exposure to Fenfluramine or
Dexfenfluramine: U.S. Department of Health and Human Services Interim Public
Health Recommendations, November 1997. MMWR Morb Wkly Rep. 1997; 46:
1061-1066.
4. Roth B. Drugs and valvular heart disease. N Eng J Med. 2007; 356.
5. Rothman R, Baumann M, Savage J, et al. Evidence for possible involvement of 5-
HT2B receptors in the cardiac valvulopathy associated with fenfluramine and
other serotonergic medications. Circulation. 2000; 102: 2836-2841.
6. Hopkins P and Polukoff G. Risk of valvular heart disease associated with use of
fenfluramine. BMC Cardiovascular Disorders. 2003; 3.
7. Rothman R and Baumann M. Serotonergic drugs and valvular heart disease.
Expert Opin Drug Saf. 1009; 8.
8. Connolly H, Crary J, McGoon M, Hensrud D, Edwards B, Edwards W, Schaff H.
Valvular heart disease associated with fenfluramine-phentermine. N Eng J Med.
1997; 337.

References
9. Dahl C, Allen M, Urie P, Hopkins P. Valvular regurgitation and surgery associated
with fenfluramine use: and analysis of 5743 individuals. BMC Medicine. 2008;6.
10. Ceulemans B, Neels P, Boel M, Jorens P, Lagae L. Successful use of fenfluramine as
add-on treatment in dravet syndrome: a two year prospective follow up. Epilepsia.
2013;17: 1131-1139.
11. Ceulemans B, Boel M, Leyssens K. et al. Successful use of fenfluramine as add-on
treatment in Dravet syndrome. Developmental Medicine and Child Neurology.
Conference: 12th International Child Neurology Congress and the 11th Asian and
Oceanian Congress of Child Neurology Brisbane, QLD Australia. Conference Start:
20120527 Conference End: 20120601. Conference Publication. 2012. Date of
Publication: June 2012.
12. Weissman, N. Appetite suppressants and valvular heart disease. Am J Med Sci.
2001;321: 285-291.
13. Baumann M, Ayestas M, Dersch C, Partilla J, Rothman R. Serotonin transporters,
serotonin release, and the mechanism of fenfluramine neurotoxicity. Ann N Y Acad
Sci. 2000;914: 172-186.
14. Isbister G, Buckley N, Whyte I. Serotonin toxicity: a practical approach to diagnosis
and treatment. MJA. 2007;187: 361-365
15. McCann U, Seiden L, Rubin L, et al. Brain Serotonin Neurotoxicity and Primary
Pulmonary Hypertension From Fenfluramine and Dexfenfluramine: A Systematic
Review of the Evidence. JAMA. 1997;278: 666-672.
16. Fenfluramine. PharmGKB.
https://www.pharmgkb.org/drug/PA449592#tabview=tab2&subtab=31

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