Current recreational drugs: RX462 Drug Abuse & Society, Spring 2015 Class presentations

Drug Abuse & Society (RX 462)
Spring 2015 Presentations
Instructor: Brian J Piper, PhD

Contents*
Drug Author(s) Page
absinthe Stephanie Grant 3
ayahuasca Anonymous# 36
butane Anonymous# 61
e-Cigarette Brian Piper 82
hookah Jeremy Bishop 113
HU-210 Shannon Mockler & Kaitlyn Kelly 132
ketamine Kris Ravin 163
kratom Anonymous# 210
mephedrone Marcus Guilmette & Clarisse Baba 228
psilocybin Desiree Hamler & Danyle Boobar 266
Zohydro Nathan Papsadora 303
25I-NBOMe Anonymous# 322
*each presentation includes history, epidemiology, pharmacokinetics, & pharmacodynamics
#author name not listed at the request of the pharmacy student

Absinthe
Stephanie Grant
http://commons.wikimedia.org/wiki/File:Artemisia_absinthium_%E2%80%94_Flora_Batava_%E2%80%94_Volume_v8.jpg https://www.pinterest.com/wmthompson1971/cannabis-mushrooms-and-absinthe/

What is absinth?
• Essential oil extracted from Artemisia absinthium L.
(wormwood)
• Silvery grey half shrub that is native to central Europe and
Asia
• Harvested during the flowering period from June – September
• Oil concentration of 0.2-1.5%
• Oil is dark green, blue, or brown
• Extremely bitter and aromatic
• Thujone 40-90% of the essential oil
• Consists of two isomers; α-thujone & β-thujone
• β-thujone dominates (70-90% of thujone content)
Lachenmeier D, Walch S, Padosch S, Kroner L. Absinthe- A Review. Critical Reviews in Food Science and Nutrition. 2006;46(5):365-377

The history of absinthe
• Name derived from the Greek- apsinthion, the name of a star
that fell into water and turned it bitter (undrinkable)
• Ancient Egyptians used wormwood as an anti-helmintic agent
• Pierre Ordinaire, a French doctor living in Switzerland,
patented an herbal elixir of wormwood
• The French army used the elixir for malaria prevention in the
1840’s
• Recreational use began in France not long after, and then
spread to the rest of Europe and America
Montagne M. Drugs on the Internet, Part V:Absinthe, Return of the Emerald Mask. Substance Abuse & Misuse. 2013;48:506-512.

The history of absinthe
• Recreational use first became popular with well-off
individuals, as well as bohemian artists and writers
• Absinthe was one of the first alcoholic beverages to be widely
enjoyed by both men and women
• Widespread manufacture in the late 1800’s led to a steep
reduction in price
• Usage peaked at the turn of the 20th century
• Poor grape harvests led to reduced wine consumption
• Absinthe became even cheaper than bread
• Marketing efforts increased and led to use of absinthe in all
social classes

Marketing efforts
http://www.absinthes.com/themag/wp-content/uploads/2012/09/Le-Monde-Illustre-1892-Cafe-Scene_mini.jpg

L’heure Verte
http://absinthe.com.au/absinthe-history/

Famous artists and absinthe
• Vincent Van Gogh
• Paul Gaugin
• Oscar Wilde
• Charles Baudelaire
• Edgar Allen Poe
Vincent Van Gogh: Still life
with absinthe
Padosch S, Lachenmeier D, Kroner L. Absinthism: A fictitious 19th Century Syndrome with Present Impact. Substance Abuse Treatment, Prevention,
and Policy. 2006;1(14):1-14.

The story of Jean Lanfray & the beginning of absinthe
prohibition
• In August of 1905, a domestic tragedy occurred in Commugny,
Switzerland
• A laborer, Jean Lafray, shot his two young daughters and
pregnant wife
• He had been drinking wine and brandy heavily all day,
preceded by two early morning shots of absinthe
• Following several years of building absinthe sentiment, the
press popularized the story, blaming the crime on absinthe
• A petition to prohibit absinthe gathered 82,000 signatures
over several days
Hicks J. The Devil in a Little Green Bottle: A History of Absinthe.Chemical Heritage Magazine. 28(3):1-5.

The story of Jean Lanfray & the beginning of absinthe
prohibition
• At Lanfray’s trial, a swiss psychiatrist, Albert Mahaim, declared
that Lanfray was stricken by “absinthe madness”
• Declared guilty, he hung himself in prison 4 days later
• After several Swiss cantons declared absinthe illegal, the
country declared national prohibition in 1910
• Belgium in 1905, The Netherlands in 1910, and Germany in
1923
• The US banned absinthe in 1912
Hicks J. The Devil in a Little Green Bottle: A History of Absinthe.Chemical Heritage Magazine. 28(3):1-5.

Anti-absinthe propaganda
http://www.museeabsinthe.com/absintheLIVRES6.htmlhttps://www.pinterest.com/jkmatwood/absinthe-o-combien-je-t-aime-tellement/

Absinthism
Padosch S, Lachenmeier D, Kroner L. Absinthism: a ficticious 19th century syndrome with present impact. Substance abuse treatment, prevention,
and policy. 2006;1(14):1-14.

Comparison of pre-ban, post-ban, and
current absinthe compositions
Lachenmeier D, Nathan-Maister D, Breax T, Sohnius E, Schoeberl K, Kuballa T. Chemical Composition of Vintage Preban Absinthe with Special Reference to
Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations. Journal of Agricultural and Food Chemistry. 2008;56:3073-3081.

Current absinthe legislation
• United States- “Thujone-free” preparations are legal (≤10
mg/L)
• European Union:
– 5 mg/kg in alcoholic beverages with up to 25% alcohol
– 10 mg/kg in alcoholic beverages with more than 25% alcohol
– 35 mg/kg in bitters
http://www.absinthes.com/product_info.php?products_id=899http://magazine.foxnews.com/food-wellness/celebrating-national-absinthe-day
Absinthe legal status. Erowid Vault. https://www.erowid.org/chemicals/absinthe/absinthe_law.shtml Published
March 27th, 1999. Updated February 10th, 2015. Accessed March 21st, 2015.

How are absinthe drinks manufactured?
http://en.wikipedia.org/wiki/Absinthe
http://www.mutineermagazine.com/blog/2011/06/so-you-want-to-be-an-absinthe-connoisseur-part-1/Lachenmeier D, Walch S, Padosch S, Kroner L. Absinthe- A Review. Critical Reviews in Food
Science and Nutrition. 2006;46(5):365-377

The absinthe ritual
The Wormwood Society. Serving Absinthe: The Proper Way to Serve Absinthe in Society. http://www.wormwoodsociety.org/index.php/serving-absinthe-
mainmenu-228. Accessed March 20th, 2015

The absinthe ritual
1. Absinthe is poured into the glass (about 1/5 full)
2. The absinthe spoon is placed across the mouth of the glass
3. A sugar cube is placed on the spoon
4. Ice cold water is slowly poured over the sugar cube (enough
to dilute to 3-5 parts water to 1 part absinthe)
5. The essential oils are not soluble in water and they form a
cloudy precipitate
The Wormwood Society. Serving Absinthe: The Proper Way to Serve Absinthe in Society. http://www.wormwoodsociety.org/index.php/serving-absinthe-
mainmenu-228. Accessed March 20th, 2015

The Czech Method
https://www.youtube.com/watch?v=oQIYH7G007A

α-Thujone Pharmacodynamics
• GABAA receptor antagonist
– Intraperitoneal-60 mg/kg in mice induces a tonic convulsion, leading
to death within 1 minute
– Diazepam or phenobarbital given 15 minutes prior leads to almost all
mice surviving
• Negative allosteric modulator of GABAA receptors
• At higher concentrations, independent receptor effects have
been seen
• Competitive inhibitor of the non-competitive blocker site of the
GABA gated chloride channel
• Ethanol enhances GABAA receptor function, which may
modulate α-thujone antagonist function
• 5HT3 serotonin negative allosteric modulator
– Influences agonist induced sensitization
Johnston G, Hanrahan J, Chebib M, Duke R, Mewett K. Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin. Advances in
Pharmacology. 2006;54:285-314.

Thujone toxicity
Erb A. Die grüne Fee Thujon. Bayerische Julius-Maximilians-Universität Würzburg;2003.

α-Thujone is metabolized primarily by CYP3A4,
CYP2A6, & CYP2B6
Abass K, Reponen P, Mattila S, Pelkonen O. Metabolism of alpha-thujone in Human Hepatic Preparations in vitro. Xenobiotica. 2011;41(2):101-111.

α-Thujone inhibits CYP2A6 and CYP2B6 & may
interact with bupropion & nicotine
Abass K, Reponen P, Mattila S, Pelkonen O. Metabolism of alpha-thujone in Human Hepatic Preparations in vitro. Xenobiotica. 2011;41(2):101-111.

Absinthe: Attention, Performance & Mood
Under the Influence of Thujone
Study Type Study
Population
Study
Methods
Monitoring Treatment
Arms
Randomized,
Controlled,
Cross-Over
Study
• 10 F
• 15M
• Age 19-58
(Average 33.7)
• 3 Excluded
due to
inadequate
alcohol
absorption
• Attain BAC of
0.05%
• Men:
0.028 mg/kg
(10 mg/L) &
0.28 mg/kg
(100 mg/L)
• Women:
0.024 mg/kg
(10 mg/L) &
0.24 mg/kg
(100 mg/L)
•All matched
for taste &
color
•Visual
attention
performance
test (peripheral
& central)
•Basal mood
test
questionnaire
•General
activation-high
activation state
scale
1. Alcohol only;
No α-thujone
2. 10 mg/L
3. 100 mg/L
Dettling A, Grass H, Schuff A, Skopp G, Strohbeck-Kuehner P, Haffner H.-Th. Absinthe: Attention Performance and Mood under the Influence ofThujone.
Journal of Studies On Alcohol. 2004;65(5):573-581.

The investigators used a visual attention
performance test to assess drug affects
• 3 boards situated in front of and peripherally to the test
subject
• Central board has 9 lamps
• Peripheral boards have 6 lamps
• Lamps flash in intervals of 1.2 seconds and produce
random shapes
• 4 minute testing period, 50 signals
• Subjects pushed a button when a square formed

Attention performance was not significantly
changed by alcohol or alcohol + low α-
thujone
Alcohol only Results
Alcohol + 10 mg/ml α-thujone
T0= 0% BAC
T1=
30 minutes post
administration
T2=
90 minutes post
administration

Attention performance was significantly
changed by alcohol + high α-thujone
Alcohol + 100 mg/ml α-thujone

False alarm reactions were significantly initially
increased by 100 mg/L α-thujone

Correct peripheral reaction was significantly
reduced by 100 mg/L α-thujone

Oil of wormwood poisoning case report
• 31 year old man purchased oil of wormwood on the
internet (assuming it was absinthe)
• No hx of renal or neuromuscular disease, or alcohol
dependence/abuse
• Drank ~10 mL
• Found several hours later in an “agitated, incoherent,
and disoriented state”
• Paramedics noted tonic-clonic seizures
• “Lethargic but belligerent” in the ER
Weisbord S, Soule J, Kimmel P. Poison on Line- Acute Renal Failure Caused by Oil of Wormwood Purchased Through the Internet. New England
Journal of Medicine. 1997;337(12):825-827.

• RR, BP, HR WNL
• Small tongue laceration
• Mental status improved after administration of
haloperidol
• UA showed 4+ blood
• Pt developed muscle pain on day 2
• Heart failure developed- treated with diuretics &
sodium restriction
• Rhabdomyolysis, HF, and renal failure improved and
pt was discharged 8 days after ingestion

Summary
• Oil of wormwood has been used as a medical remedy
for thousands of years
• Absinthe has been used recreationally since the
1800’s, despite prohibition efforts
• α-thujone is the principal psychoactive component
• α-thujone acts as a negative allosteric modulator of
the GABAA receptor, but at higher concentrations can
act independently as a GABAA antagonist

Summary
• α-thujone also acts as a negative allosteric modulator of
5HT3 serotonin receptors
• Higher α-thujone leads to decreased attention
performance and increased anxiety
• LD50 levels have been reported but vary widely
depending on route of administration
• Despite rumors of higher thujone content and heavy
metals in pre-ban absinthe, testing has not validated
these theories
• Absinthism symptoms do seem to match some symptoms
of recently reported thujone toxicity

Learning Objectives
• What is Ayahuasca?
• General Properties
• Dosage
• Effects
• History
• Epidemiology
• Experiences
• Pharmacokinetics
• Pharmacodynamics
• Medical/Therapeutic Indications
• Toxicology
• Legal Implications
• Impact on Life
• Future Predictions
https://pbs.twimg.com/profile_images/992361622/shaman.jpg

What is Ayahuasca?
– Plant-based hallucinogenic
– “Vine of the souls”: Quechua meaning of Ayahuasca.
– Comprised of the bark and stems of Banisteriopsis
caapi and the leaves of Psychotria viridis. B. caapi
contains 3 main B-carbolines: harmine, harmaline,
and tetrahydroharmaline (THH). Harmine and Harmaline
form two alkaloids: harmol and harmalol, respectively.
Trace amounts of the alkaloids are found in ayahuasca but significant levels have
been measured in plasma. This is thought to be formed in vivo by O-demethylation
of harmine and harmaline. P. viridis contains N,N-dimethyltryptamine (DMT).
– Banisteriopsis caapi is pictured top right and is also called Hoasca.
https://encrypted-tbn2.gstatic.com/
images?q=tbn:ANd9GcTSqGt8xoFxS_CH3sP1KwYKvTPU3z
qXTDXzAiuahVYO57WVCZPe
http://www.plantteacher.com/wp-content/uploads/2010/01/Ayahuasca_Kit_1_504.jpg
Grob, C. S., McKenna D. J.,Callaway J. C., et. al. Human
pharmacology of hoasca, a plant hallucinogen used in
ritual context in Brazil. Journal of Nervous and Mental
Disease, 184 : 86-94.

General Properties
• Common Names
– Caapi
– Yagé
– Vegetal
– Aya
• Common Routes of Administration
– Beverage/Tea
– In traditional rituals, the ingredients are boiled or soaked together. The leaves
of P.viridis are essential for the psychoactive effect to render the tea orally
active. Ayahuasca is the only psychedelic agent that depends on a synergistic
interaction between two plant substances. The B-carboline alkaloids in the
bark of B. caapi are potent monoamine oxidase-A (MAOA) inhibitors. The
P.viridis leaves containing DMT are not orally active when ingested by itself
(even at doses up to 1000mg), but will become active when ingested in the
presence of a peripheral MAO inhibitor, such as the components in B. caapi.
Kuhn C, Swartzwelder S, Wilson W. 2014. Buzzed. 4th edition. 104,109,123,136.
http://iamspirituality.com/wp-
content/uploads/2013/05/ayahuasca-300x225.jpg

Effects
Item Placebo 0.6 mg/kg 0.85 mg/kg
1 High (I) 1/18 15/18 17/18
2 Body feels
different (S)
4/18 12/18 17/18
3 Visual effects
(P)
2/18 10/18 17/18
4 A “rush” (S) 0/18 9/18 17/18
5 Change in rate
of time passing
(C)
2/18 12/18 16/18
6 Eyes open visual
field vibrating or
jiggling (P)
2/18 10/18 15/18
7 Electric/tingling
feeling (S)
1/18 9/18 15/18
8 Change in
quality of
thinking (C)
2/18 8/18 15/18
9 Change in visual
distinctiveness
of objects in
room (P)
4/18 7/18 15/18
10 Sounds in room
sound different
(P)
2/18 5/18 15/18
11 Urge to close
eyes (V)
5/18 8/18 14/18
12 Change in
distinctiveness
of sounds (P)
2/18 7/18 14/18
13 Change in rate
of thinking (C)
1/18 7/18 14/18
14 Excited (A) 1/18 7/18 14/18
Physical/Psychological Short-term Effects
• Period of intense
nausea/vomiting, period of
anxiety/fear, followed by an
intense hallucinatory and
dissociative experience
• Mostly visual, also have
increased sensitivity to sensory
stimuli
• Profoundly altered state of
awareness and perceptions of
otherworldly imagery
• “Profound sense of insight”
• You can have closed-eye visuals
• Increased blood pressure and
heart rate
Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003). Human
pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite
excretion, and pharmacokinetics. J Pharmacol Exp Ther 306, 73 – 83.

Epidemiology
• There are an estimated 20,000 regular religious users of ayahuasca.
• Ayahuasca religions are present in 23 countries.
– Peru, Ecuador, and Brazil are popular places for the tradition.
http://www.theayahuascaretreat.com/is-ayahuasca-legal-map.gif
Kuhn C, Swartzwelder S, Wilson W.
2014. Buzzed. 4th edition.
104,109,123,136.

Epidemiology
Sociodemographic data as means (standard deviation) for age, years of
education, employment and income and as frequencies for race, marital
status and religion.
Ayahuasca Users:
Average Age: 37
Average Years of Education: 11
The majority of ayahuasca users are white or mestizos
Most are either married or never married
Religion: Almost all are Daime/Barquinha with some Catholics

History
• Shamans
– Richard Schultes, an ethnobotanist, first documented use of
the drug by indigenous peoples of the Amazon
– Despite its great hallucinogenic capabilities, it is not usually
used recreationally but as a pharmacological aid to personal
insight and enlightenment. Considered a “spiritual awakening.”
• When ayahuasca is taken in a group setting, vomiting is
considered a normal part of the experience and are
encouraged. It is believed that you are purging out the
negative energy and emotions.
• It has migrated from South America to the US recently.
http://www.sapaninka.com/img/ayahuasca-ceremony.jpg
http://doorofperception.com/wp-content/uploads/schultes-2.jpg
Grim, R. 2009. This Is Your Country on Drugs: The Secret History of Getting High in America. Hoboken, NJ: Wiley, Print. 144-151.

History
• The ayahuasca beverage is unique in that it is the only
traditionally used psychedelic where the enzyme
inhibiting principles in one plant (B-carbolines) are
used to facilitate the oral activity of the psychoactive
principles in another plant (DMT).
• Ayahuasca differs markedly from the effects of
parenterally ingested DMT:
– The psychologial effects are less intense than parenterally
administered DMT.
– Peripheral autonomic changes in blood pressure, heart
rate, etc., are less pronounced in ayahuasca than
parenteral DMT.
Riba J, Rodríguez-Fornells A, Urbano G, et al. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy
volunteers. Psychopharmacology. 2001;154:85–95.

Ayahuasca and the Brain
• https://youtu.be/aufjjU0EYxk
• (start at 1:56)
• Ayahuasca brings up past experiences
– Usually causes people to reevaluate past negative
experiences and they will have a new positive
outlook on the situation
– In some rare instances, bringing up past negative
experiences can cause the person to experience a
“bad trip”
http://www.ayahuascatimes.com/wp-content/uploads/2014/09/8384110298_da510e0347_z.jpg

Experiences
– “But, to put it in perspective, Ayahuasca, with a
Shaman, helped me kick alcohol, smoking, casual
sex, and a list of other self destructive behaviors.”
– “The ayahuasca trip was very different than LSD or
'shrooms for me; the hallucinations were much
more pronounced, the emotions easier to identify,
the introspection clearer, and I retained (for the
most part) a larger hold on rationality.”
“Ayahuasca.” Erowid Ayahuasca Vault. N.p., n.d. Web. 4 Apr 2015.

Experiences
– “In this state of what must be shamanic
ecstasy I stood up and found that my
body would move freely and completely
to the universal rhythm. I’m not sure
what music was playing, I think part or
most of the music was created by the
audio ‘hallucinations’. I danced in this
state, I became translucent, not of body, I
was a weightless consciousness
perceiving the full universe at once and
engaging with it at the same time almost
as if to create some sort of balance. This
was the best moment of my life, nothing
can explain it properly.”
http://sciencenotes.ucsc.edu/2011/images/features/ayahuasca.jpg
“Ayahuasca.” Erowid Ayahuasca Vault. N.p., n.d. Web. 4 Apr 2015.

Ayahuasca Visions
http://shamanism.files.wordpress.com/2011/12/ayari-huarmi-pablo-amaringo.jpg http://images.fineartamerica.com/images-medium-large-5/alto-cielo-pablo-amaringo.jpg

Pharmcokinetics: Dosage
• The concentrations and proportions of alkaloids and plant
ingredients varies greatly among different batches of ayahuasca, as
there is not a standard way to prepare the tea.
– A typical 100mL dose of ayahuasca collected from several samples of
tea from a Brazilian church, Un˜iao do Vegetal (UDV), contains 24 mg
DMT, 107 mg THH, 20 mg of harmaline, and 170 mg of harmine.
– A different batch obtained from Peru contained 728 mg total alkaloid,
with 60 mg DMT, 160 mg THH, 41 mg harmaline, and 467 mg of
harmine.
• Harmaline administered intraperitoneally in mice (5 mg/kg) causes
100% inhibition two hours after injection. The activity quickly falls
off after the two hours. The human dose equivalent would be 375
mg for a 75-kg adult, but even a dose of one-half or less would also
be effective based on the amount of harmine measured in the liver.
Yritia, M., Riba, J., Ortuno, J., et al. 2002. Determination of N,N-dimethyltryptamine and beta-carboline alkaloids in human plasma following oral
administration of ayahuasca. J Chromatogr B Anal Technol Biomed Life Sci. 779, 271 – 281

Pharmacokinetics
• Interactions:
– Ayahuasca is a Monoamine Oxidase Inhibitor (MAOI) so it should be treated the same as a
MAOI pharmaceutical product – avoid aged, outdated, and overripe food.
– Although there are no cases of fatality from a Food-Drug Interaction, there is the potential for
one.
– Caution is advised when combining pharmaceutical and herbal supplements with ayahuasca.
It is especially important not to take selective serotonin reuptake inhibitors (SSRI) because it
could induce serotonin syndrome.
• A list of medications to be careful of with MAOIs:
– other MAOIs
– SSRI’s
– amphetamines
– antihypertensives
– appetite suppressants
– medicine for asthma, bronchitis, or other breathing problems
– antihistamines, medicines for colds, sinus problems, hay fever, or allergies
– central nervous system depressants
– antipsychotics
– alcohol
Callaway JC, Grob CS. Ayahuasca preparations and serotonin reuptake inhibitors: a potential combination for severe adverse interactions. J Psychoactive
Drugs. 1998;30:367–369.

Pharmacokinetics
Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003). Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion,
and pharmacokinetics. J Pharmacol Exp Ther 306, 73 – 83
• Plasma concentration-time curves
• Open circles, low 0.6 mg of
DMT/kg dose of ayahuasca
• Filled circles, high 0.85 mg DMT/kg
dose of ayahuasca.
High variability in the bioavailability
of ayahuasca alkaloids in humans:
Cmax and AUC values increased with
dose for all measured compounds.
DMT showed a Tmax of 1.5 h (median)
after both the low and high doses.
Both harmaline and THH plasma
concentrations peaked later than
DMT, and their Tmax values were
larger after the high relative to the
low ayahuasca dose. An unexpected
finding was the absence of
measurable harmine plasma levels
except for a few time points in 4 of
18 volunteers, precluding the
calculation of pharmacokinetic
parameters for this alkaloid.

Pharmacokinetics
• There are measurable DMT plasma levels along with small
levels of circulating harmine that cause psychotropic effects
in the central nervous system. These levels and DMT’s MAO
inhibitor effect suggest an interaction between harmine
and DMT taking place in the gastrointestinal tract and the
liver. Harmine’s effects at a peripheral level seems to
prevent first-pass metabolism of DMT and allow its access
to the central nervous system. Prescription antidepressants
work by various means to keep serotonin in the synapses
longer. The DMT in ayahuasca binds to 5-HTP receptor sites.
DMT binds at a high rate, and the body adapts to this by
increasing the number of 5-HTP receptor sites, and makes
better use of natural serotonin levels.
Callaway J. & al. 1999. Pharmacokinetics of Hoasca alkaloids in healthy humans. Journal of Etnopharmacology, 65: 243-256.

Pharmacodynamics
• A time pattern was identified when a study looked at
EEG modifications to measure when the central
effects of ayahuasca occurred. They began as early as
15-30 min, peaked between 45 and 120 min and
decreased thereafter to return to baseline levels at 4-
6 h after administration. This study correlated with
previously reported subjective effects.
Don NS, McDonough BE, Moura G, et al. Effects of Ayahuasca on the human EEG. Phytomedicine.1998;5:87–96.

Pharmacodynamics
• DMT does not seem to induce tolerance.
• Long-term effects of DMT use/abuse are unknown.
• The addiction liability of DMT is also unknown.
• There is no evidence to suggest ayahuasca causes lasting
physiological or neurological deficits.
• Individuals do not go through withdrawals.
• It is rare for people to take it for consecutive days over an
extended period of time.
• Potential for Abuse: very low
• There is no evidence suggesting psychological
maladjustment, cognitive impairment, or mental health
deterioration from using ayahuasca.
Callaway J.C. 1999. Phytochemistry and neuropharmacology of ayahuasca. Thunder's mouth press, New York. pp-259-261.

Therapeutic/Medical Indications
• Treatment of Serotonergic Deficits
– Alcoholism
– Depression
– Autism
– Schizophrenia
– Attention Deficit Hyperactivity Disorder
– Senile Dementias
– Anxiety States
– Affective Disorders
– Substance Abuse
• Immune Modulation
• Parkinson’s
– Dopamine deficiency is characteristic of Parkinson's disease (PD) and
treatments aim at inhibiting monoamine oxidases (MAOs), thus preventing its
breakdown. An investigation is in progress to determine if reports of PD
patients showing improvements are true.
Schwarz, M. J., Houghton, P. J., Rose, S., Jenner, P., & Lees, A. D. (2003). Activities of extract and constituents of Banisteriopsis caapi relevant to
parkinsonism. Pharmacol Biochem Behav. 75, 627 – 633.
http://www.treatment4addiction.com/blog/wp-
content/uploads/alcoholism.jpg
Osório Fde L, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Rev
Bras Psiquiatr. 2015 Jan-Mar;37(1):13-20.

Toxicology
• The ayahuasca LD50 is about 20 times greater
than the average dose given in ceremonial
preparations. This is based on the LD50 of DMT
and harmala alkaloids. The ayahuasca LD50 is
similar to the LD50 of other hallucinogens, such
as psilocybin.
• No known deaths from ayahuasca alone, all
deaths associated with ayahuasca were due to
taking multiple substances, drug-drug
interactions, or from pre-existing conditions.
Gable S. 2007. Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids. Addiction, 102, 24–34.

Legal Implications
• The legal status of ayahuasca in the U.S. is ambiguous
because pure DMT (N,N-dimethyltryptamine) is a
Schedule I Controlled Substance, yet plants containing
DMT and B-carbolines are not a controlled substance
internationally or in the USA.
• Federal laws protect the religious use in Canada, the
US, Holland, and Brazil. Two Brazilian churches in the
US have permission to import the plant ingredients
and use ayahuasca in their ceremonies. Ayahuasca is
now part of Peru’s National Cultural Heritage.
• Ayahuasca’s plant components are easily found and
legally sold online.
http://www.deadiversion.usdoj.gov/drug_chem_info/dmt.pdf#search=ayahuasca

Impact on Life
• Members of Un˜iao do Vegetal (UDV) are under the impression long term
use of ayahuasca tea led them to having significant improvements in work,
family, and interpersonal interactions because of their improved mental
and physical health. Many shamans, who have taken ayahuasca several
times weekly their entire lives, have lived much longer than the average
person. This could be due to their diet or health regimen, but most of
them account ayahuasca and UDV as the reason. A study was performed
comparing members of UDV and non-membered controls to analyze the
impact of ayahuasca on one’s life. Only one subject among the controls
had a past psychiatric disorder that was no longer present. However, prior
to membership in the UDV, 11 of the UDV subjects had diagnoses of
alcohol misuse disorders (5 of which also had a history of violent behavior
when binge drinking), 2 had past major depressive disorders, 4 had past
histories of drug misuse (cocaine and amphetamines), 11 were addicted to
tobacco, and 3 had past phobic anxiety disorders. All of their diagnoses
went away once they joined the UDV and began ingesting ayahuasca
regularly.
Bouso JC, González D, Fondevila S, et al. Personality, psychopathology, life attitudes, and neuropsychological performance among ritual users of Ayahuasca: a
longitudinal study. PLoS One. 2012;7(8):e42421.

Investigational New Drug (IND)
Application
• In order to meet the guidelines set forth for an
IND, the preparation of ayahuasca would have
to be a freeze-dried aqueous extract made
into capsules. Although not ‘‘traditional,’’ this
preparation can be more easily standardized
and is likely to have longer term stability than
an aqueous decoction. It will be easier in
capsule form to have a standard amount of
DMT, THH, and harmine.
McKenna DJ. 2004. Clinical investigations of the therapeutic potential of ayahuasca: rationale and regulatory challenges. Pharmacology &
Therapeutics. 102:111–129

Future Predictions/Expectations
• A growing number of people in the US are using
ayahuasca in religious ceremonies and
recreational purposes. There has also been a
large increase of “ayahuasca tourism” in the
Amazon over the past decade. Even so, ayahuasca
is still relatively uncommon and not generally
accepted in society. I predict it will be many,
many years before extensive studies are done to
examine potential medical benefits. Possibly
someday, it won’t be a scheduled drug since it
doesn’t seem to cause harm or addiction. I expect
ayahuasca to continue to grow in appeal.

Butane
Anonymous
March 31,2015

Objectives
• What is Butane?
• Discovery and history of Butane
• Epidemiology
• Methods of inhalation
• Effects of inhalation
• Dangers of use
• Regulations In Maine

What is Butane?1,2
• Colorless
• Faint disagreeable odor
• Considered to be
odorless to some
• Poorly water soluble
• Flammable
http://www.shroomery.org/forums/sho
wflat.php/Number/19371274

Butane1,2
• Used to produce
– Ethylene
– 1,3,-butadiene
• Used as
– Refrigerant
– Aerosol propellant
– Constituent in LPG
• Main component of liquid gas lighter refills

Discovery of Butane3
• Doctor of chemistry with degrees
from Harvard, Yale and George
Washington University
• Worked at the U.S. Bureau of
Mines
• 1911: A motor car owner
complained that the gasoline he
purchased was evaporating rapidly
• Snelling thought it would be
interesting to look into the fumes
that were disappearing
• Snelling determined components
to be butane, propane, and several
hydrocarbons
Dr. Walter O. Snelling

Epidemiology4,5
• Recreational inhalation use spread from United Kingdom to
the United States in 1970
• Males >Women
• Teenagers
– 12-19 years of age
• From any socioeconomic class
– Inexpensive
– Easily accessible
• No personality more vulnerable
• About 10% of those who start become habitual users
– Alcohol
– Drugs

Inhalant Most Common in 12-19 Years
of Age4

Methods Of Inhalation2
• Inhaling from a plastic bag or empty potato
chip bag
– Bagging/Huffing
• Liquids are inhaled from a handkerchief or
plastic bottle
– Huffing
• Lighter fluid refills usually sprayed directly into
the mouth

Effects of Inhalation2
• Onset and recovery rapid
• Small doses lead to
– Euphoria
– Disinhibition
– Delusion
– Hallucinations
– Behavioral disturbances
– Ataxia
– Confusion
• Experienced abusers can maintain a high for over
12 hours by repeated sniffing

Effects of Inhalation2
• Larger doses result in
– CNS depression
• Ataxia
• Nystagmus
• Drowsiness
• Vagal Depression occurs from laryngeal
stimulation from butane or aerosol
propellants being directly sprayed into the
throat

Cardiac Arrhythmias Equal For All
Users 2
• Cardiac arrhythmias account for over half of the
deaths
• Mechanism thought to be sensitization of the
myocardium to adrenaline and sympathetic
stimulation
• Once the arrhythmia has developed victim
becomes resistant to correction
• The risk of sudden arrhythmia remains for several
hours after inhalation
• Any user is at risk

Mechanism Unknown6
• Little is know about the mechanism of action
in the body
• Does not act directly through GABA-mediated
mechanisms
• Psychoactive concentrations inhibit N-methyl-
D-aspartate (NMDA)- sensitive glutamate
channels and neuronal nicotinic acetylcholine
receptor

Metabolism of Volatile Substances7
• Study conducted using mice to determine if
hydrocarbons are metabolized in mice or not
• Mice inhaled various gases such as propane,
n-butane and iso-butane
• Each hydrocarbon was mixed individually with
oxygen
• The animals were exposed to the gases for an
hour and then their organs were examined

Results7
• The in vivo metabolism of blood and organs of
the mice after inhalation for one hour showed
production of methyl ethyl ketones from n-
butane
• Presumed that n-butane first converted to
secondary alcohols and then to ketones by
alcohol dehydrogenase
• The production of these metabolites suggest the
occurrence (𝜔 − 1)-oxidation as the major
pathway

Toxicity1
• Acute toxicity studied in animals
• LC50 for rats 658 mg/L (4h)
• LC50 for dogs ranged from 474 to 592mg/L
• Concentration of 308mg/L caused light
anesthesia in mice within 25 minutes
• Exposure to 521mg/L similar effect after one
minute
• After inhalation, dogs experienced sensitized the
myocardium to epinephrine-induced cardiac
arrhythmias

Butane Among Highest Fatality Rate4

Propellants Highest Rate Of Use
Compared To Other Categories4

Severe Issue in the United Kingdom5
• The Cigarette Lighter Refill (Safety)
Regulations 1999
– Made it an offence to supply cigarette lighter refill
canisters to anyone under the age of 18
• Intoxicating Substances (Supply) Act 1985
– Made it illegal to sell anyone under the age of 18 if
there is any reasonable cause to think that the
substance may be inhaled for intoxication
purposes

§2383-C. Unlawful use or possession
of inhalants8
– 1. Prohibited acts. A person may not intentionally or
knowingly:
• A. Inhale, ingest, apply or smell the gases, vapors or fumes
of any gas, hazardous inhalant, substance containing a
volatile chemical or substance containing a chemical
material capable of releasing toxic vapors or fumes for the
purpose of causing intoxication, euphoria, inebriation,
excitement, stupefaction or the dulling of that person's brain
or nervous system; or [1997, c. 325,§1 (NEW).]
• B. Possess any gas, hazardous inhalant, substance containing
a volatile chemical or substance containing a chemical
material capable of releasing toxic vapors with the intent to
violate paragraph A. [1997, c. 325, §1 (NEW).][ 1997, c.
325, §1 (NEW) .]

§2383-C. Unlawful use or possession
of inhalants8
• 3. Presumption regarding violations. Proof that a person intentionally or knowingly inhaled,
ingested, applied or used a substance in a manner contrary to the directions for use, cautions or
warnings on a label of a container of the substance gives rise to a presumption that the person
violated subsection 1.[ 1997, c. 325, §1 (NEW) .]
• 4. Presumption regarding ingredients. For the purposes of this section, it is presumed that the
ingredients in a container are, in fact, the ingredients listed on a label of the container or the
ingredients listed for that substance in databases maintained or relied upon by a poison control
center certified by a national association of poison control centers.[ 1997, c. 325, §1 (NEW) .]
• 5. Penalties. A person who violates this section commits a civil violation for which a forfeiture,
which may not be suspended except as provided in subsection 6, must be adjudged as follows:
– A. Not less than $100 or more than $300 for the first offense; [1997, c. 325, §1 (NEW).]
– B. Not less than $200 or more than $500 for the 2nd offense; and [1997, c. 325, §1 (NEW).]
– C. Five hundred dollars for the 3rd and each subsequent offense. [1997, c. 325, §1 (NEW).]
• 6. Additional orders. In addition to the civil forfeitures required by subsection 5, the judge may
order the person to perform specified work for the benefit of the State, the municipality or other
public entity or charitable institution or to undergo evaluation, education or treatment with a
licensed social worker or a licensed substance abuse counselor. If the judge orders the person to
perform specified work or to undergo evaluation, education or treatment, the judge may suspend a
forfeiture imposed pursuant to subsection 5.[ 1997, c. 325, §1 (NEW) .]

References
1. Mckee RH, Herron D, Saperstein M, Podhasky P, Hoffman GM, Roberts L. The toxicological
properties of petroleum gases. Int J Toxicol. 2014;33(1 Suppl):28S-51S.
2. Bouche MP, Lambert WE, Van bocxlaer JF, Piette MH, De leenheer AP. Quantitative determination
of n-propane, iso-butane, and n-butane by headspace GC-MS in intoxications by inhalation of
lighter fluid. J Anal Toxicol. 2002;26(1):35-42.
3. LPGA Times. Janurary 1962.
4. Marsolek MR - Pediatrics (2010) Inhalant abuse monitoring trends by using poison control data
1993-2008.pdf
5. Spiller H. Epidemiology of Volatile Substance Abuse(VSA) Cases Reported to US Poison Center. Am
J Drug Alcohol Abuse.2004;30(1):155-165.
6. Ruiz P, Strain EC. The Substance Abuse Handbook. Lippincott Williams & Wilkins; 2014.
7. Tsukamoto et. all Study on the metabolism of volatile hydrocarbons in mice.J. Tox. Sci.
1985;10(1):323-332.
8. §2383-C. Unlawful use or possession of inhalants. Available at:
http://www.mainelegislature.org/legis/statutes/22/title22sec2383-C.html. Accessed March 30,
2015.

Overview of e-Cigarettes
Brian J. Piper, Ph.D., M.S.
School of Pharmacy, Husson
University

Goals
• What is an e-Cigarette?
• History
• Efficacy
• Safety

History
• 1963: Herbert Gilbert patented steam dispensing
product
• 2003: pharmacist Hon Lik invents eCigarette
dispensing nicotine
• 2004: Ruyen begins selling eCigs
• 2010: FDA decides e-Cigs are drug/delivery
devices
• 2012: Cigarette companies in US
get on board
Hon Lik

Components
Cartridge: 150-300 puffs, may contain flavors
Video: http://www.sciencesetavenir.fr/sante/20131007.OBS0070/i-was-sure-that-the-electronic-cigarette-would-be-welcomed-with-open-arms.html

Terminology
• vapor (n): gaseous particles of drugs
• vaping (v): process of inhaling vapor from
personal vaporizer
• vapers (n): people that use e-Cigs
http://www.nytimes.com/2013/06/13/busines
s/e-cigarettes-are-in-vogue-and-at-a-
crossroads.html?pagewanted=all&_r=0

Contents of Cartridge
• Majority
– propylene glycol ( > half)
– glycerin
– nicotine (various levels)
– various flavors
• Trace
– diethylene glycol (0.1% in 1/18 samples)
– tobacco specific nitrosamines
Cahn & Siegel J Public Health Policy 32 (2011) p. 22.

Tobacco Specific Nitrosamines
Cahn & Siegel J Public Health Policy 32 (2011) p. 22.

Relevant?
• Formaldehyde = carcinogen
• 4 sec
• distribution?
Jensen et al. New Engl J Med 372 (2015) 392-393.

Nicotine Poisonings
• Possible in theory (>500 mg can be fatal)
• Case 1.1: 36 year-old women drinks 20 ml (18 mg), no
symptoms
• Case 1.2: same women drinks 50 ml of 30 mg/ml (1500 mg),
nausea, abdominal pain, vomiting
• Case 2: 13 year-old boy drinks 3 ml, nausea & shivering
Christensen et al. Clinical Toxicology (2013) Cantrall J Community Health 51 (2013) 290-291.

Rare Case Reports
• 1: Atlanta women has fire from her E-hit
• 2: 18 year-old UK woman escapes injury
• 3: 3 year-old Utah boy car-seat catches fire from White-Rhino mishap
http://www.nydailynews.com/news/national/boy-burned-mom-charging-e-cigarette-explodes-article-1.1465767

Rare Case Reports
• 4: Florida man has battery explode, teeth/tongue damage
• 5: UK man suffers leg injuries
• 6: 62 year-old UK man dies following explosion that ignited his oxygen

Adverse Events
• Nicotine increases heart-rate and blood
pressure.
• E-Cig adverse effects are likely due to inhaling
propylene glycol but are transient in
small/short-term studies.

Adverse Events (N = 40)
Coponnetto et al. Exp Rev Respir Med 2012: 6(1):63-74.

Do e-Cigs reduce craving?
• Smokers (1 ppd, age 48, N= 40) that had not
smoked for 12 hours received electronic nicotine
delivery device (ENDD, 16 or 0 mg) or usual
cigarette
• self-report
Bullen Tobacco Control 19 (2010) 98-103.

What is the PK profile for e-Cigs
• Smokers (1 ppd, age 48, N= 40) that had not
smoked for 12 hours were received electronic
nicotine delivery device (ENDD, 16 or 0 mg) or
usual cigarette
Bullen et al. Tobacco Control 19 (2010) 98-103.
Cigarette e-Cigarette
Tmax (min) 14.3 19.6
Cmax (ng/ml) 13.4* 1.3
* p < .05
N = 9

Do e-Cigs aid smoking cessation?
Nicotine Replacement Studies e-Cigarette Studies
# RCTs many 2 (many ongoing)
psychological support high low
participants exclude mentally ill naturalistic
1 year abstinence doubled (20% vs 10%) ?

• Superiority trial of adults (age = 40s, 18
cig/day). Participants randomized (4:4:1) to:
– Elution e-Cig (“placebo”: 0 mg/ml nicotine)
– Elution e-Cig (16 mg/ml nicotine)
– nicotine patch (21 mg/24 hours)
Bullen et al. Lancet 382 (2013) 1629-1637.

e-Cig (16 mg)
(N = 289)
e-Cig (0 mg)
(N=295)
Nicotine Patch
(N=77)
use of psychological support 40% 36% 36%
use of study product at 3 months 51% 53% 18%
drop-out of study 17% 27% 22%
smoking abstinence at 6 months
days to relapse
recommend product to friend

e-Cig (16 mg)
(N = 289)
e-Cig (0 mg)
(N=295)
Nicotine Patch
(N=77)
use of psychological support 40% 36% 36%
use of study product at 3 months 51% 53% 18%
drop-out of study 17% 27% 22%
smoking abstinence at 6 months 7.3% 4.1% 5.8%
days to relapse 35* 12 14
recommend product to friend 85%* 88%* 50%
* p < .05 versus patch

Do e-Cigs aid in smoking reduction?
• Smokers (N = 300), not planning to quit,
randomized to:
Caponotto et al. (2013) PLoS One 8(6): e66317.

• Study completion rates:
– A (7.2/7.2 nic): 65%
– B (7.2/5.4 nic): 63%
– C (0 nic): 55%

• One-year smoking cessation rates (not significant but … )
– A (7.2/7.2 nic): 13%
– B (7.2/5.4 nic): 9%
– C (0 nic): 4%
-----------------------------------------------------

Center’s for Disease Control (2013). Morbidity Mortality Weekly Report 62(35), 729-730.

Comparison
Pros Cons
Less adverse health consequences Renormalizing taboo behavior; long-
term safety of inhaled propylene glycol
vapor?
No second-hand smoke Second-hand mist contains nicotine
Pharmacokinetics mimics smoking Requires practice, lower Cmax
Replicates motor pattern of smoking Heavier than cigarette
Relieves withdrawal and craving Reinforcing/addictive
Cleaner Disposal of cartridge and batteries, some
flavors linger in air
Readily available Limited quality control on nicotine
concentration. Contaminants?
Modified from Polosa et al. Harm Reduction Journal 10: 19.

Summary
• E-cigs, relative to traditional cigarettes, have
the potential for substantial harm reduction.
• Based on limited and short-term evidence,
adverse effects appear minimal. Inconsistency
in manufacture is a concern.
• E-cigs appear as (in)effective as NRT in
smoking cessation.
• 1.8 million middle-and high-school students in
U.S. tried e-Cigs in 2012.
http://video.foxnews.com/v/3093455571001/are-e-cigarettes-any-healthier-for-you/#sp=show-clips

Key References
• C Bullen, H McRobbie, S Thornley, M Glover, R Rin, & M Lausgen, Effect of an
electronic nicotine delivery device (e cigarette) on desire to smoke and
withdrawal, user preferences, and nicotine delivery: Randomized cross-over
trial. Tobacco Control 19 (2010) 98-103.
• Z Cahn, M Siegel, Electronic cigarette as a harm reduction strategy for tobacco
control: A step forward or a repeat of past mistakes. J Public Health Policy 32
(2011) 16-31.
• FL Cantrall, Adverse effects of e-Cigarette exposures. J Community Health
(2013) in press.

Ethical, Legal Questions+
• What limitations on sales (18, 21?) are warranted?
• Should bans on smoking in public places, outdoor
and indoor, also apply to e-Cigs?
• Should restrictions on advertising (e.g. movies)
also apply to e-Cigs?
• How will they be taxed?
• What is the safety of e-Cigs during pregnancy?
• What other drugs (THC, morphine) can be
administered using this technology?

Self-Test
• T/F: The nicotine Cmax is equivalent following
cigarette and the e-Cig administration.

Hookah Smoking
By: Jeremy Bishop

Objectives
 History & background
 Epidemiology
 Social views
 Health effects
 Pharmacodynamics
 Pharmacokinetics
 Cessation
 Legal issues

Commonly Known As
 Hookah
 Shisha
 Sheesha
 Waterpipe
 Narghile
 Hubble Bubble

History
 Originated in Persia and India
 16
th
century
 Created as less harmful tobacco intake
 Middle east and parts of Asia
 Status symbol in 19
th
century
 Moved into Europe followed by Americas
 Hookah bars and cafes

Background
 Maassel
 Flavored or sweetened
 Heated by coals
 Hose from base to smoker
 Smoke enters base with water
 Smoke passes through water
bubbles then through hose to
smoker

Epidemiology
 Estimated 100 million daily users worldwide
 Most common in middle eastern and asian populations
 Growing use in UK, and United States
 Mostly teens and college students
 Some colleges have hookah clubs
 3
rd
most common source of tobacco (NYTS 2012)
 Low interest in quitting

Societal Views
 Less harmful than other tobacco forms
 Water bubbles remove harmful substances from smoke
 Cafes and bars for consumption
 Factors to increased use:
 Flavored tobacco
 Availability
 Social media
 Lack of policies and
regulations

Health Effects
 Associated with increase risk of:
 Lung cancer
 Altered pulmonary function
 Coronary heart disease
 Arteriosclerosis
 Fetal effects
 Infections
 Second hand smoke

Comparison to Cigarettes
 Frequency
 Multiple cigarettes daily vs. occasional hookah session
 1 hr session > 100-200x smoke volume of one cigarette
 1 hr session daily equates to ~half to whole pack of
cigarettes daily
 At least as harmful as cigarettes
 Contains nicotine, tar, NO, PAH, nitrosamines,
heavy metals, and volatile organic compounds

*p < 0.05.
change
(bpm) Mean
systolic
change
(mmHg)
Mean
diastolic
change
(mmHg) MAP
change
(mmHg)
Mean carbon
monoxide
change (ppm)
Shisha 14* 15* 10* 12* 32*
Cigarettes 23* 12* 4* 7* 10*
Mean value before
smoking shisha
(standard deviation)
Mean value after
smoking shisha
(standard deviation)
Mean change
(95% confidence
interval)
Systolic blood pressure
(mmHg)
129 (12) 144 (16) 15 (11-19) *
Diastolic blood pressure
(mmHg)
80 (8) 90 (14) 10 (6-12) *
Mean arterial blood
pressure (mmHg)
96 (8) 108 (13) 12 (8-14) *
Heart rate (bpm) 77 (8) 91 (11) 14 (12-16) *
Carbon monoxide (ppm) 3 (2) 35 (17) 32 (27-36) *
*p < 0.0001.

Pharmacokinetics
 Rapidly absorbed into
lungs
 Bioavailability ~ 8%
 Peak concentration ~ 45
mins
 TSNA
 Peak concentration – 5-
20 pg/mL
 T1/2 – 10-18 days
 Increased levels of:
 Tar (100 fold)
 Nicotine (4 fold)
 CO (11 fold)
 PAHs (2-5 fold)
 CYP450 interactions
 CYP1A1/2 induction
 CYP2E1,
CYP2A1/2 and
CYP2B1/2 Induction

Pharmacodynamics
 Nicotine:
 Binds nicotinic cholinergic receptors
 Releases neurotransmitters (dopamine)
 Desensitization / Tolerance
 Withdrawal:
 Increase release of Corticotropin releasing factor
 Decreased dopamine activity

Cessation
 None targeting hookah smoking
 Treat similar to cigarette addiction
 Nicotine replacement therapy

Legal side
 Cigarettes or smokeless tobacco sale laws
 Does not include tobacco used for a hookah
 Allows selling to anyone
 Flavoring
 Smoke free laws

References
 Aljarrah, K et al. Perceptions of hookah smoking harmfulness: predictors and
characteristics among current hookah users. Tob Induc Dis.. 2009; 5: 16.
 Griffiths, M et al. Hubble Bubble Trouble: The Need for Education About and
Regulation of Hookah Smoking. Journal of Public Policy & Marketing: Spring 2011,
Vol. 30, No. 1, pp. 119-132.
 Jacob, P et al. Comparison of Nicotine and Carcinogen Exposure with Water
pipe and Cigarette Smoking. Cancer Epidemiol Biomarkers Prev. 2013 May;
22(5): 765–772.
 Jacob, P et al. Nicotine, Carbon Monoxide, and Carcinogen Exposure after a
Single Use of a Waterpipe. Cancer Epidemiol Biomarkers Prev. 2011 Nov;
20(11): 2345–2353.
 Kadhum, M. Measuring the acute cardiovascular effects of shisha smoking: a
cross-sectional study. JRSM Open. 5(6): 1–7.
 Kumar, S et al. A review of air quality, biological indicators and health effects of
second-hand waterpipe smoke exposure. Tob Control. 2015; 24: 54-59.
 Noonan, D. Kulbok, P. New tobacco trends: Waterpipe (hookah) smoking and
implications for healthcare providers. J Am Acad Nurse Pract.. 2009; 21: 258–
260.

References
 Maziak, W et al. Interventions for waterpipe smoking cessation. Cochrane
Database Syst Rev. 2007 Oct 17;(4).
 Maziak, W et al. The global epidemiology of waterpipe smoking. Tob Control.
Published Online First: September 2014. doi:10.1136/tobaccocontrol-2014-
051903.
 Sameer-ur-Rehman, et al. Cross-sectional study identifying forms of tobacco
used by Shisha smokers in Pakistan. J Pak Med Assoc. 2012; 62: 192.
 Shihadeh, A et al. Toxicant content, physical properties and biological activity
of waterpipe tobacco smoke and its tobacco free alternatives. Tob control.
2015; 24: 22-30.
 Shishani, K et al. Hookah Use: Going Down in Smoke. J Addict Nurs. 2012; 23:
112–115.
 Tobacco control legal consortium. Regulatory Options for Hookahs & Water
Pipes. 2013 Feb; 7.
 Zevin, S. Benowitz, N. Drug interactions with tobacco smoking. An update.
Clin Pharmacokinet. 1999 Jun; 36(6): 425-38.

HU-210
Kaitlin Kelley & Shannon Mockler

Objectives
• Introduction
– Overview
– AKA
– Package Contents
• History
• Epidemiology
• Toxicology
• Social status
• Health issues
• Future predictions
http://sobercollege.com/2014/synt
hetic-cannabinoids/
http://theconversation.com/legal-highs-what-should-we-do-about-synthetic-
cannabis-10386

Introduction and Overview
• Synthetic cannabinoid
• Combined with JWH-018 and CP-47,497 to formulate
Spice/K2
• Belongs to the same chemical class as Δ9-
tetrahydrocannabinol (THC), which is the primary
constituent in marijuana

Also known as…..
• K2
• Spice
• Yukon Gold
• Mr. Nice Guy
• Earthquake
• Genie
• Black Mamba
• K3
• K3 Legal
• Red X Dawn
• Stinger
• Skunk
• Pulse
• Spice Silver
• And the list goes on...

Contents
http://www.emcdda.europa.eu/attachements.cfm/att_80086_EN_Spice%20Thematic%20paper%20—%20final%20version.pdf

History
Dr. Raphael Mechoulam
“Father of Marijuana Research”
First synthesized: 1988- Hebrew University, Israel

History
• First documented sale was on the internet in
2004
• March 2009- First identification of HU-210 in
Spice in the United States
– DEA seizure of a shipment of Spice
• June 2009- First identification of HU-210 in Spice
products in the United Kingdom
http://www.pictures4cool.com/american-flag.html https://studentaffairs.duke.edu/blog-entry/flag-week-united-kingdom

History
http://journal.frontiersin.org/article/10.3389/fnbeh.2011.00060/full

Legal Activity
• Schedule I drug
– Austria, Germany, the Netherlands, Switzerland,
Canada, UK, & USA
– HU210 was placed in the Schedule I category,
because out of the ingredients in Spice, it is the most
similar to THC
• France, Hungary, Luxembourg, Poland, Lithuania, and
Sweden have taken legal actions to ban “Spice” products
and related compounds
http://www.clker.com/clipart-77690.html
http://www.stanleysautobody.com/your-legal-rights.php

Global Drug Survey 2014
http://www.globaldrugsurvey.com/facts-figures/the-global-drug-survey-2014-findings/

Epidemiology
• 2011, unpaid, online-based anonymous survey
– Recruitment:
• drug forums & message boards aimed at Spice
products
• Questions about demographic information & Spice use
– frequency of use
– age of first use
– safety of use
– source
– effects

Epidemiology (continued)
• 168 participants from over a dozen countries and
all but 8 of the U.S states
• Demographics
– Caucasian (90%),
– male (83%)
– never been married (67%)
• Education
• (96%) high school education
• (48%) had received college degrees

Epidemiology (continued)
• Acquisition-
– (87%) shops (gas stations, head shops,
convenience store)
– (38%) internet
– (29%) friends/family
• Majority polysubstance users (both legal and illegal)
• Students don’t see the harm in using synthetic
cannabinoids

Pharmacokinetics
• Largely unknown
• Bioavailability
– oral and inhalation= degree is unknown
• Duration of action much longer than that of Δ9-THC
– 24 hours compared to less than 5 hours
• LD 50
– mouse- 300 mg/kg
– rat- 980 mg/kg
– rabbit- 3200 mg/kg

Pharmacodynamics
• CB1 receptor agonist activity
• Mild CB2 receptor activity
• CB receptors activate many intracellular signal
transduction pathways
– inhibition of ion channels
– the mobilization of arachidonic acid
– attenuation of cAMP
• HU-210 is lipophilic → cross BBB & more potent than
Δ9-THC at binding to the CB1 receptor

Pharmacodynamics (cont’d)
• HU-210 regulates Ca2+ channel
– important in controlling the activity of numerous
enzymes
• Possible consequence of note
– interference in various Ca2+-dependent
processes, like the synthesis of nitric oxide
synthase (NOS)
– inhibition of NOS plays a role in the effects of
HU-210 on brain function

Toxicology
• Mostly unknown
• Increased report of death and exposure due to Spice use
has become a “significant public health concern”
• Poison control centers around the U.S. reported an
exponential increase in calls due to Spice exposure
– Over 6,000 calls for assistance in 2011, compared to
2 years prior in 2009 where there were only 53

Methods of use
• #1 method = rolled in papers & smoked like
marijuana
• Other methods include:
– smoked in a pipe
– steeping the ‘herbs’ in tea
http://www.marijuanaalternatives.com/rollingpap
ers.htm

Clinical Presentations
• Most return to normal after 2-4 hours
• Majority of cases presented with:
– Altered mental status
• Seizures
• Hallucinations
• Expression of vivid dreams
• Anxiety
– Tachycardia
https://www.healthtap.com/topics/tactile-

“The Spice Girls”
● 2 women- early twenties
● “Banana Cream Nuke”
○ Purchased at a local shop-
$30
○ “Not for human
consumption”
● Patient #1- anxious, trembly,
irregular heart beat - no actual
physical abnormalities
● Patient #2- “psychotic” -
refused exam

“50 Shades of Grey”
• 19 year old woman was brought to the ED after
reportedly having a seizure while smoking with friends
• Paramedics arrived she was awake
– agitated and required physical restraints
• Physical examination
– Elevated BP, RR, and P
• Urine drug screen-negative drugs
http://www.medpagetoday.com/Geriatrics/GeneralGeria
trics/32850

“The Gold Mine”
• 17 yo male- brought into ED by parents- “dangerous
behaviors” & jerking motions
• “Humboldt Gold”
• Symptoms
– agitation
– hallucinations
• Physical exam
– tachycardia, BP, dilated pupils, flushed skin
• Neurological exam
– hyperreflexia w/o clonus
http://humboldtsentinel.com/?s=cannabinoids&x=0&y=0

“For Hire”
• Germany 2009
• 20 year old male; polysubstance user
• Threatened with losing his job
• Admits to smoking 1g/day for 8 mo, which increased
rapidly to 3g/day of Spice per day
• Forced abstinence (2 days) due to shortages in supply →
Symptoms began (internal unrest, tremors,
palpitations…)
• “Did not feel confident” in stopping the use on his own
→ PCP prescribed zopiclone

“So Frothy”
• 19 yo male- possible seizure
• Screaming, swinging fists & frightened
• Reported seizure-like activity, followed by foaming at
the mouth, cyanosis, & unresponsiveness
• Physical exam prior to ED arrival
– very rapid pulse (220 bpm)
• Physical exam upon ED arrival
– pulse dropped slightly to 180 bpm
– drowsy
http://genius.com/2195164/President-barack-obama-address-to-the-nation-on-syria/Others-foaming-at-the-mouth-gasping-for-breath

“Fainting Goat”
• 24 yo male
• Presented to the ED with chest pain, nausea, vomiting,
and syncope twenty minutes after smoking 3 grams of
K2
• At the ED
– anxious
– vital signs- P of 95 BPM
• Physical exam was unremarkable

Health and other issues
• Synthetic cannabinoid receptor agonists are becoming
increasingly popular with adolescents.
• Teens and young adults are presenting to the ED with
effects of smoking “Spice”.
• Chronic use of this drug can cause addiction syndrome
and withdrawal symptoms similar to cannabis

Social/Life Implications

HU-210 in the future
• Synthetic cannabinoid mixtures are still available online
• Manufacturers are continuously making slight structural
changes to evade legal action
• Concern about blanket legislation made against these
compounds is mounting
• Over-regulation of synthetic cannabinoids = slow
development of new drugs & over the counter products
for medicinal use

Conclusion & Summary
Video: https://www.youtube.com/watch?v=Yw2bZx7FUuc
• CB1 receptor
• Schedule I
• More potent and longer duration of action than Δ9-THC
(24 hours vs 5 hours)
• Feelings with use are not calm and relaxing like natural,
but of anxiety and discomfort

Resources
• Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. Synthetic cannabinoids:
Epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depen. 2014;1-30.
• Devane W, Breuer A, Sheskin T, Jaerbe T, Eisen M, & Mechoulam R. J Med Chem. 1992;35(11):2065-
2069.
• Hruba L, McMahon LR. The cannabinoid agonist HU-210: Pseudo-irreversible discriminative stimulus
effects in rhesus monkeys. Eur J Pharmacol. 2014;727:35-42.
• Jiang W, Zhang Y, Xiao L, et al. Cannabinoids promote embryonic and adult hippocampus neurogenesis
and produce anxiolytic- and antidepressant-like effects. J Clin Invest. 2005;115(11):3104-3116.
• Johnston, L. D., O'Malley, P. M., Miech, R.A., Bachman, J. G., & Schulenberg, J. E. . Monitoring the
Future national results on adolescent drug use: Overview of key findings, 2014. 2015.
• Ottani A & Giuliani D. HU 210: A potent tool for investigations of the cannabinoid system. CNS Drug
Review. 2001;7(2):131-145.
• Schneir AB, Cullen J, & Ly BT. “Spice” girls: Synthetic cannabinoid intoxication. J Emerg Med.
2011;40(3):296-299.
• Slipetz DM, O’Neill GP, Favreau L, et al. Activation of the human peripheral cannabinoid receptor results
in inhibition of adenylyl cyclase. Mol Pharmocol. 1995;48:352-61.

RX462: Drug Abuse and Society
Kris Ravin
Ketamine

“Ketamine Tiger” by Marisa Wood Bassett

• History
• Notable People
• Epidemiology
• Ketamine in Medicine and Society
• Laws
• Interactions
• Toxicology
Outline

• 1958: Phencyclidine (PCP) was introduced as an agent for
clinical anesthesia by Parke Davis.
• Problems with this drug arose due to patients experiencing
manic episodes with hallucinations and delirium.
• Dr. Gottlieb, an affiliate of Parke Davis, proposed further
studies into PCP in creating a model for schizophrenia.
• 1959: Work on creating PCP analogs to reduce manic episodes
and to create a more successful anesthetic began but were
initially unsuccessful.
History1

• 1962: Calvin Lee Stevens, began synthesizing a series of PCP
derivatives in hopes of creating a better anesthetic agent.
• One chemical, CI-581, was found to have reduced half life and
delirium on monkey models. It was then submitted for human
clinical trials.
• August 3rd, 1964: Ketamine human trials began. Studies were
conducted on human prisoners.
• The first administration of ketamine was by anesthesiologist,
Guenter Corssen.
History1

• 1970-Ketamine was approved by
the FDA.
• Following its approval, Ketamine
was used in the Vietnam War as an
anesthetic and an analgesic.
• Concerns rose about the delirium
that occurred during the drug’s use.
• Late 1970s: Dr. Elmer Zsigmond and
Dr. Edward F. Domino found that the
used of benzodiazepines
suppressed the delirious effects of
ketamine.
History1

• Late 1970s: Abuse of
ketamine first started
appearing on the
West Coast of the US.
• Early 1980s: Abuse
became common in
the US in many
subcultures including
the “New Age
spiritualists.”
History of Abuse1,2

• Mid 1980s: The drug
became popular in
the dance music
culture when it was
used as a cutting
agent in ecstasy
tablets.
• 1990s: Reports in the
UK of club goers
ingesting ketamine
thinking it was
MDMA.
History of Abuse

• A physician, neuroscientist, psychoanalyst, and “psychonaut”
• Wrote many books on human-dolphin communication
• Attempted to develop a computer system, JANUS, that would allow human-
dolphin communication.
• Created the isolation tank.
• He was also an avid ketamine and LSD user.
• Wrote the book “The Scientist” about his experiences.
John C. Lilly1

• A yoga teacher, was married to a highly respected clinical
anesthesiologist, Howard Alltounian.
• Fell in love on their experience tripping on ketamine together and
became married after a week.
• Together, they wrote the book “Journeys into the Bright World”
about their experiences.
Marcia Moore1

• Monitoring the Future has conducted research
into the use of ketamine among 8th, 10th, and
12th graders in the US.
• They have not looked at the disapproval rating
or the availability of ketamine in their surveys.
Monitoring the Future3
2000 2002 2011
8th Graders 1.6% 1.3% 0.8%
10th Graders 2.1% 2.1% 1.2%
12th Graders 2.5% 2.5% 1.7%
Percent of students claiming they have tried ketamine

• Tracking of ketamine use in the world has been very limited.
• The WHO sent a questionnaire to 74 countries:
– 20 countries reported ketamine was abused
– 21 countries said that it was not abused
– 2 countries claimed they suspected abuse
• Tracking of ketamine use in the United States in the data sent to the
WHO was based off of the Monitoring the Future results.
World Health Organization (WHO)4

• The most complete data submitted to the WHO was from
Australia’s “Illicit Drug Reporting System”
• Australia reported that use of 0.3% in ages 14 and over.
• They also found that 2/3rds of this population was male.
• Australia extensively monitors drugs associated with the
electronic dance music culture.
World Health Organization (WHO)4

• Ketamine is common in the electronic dance music drug culture
along with MDMA, GHB, and LSD.
• The drug scene of the electronic music derives from the desire to
increase sensation affiliated with auditory and visual stimulation.
• 1980s in the US
• 1990s in the UK
• Ketamine is sold on the drug market under the names: “K”, “Special
K”, “Kats”, “Queso”
Ketamine in the Electronic Dance
Music Culture2,4,5

• Ketamine is a Schedule III substance in the United States.
• The US Department of Justice claims the majority of the
ketamine that is in the illegal market is smuggled in from
Mexico.
• The major distributers are Caucasian males between the ages
of 17 and 25.
Legal Aspects5

• Ketamine was a revolutionary anesthetic
agent upon its introduction as a replacement
for PCP.
• Today it is the most commonly used pediatric
anesthetic due to its safety profile.
• It is also a very common anesthetic in
veterinary medicine.
• It has found efficacy in reducing post
operative pain.
Ketamine in Medicine6

Ketamine is currently being research as treatment
for “treatment-resistant depression.”
• One study looked at 18 patients with depression
who were resistant to typical methods of treating
depression.
• They were given a sub-anesthetic dose
(o.5mg/kg).
• 12 of these patients had 50% reduction in
depression scores lasting, on average, 2 weeks.
Ketamine in Resistant Depression6

• Ketamine is manufactured as Ketamine HCl in a
solution.
• In a clinical setting, ketamine is given through IV
or IM administration.
• Recreationally, the ketamine solution is usually
evaporated into a dry crystal form.
• It is most commonly consumed through nasal
insufflation.
• It is also formulated into tablets or capsules and
taken through oral route or smoked in its dry
powder form.
Routes of Administration4

• Surgical Anesthesia:
IV: 2 mg/kg body weight over 60 seconds
IM: 10 mg/kg body weight
• Through IV administration, a response is seen
in 60 seconds and lasts 5 to 10 minutes
• Through IM administration, a response is seen
in 3 to 4 minutes and lasts 12 to 25 minutes
Dose4

• Recreational use:
A line of Ketamine is usually between 60 and 250 mg
• Analgesia
Analgesia can be obtained at a dose of 0.2 to 0.75 mg/kg
• Bioavailability:
Intranasal route: 50% absorbed
IM: 93% absorbed
IV: 100% absorbed
Dose4,8

• Ketamine is highly lipid soluble.
• Only 12% of ketamine becomes bound to
plasma proteins.
• The concentration of Ketamine in the tissues is
4 to 5 times that of the tissues.
• Rapid transport across the BBB through the
transcellular lipophilic pathway.
Distribution

• Ketamine is
metabolized in the liver.
• It is converted into the
active metabolite
Norketamine.
• Norketamine has 33%
affinity of ketamine to
the NMDA receptor.
Metabolism7

• T1/2 = 2.5 hours
• 90% of ketamine is excreted in the urine
• 2-4% excreted is not metabolized.
• Clearance is about 15 mL/min/kg
Elimination7,8

• Ketamine is a non-competitive antagonist of the NMDA receptor.
• It binds to the PCP-binding site.
• Ketamine is supplied as a racemic mixture of two enantiomers
-S-Ketamine
-R-Ketamine
• The “S” enantiomer has 3 to 4 times the affinity for the PCP binding
site of the NMDA channel than the “R” enantiomer.
NMDA Receptor4,6

• NMDA receptors are associated with sensory input in the thalamic, limbic
and cortical levels.
• By inhibiting these receptors, ketamine is able to create a dissociative
feeling.
• This also produces visual disturbances, loss of spatial awareness, and loss
in ability to create memory or process emotions.
Thalamo-neocortical Limbic
Inhibition4,6

• Ketamine also acts as a partial agonist of the mu-opioid
receptor.
• This is important in ketamine’s analgesic properties at
subanesthetic doses.
• Norketamine, ketamine’s major metabolite is important in
ketamine’s interaction with the mu-opioid receptor.
• Ketamine also acts as an agonist on the alpha and beta
adrenergic receptors.
Mu-Opioid Receptor4,6

• The interaction between the NMDA receptor and the mu-Opioid
receptor is an important mechanism in the development of opioid
addiction and withdrawal symptoms.
• Ketamine, as well as other NMDA antagonists, has shown to reduce
the development of morphine addiction and withdrawals in mice
models.
Ketamine and Opioid Adiction4,6

• The addictive nature of ketamine is likely due to its action on the
nucleus accumbens.
• Ketamine has the ability to mobilize dopamine vesicles to the site of
release in the Nucleus accumbens.
• Rat studies have shown an initial increase in the release of
dopamine in the nucleus accumbens by up to 5x the normal release.
• In addition to this mechanisms influence on addiction, it may also
play a role in the euphoria and psychotropic effects of ketamine.
Nucleus Accumbens4,6

• Frequent abusers of ketamine have been found to have a
rapid increase in dose to achieve desire effects.
• Some users have seen an increase in dose by 600% from their
first time using ketamine to their current dosing.
• This increase can be attributed to
– decrease in receptor binding affinity
– increase in liver enzymes
Ketamine Tolerance6

• There is currently no specific data on withdrawal symptoms in
ketamine abusers.
• There have been reports on observed symptoms which
include.
– Cravings (major symptom seen)
– Anxiety
– Shaking
– Sweating
– Heart palpitations
Withdrawals4,6

• Ketamine causes an increase in BP so drugs such as amphetamines
and cocaine which increase BP should not be taken.
– Levothyroxine has also found to increase BP synergistically with
ketamine.
• Ketamine causes respiratory depression, depressants such as
opioids, alcohol, H1 antagonists, and muscle relaxers when
administered with ketamine can cause dangerous respiratory
depression.
• Hallucinogenic effect of ketamine can be amplified by other
hallucinogenic agents such as LSD, marijuanna, and psilocybin.
• Benzodiazepines are found to prolong the half-life of ketamine.
• Barbiturates are incompatible with ketamine and can form a
precipitate when administered in the same syringe.
Interactions7

• In adult mice, the LD50 is 224 +/- 4mg/kg
• In adult rats, the LD50 is 229 +/- 5 mg/kg
• These doses are about 10x the anesthetic
dose of ketamine.
LD504

• Death usually occurs from polysubstance use rather than
ketamine alone.
• Drugs that have respiratory depressive effects such as opioids,
alcohol, barbituates, and benzodiazepines, administered with
ketamine can result in insufficient oxygen intake.
• Drugs with cardio-stimulating effects such as amphetamines
and cocaine in combination with ketamine can synergistically
increase heart rate.
Death From Ketamine9

• Ketamine’s antagonist abilities on the NMDA receptors of the
thalamo-neocortical and limbic systems cuts off the afferent
signaling from sensory organs producing a sense of
“disconnection” from the body.
• When in this state ketamine users lose perception of their
surroundings and enter a “trance-like” state.
• This experience is termed by ketamine users as a “K-hole”
K-Hole4,9

• Chronic users have been found to develop ulcerative cystitis.
• This results in thickening of the bladder, reduced bladder
capacity, and sever inflammation.
• Users experience frequent urination and hematuria.
Bladder Complications6

• High dose ketamine
users can develop
hydronephrosis(water
in the kidney).
• Some users can also
develop necrosis of the
dermis layer of the
kidneys.
Kidney Dysfunction6

• Abdominal pain, termed “K-cramps”, have
been noted by users.
• This is likely due to oral consumption of
ketamine or through “post-nasal drip” after
nasal administration.
GI Problems9

• Frequent ketamine users experience short and
long term memory loss.
• Other complication include problems with
spatial memory, visual recognition, language,
and “jolt” or “shock” sensations when moving
their eyes.
• These complications are mostly reversible
when the drug is no longer abused.
Cognitive Impairment9

• Ketamine is not assigned to a pregnancy category by the FDA.
It is considered clinically safe for use during pregnancy, labor,
and during deliver.
• Ketamine is not considered a teratogen alone.
• In CF-1 mice ketamine has been shown to increase the
teratogenic effects of cocaine.
• Mice were given 50 mg/kg/day of ketamine and 20
mg/kg/day.
Pregnancy4,8

• Unlike opioids and benzodiazepines, there is no reversible drug to
treat ketamine intoxication.
• Cases where the patient is experiencing severe respiratory
depression, a bag mask is used.
• If the patient is salivating excessively, atropine can be used.
• Patients experiencing high levels of anxiety can be treated with
benzodiazepines.
• Patients should be removed from areas of excessive auditory and
visual stimulation.
• Anti psychotics SHOULD NOT be used.
Treating Ketamine Intoxication10

• 1. Domino EF, Taming the Ketamine Tiger. Anesthesiology 2010;113(3):678-684.
doi: 10.1097/ALN.0b013e3181ed09a2.
• 2. Center for Substance Abuse Research Available at:
http://www.cesar.umd.edu/cesar/drugs/ketamine.asp. Accessed March 22, 2015.
• 3. Monitoring the Future: National Results on Adolescent Drug Use 2011. Available
at: http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2011.
Accessed March 22, 2015.
• 4.World Health Organization. Critical Review of Ketamine. Available at:
http://www.who.int/medicines/areas/quality_safety/4.3KetamineCritReview.
Accessed March 22, 2015.
• 5.US Department of Justice. Intelligence Bulletin: Ketamine. Available at:
http://www.justice.gov/archive/ndic/pubs10/10255/10255p. Accessed March 22,
2015.
Work Cited

• 6. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical
experience. Can J Anaesth. 1989;36(2):186-97.
• 7.Medsafe. Ketalar. Available at:
http://www.medsafe.govt.nz/Profs/Datasheet/k/ketalar100mginj. Accessed March
22, 2015.
• 8. Clinical Pharmacology. Ketamine Monograph. Available at:
http://www.clinicalpharmacology-
ip.com/Forms/drugoptions.aspx?cpnum=333&n=Ketamine&t=0. Accessed March
22, 2015.
• 9. Kalsi SS, Wood DM, Dargan PI. The epidemiology and patterns of acute and
chronic toxicity associated with recreational ketamine use. Emerg Health Threats J.
2011;4:7107.
• 10. Up toDate. Ketamine Poisoning. Available at:
http://www.uptodate.com/contents/ketamine-
poisoning?source=search_result&search=ketamine
intoxication&selectedTitle=1~8. Accessed March 22, 2015.

Kratom:
Mitragyna speciosa
Anonymous
Husson University
Pharm.D. 2016
http://commons.wikimedia.org/wiki/File:Young_Kratom
_Tree.JPG

Objectives:
• Learn the basic characteristics of
the drug
• Review the history of kratom use
• Understand the epidemiology
associated with kratom use
• Elaborate on the
pharmacodynamics and
pharmacokinetics
• Learn about modern uses of the
drug
• Review the safety profile and
potential concerns
http://www.mrniceguystl.com/blog/2014/12/22/got-
kratom

So What is Kratom?1,2
• Indigenous plant
from Southeast Asia
– Mitragyna speciosa
– Rubiaceae family
– Malaysia, Thailand
• Effects:
– Energizing
– Pain Relief
– Psychostimulant
– Opiate-like
• Alkaloids
– Mitragynine
– 7-hydroxymitragynine
• Least abundant, more potent
analgesic
http://www.marijuanaseedsavings.com/making-kratom-tea.html

Different Kratom Options
http://kratomonline.org/az/most-potent-
kratom/
http://kratompowders.org/kratom-
tinctures/
http://www.thistexanwife.c
om/
http://livehardplayharder.com/2015/03/12/what-is-
kratom/

Kratom History2,3
• Reports of kratom use dates back to a time
between the 1800 and 1900s
• Earliest report:
– 1836, Malaysia
– Opium substitute
• 1900s:
– Opium addiction
treatment in Malaysia
and Thailand
– Replaced morphine in
treatment programs
– “..weaker effects…
shorter duration..”
• Malaysian and Thai Natives
would chew the leaves to
improve their tolerance to work
under the hot sun
• Other reported historical
benefits include:
– Analgesia
– Antidiarrheal
– Antitussive
– Stimulant

The Beginning of an End4
• Thai citizens were utilizing kratom as an alternative to
opium
• At the time, opium was taxed by the government
• Thailand illegalized the use of kratom on August 23,
1943
– Kratom Act 2486
– Required that no new trees be planted
– Required all existing trees to be cut down
• Malaysia followed suit, 60 years later in 2003

Legality in the U.S.2
• Currently not illegal, federally
• Classified as an “herbal product”
• In 2010, the DEA placed kratom
on its “Drugs and Chemicals of
Concern” list
• This list makes it known that the
substance is not approved for any
medical condition and is not to be
advertised as such

Legalization by State8
• Red: kratom is illegal
– Note: kratom is illegal
in Ohio
• Orange: pending legislature
• Yellow: legislature that has
been amended to save kratom
(IL – kratom cannot be sold to
or possessed by minors)
• Green: legal use of kratom
• Blue: county ordinances

Epidemiology of Kratom Use in
Thailand3,6
• Southern Thailand study
conducted in high school aged
students:
– Lifetime prevalence: 2.3-4.9%
• Another study in 12 to 65 year-
old Thai citizens indicated:
– Past year use: 4.7%
– Current use: 3.8%
• Roadside survey:
– December 2005 – May
2006 in Thailand
– 1,635 drivers
– Majority ages 30-60, male
– Urinalyses determined
the presence of
mitragynine in 0.9%

United States Epidemiology7
• Limited due to the fact that
the drug is not currently
monitored by any drug
abuse survey in the U.S.
– U.S. poison center data revealed
two incidents between 2000-2005
• DEA:
– STRIDE: System to Retrieve
Information from Drug
Evidence
– First recognized in 2010: 1
report
– 2011: 44 reports
– 2012: 81 reports in first 6
months of the year
• Texas Poison Center Network
(TPCN)
– No reports of kratom
poisoning from 1998-2008
– 2009: 2 reports
– 2010: 1 report
– 2012: 4 reports
– 2013: 7 reports by September
– 11 out of 13 being males
– 11 out of 13 in their 20s

Pharmacodynamics2,3
• Primary effects come from
mitragynine, the main alkaloid
• Analgesic Effects:
– Mu and Delta
opioid receptors
• Euphoric Effects:
– Delta and Kappa
opioid receptors
• Noradrenergic and serotonergic
agonism
• α2-adrenergic receptor agonism
• 5-hydroxytryptamine2A receptor
antagonism
• Dose-dependent effects:
– Lower doses (1-5g)
• Stimulant-like effects, less than those
seen with amphetamine
– Higher doses (5-15g)
• Opioid-like effects including sedation,
analgesia, euphoria
• 7-hydroxymitragynine
– 46 times more potent than
mitragynine
– 13 times more potent than
morphine

Mitragynine Works
Through Opioid Receptors10

In vitro Pharmacokinetics1
• In vitro “P450-Glo™
screening system”
• Determined activity primarily
on CYP2D6, 2C9, and 3A4
• CYP2C9 and 2D6 inhibition
appeared to be
noncompetitive
• CYP3A4 inhibition was found
to be competitive
CYP Enzyme IC50 value
(µM)
Interaction
probability
2D6 0.45 ± 0.33 High
2C9 9.70 ± 4.80 Moderate
3A4 41.32 ± 6.74 Minimal

Pharmacokinetics in Humans8
• 6 participants, male
chronic users in
Thailand
• 3 treatment arms:
– High dose (23mg)
– Middle dose (12.5mg)
– Low dose (6.25mg)
• This study showed
that kratom
demonstrated
nonlinear kinetics
Dose Cmax
(ng/ml)
Tmax
(min)
T1/2
(hrs)
AUC
(mg/ml/
hr)
High 28 45 12.8 93.5
Middle 45.3 70 8.4 159.0
Low 116.8 30 32.6 771.1

Social3
• Citizens of Thailand and Malaysia view
kratom as a cultural part of their lives
• Other societies, UK and U.S., primarily
use kratom as a recreational drug
• 4 x 100
– Cocktail with alcohol-like effects
– M. speciosa leaves
– Soft drink w/ caffeine
– Codeine or diphenhydramine cough syrup
– Along w/ an anxiolytic, antidepressant, or
analgesic
http://www.goodfellow.af.mil/news/story.asp?id=123410174

User Experiences
• “The tea is giving me a bit of a high, somewhat like an opiate but not
nearly as strong as the stuff i am used to (oxycodone) its a nice euphoric
feeling that makes me want to sit and relax, and its very very mellow. as
opposed to an oxy high where i want to do things and get stuff done (like
work on my car lol)..”
• “About 5 minutes later, I was beginning to feel a creeping euphoria wash
over me.” “At 11:25pm (T+20), I was feeling a very intense euphoria.” “At
11:30pm (T+25), my face begins to feel warm. Over the next half hour,
warm becomes hot, and I begin sweating profusely.” “At 12:20am
(T+1:15), I began floating in and out of waking dreams..” “By 3:30am
(T+4:25) I am effectively back to baseline.”
• “I'd say that my kratom experience was probably equivalent to a
strong oxycodone experience. ”
- https://drugs-forum.com/forum/showthread.php?t=9451

Safety/Toxicology5,7,11
• None of the TPCN reports
resulted in death
– Tachycardia, hypertension,
agitation, nausea, vomiting,
etc.
• Case report:
– Middle-aged man was found
dead in his bed one morning
after consuming kratom
– Autopsy: “intoxication with
“Kratom”, possible in
combination with other
substances”
– Pneumonia was also a
contributory factor
• A Sweden cases series
reported nine deaths over a
one year span
• Associated with “Krpyton”
• Krypton is a mixture of
mitragynine and O-
desmethyltramadol
• Toxicity was confirmed via
blood samples
• Differing potencies between
formulations and
combinations of drugs are
the biggest concern

References
http://www.keepcalm-o-matic.co.uk/p/keep-calm-
and-kratom-on/
1. Hanapi, N.A., Ismail, S., Mansor, S.M., 2013. Inhibitory effect of mitragynine on
human cytochrome P450 enzyme activities. Pharmacognosy Res. 5(4), 241-246.
2. Prozialeck, W.C., Jivan, J.K., Andurkar, S.V., 2012. Pharmacology of kratom: an
emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am
Osteopath Assoc. 112, 792-799.
3. Hassan Z., Muzaimi, M., Navaratnam, V., 2013. From Kratom to mitragynine and its
derivatives: Physiological and behavioural effects related to use, abuse, and
addiction. Neurosci Biobehav Rev. 37, 138-151.
4. Ulbricht, C., Costa, D., Dao, J., 2013. An evidence-based systematic review of
kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration. J Diet
Suppl. 10(2), 152-170.
5. Rosenbaum, C.D., Carreiro, S.P., Babu, K.M., 2012. Here today, gone tomorrow…and
back again? A review of herbal marijuana alternatives (K2, Spice), synthetic
cathinones (Bath Salts), kratom, Salvia divinorum, Methoxetamine, and Piperazines.
J Med Toxicol. 8(1), 15-32.
6. Ingsathit, A., Woratanarat, P., Anukarahanonta et al., 2009. Prevalence of
psychoactive drug use among driver in Thailand: A roadside survey. Accident Anal
Prev. 41, 474-478.
7. Forrester, M.B., 2013. Kratom exposures reported to Texas poison centers. J Addict
Dis. 32(4), 396-400.
8. Kratom Legality Map. http://speciosa.org/kratom-legality-map/. Accessed April 21,
2015.
9. Trakulsrichai, S., Sathurakul, K., Auparakkitanon et al., 2014. Pharmacokinetic study
of mitragynine in kratom abuse users. Clin Toxicol. 52(4), 396.
10. Shamima A.R., Fakurazi S., Hidayat M.T., et al., 2012. Antinociceptive action of
isolated mitragynine from Mitragyna speciosa through activation of opioid receptor
system. Int J Mol Sci. 13(9):11427-11442.
11. Karinen, R., Fosen, J.T., Rogde, S. et al, 2014. An accidental poisoning with
mitragynine. Forensic Sci Int. 245, e29-e32.

Mephedrone
RX462: Drug Abuse and Society
Clarisse Baba
Marcus Guilemette
http://www.synchronium.net/2010/01/05/mephedrone-cat/

Mephedrone General
Overview 1
• Mephedrone also known as 4-methylmethcathione 4-
MMC or 4-methylephedrone
• Is a synthetic stimulant drug of the amphetamine and
cathinone classes
• It is chemically similar to the cathinone compound
found in the khat plant of eastern Africa
• It available in form of tablets or powder
• Users can swallow, snort or inject it
• With regard to effects, mephedrone shares similar
traits with MDMA, amphetamines and cocaine

Mephedrone Street Names 1
• Meow Meow
• M-Cat
• White Magic
• Bubbles
• Drone
• Plant Food
• 4-MMC
http://www.alice-in-wonderland.net/pictures/cheshire-cat-
pictures.html

Pictures of Mephedrone
http://www.theguardian.com/society/2011/oct/2
5/legal-highs-automatically-banned
http://real-i-d.net/mephedrone-
crystals.html
http://www.sabavoipdirectory.com/
viewad.php?id=MTY1MjI4

The History of Mephedrone 2
• Was first synthesized in 1929, by
Saem de Burnaga Sanchez but
gained it popularity when it was
rediscovered in 2003
• Mephedrone was first sold in
2007 in legal highs produced by
the company Neorganics
• In the beginning of 2008
mephedrone was made illegal in
Israel, where it was
manufactured
• Mephedrone became
increasingly popular in the UK
towards the end of 2009
http://www.aurorachambermusic.com/wp-content/uploads/2012/12/mystery-person-205x148.jpg

The History of Mephedrone 2
• With numerous online vendors popping up the consumer
price went down significantly
• Its huge popularity can for a large part be attributed to
the state of the MDMA and cocaine market at the time,
as prices had skyrocketed and quality was low
• Mephedrone soon became the perfect, legal, alternative
• Next to easy online ordering and next day delivery,
mephedrone is usually of very high purity and uncut
• By 2010, was available for use in most of Europe with a
high prevalence in the United Kingdom

Epidemiology 3
• A survey was conducted in the UK
• A total of 1006 individuals completed the survey
• 501 (49.8%) were males
• 505 (50.2%) females
• 349 classified as high school student (mean ± SD age
14.0 ± 1.1 years)
• 657 as a college/university (mean ± SD age
20.50 ± 6.5 years)

High School and College Survey on
Mephedrone in the UK 3
• A total of 205 (20.3%) of those
who completed the survey had
used mephedrone on at least
one occasion
• 4% reported daily use
• And all of those using daily
were 21 years of age
http://en.wikipedia.org/wiki/List_of_British_flags#/media/File:Flag_-_Union_Flag.jpg

Form of Mephedrone Use in High School and
College in Scotland 3

Source of Mephedrone Among the 205
Mephedrone Users 3

Demographic Factors Associated
with Mephedrone 4
• Survey of 1740 patrons at night life venues in
New York City
• Within the sample 8.2% reported use of
synthetic cannabinoids and 1.1 % reported the
use of mephedrone

Demographic Factors Associated with
Mephedrone (con.) 4

Methods of Mephedrone Use 5
• Oral
• Oral dose can be taken in a variety of ways
• The easiest being either mixed with water
• Or wrapped in a rizzia paper and swallowed
• Dose: 50-100 mg (light) to 150-300mg (strong)
• Onset of effects:15-45 minutes
• Duration of effect: 1-2 hours

• Insufflation
• Nasal
• Dose: 15-25mg (light)
to 75-125mg (strong)
• Onset of effects, 5-10
minutes
• Duration of effect: 1-2
hours
http://www.theguardian.com/society/2014/may/27/synthetic-drugs-injection-warning-
chem-sex

• Intravenous
• Dose, 10-20mg (light) to 60-70mg
(strong)
• Onset of effects,2-3 seconds(rush)
5-10 minutes
• Duration of effect, 5 minutes (rush)
• 15-30 minutes
http://www.talkingdrugs.org/injecting-mephedrone-what-are-the-risks

• Rectal
• Rectal administration, otherwise referred to as
plugging
• Is characterized by a faster onset relative to
oral
• Required a lower dose 100 mg
http://www.atitesting.com/ati_next_gen/skillsmodules/content/Medic
ation-Administration-2/equipment/rectal.html

Effects 6
• Mephedrone induces a state of euphoria, somewhat
similar to MDMA
• The effects of mephedrone are often described as a
cross between cocaine and MDMA
• The user feels energized, talkative and alert
• A oral dose gives a duration of around 2 hours, when
insufflated the effects generally last about 1 hour
• Prolonged use and large doses can induce negative
effects

Drug Effect (Dose Dependent) 6
• Sought after effect include
• Stimulation, alertness,
rushing
• Euphoria and
hypersensitivity
• Empathy and warmth
• Well-being and confidence
• Increased libido and sexual
disinhibition
• Talkativeness
• Time distortions
• Visual hallucinations
• Reduced appetite
http://www.tescohealthandwellbeing.com/advice/diet-and-nutrition/3392-foods-that-
increase-libido

Signs and Symptoms of
Mephedrone 6
• Elevated heart rate (tachycardia)
and palpitations
• Sweating, overheating, hot
flushes,
• Dry mouth
• Headaches
• Chest pain
• Nystagmus (eye jitters)
• Teeth grinding (bruxism) and jaw
clenching
• Coldness or numbness in fingers
or toes
http://www.biotene.com/what-is-dry-mouth

Signs and Symptoms of Mephedrone
(con.) 6
• Blurred vision, dilated pupils
• Significant nasal irritation and
tissue damage
• Agitation, aggression and
paranoia
• Soft tissue and vascular damage
(when injected)
• Insomnia and sleeping problems
• Fatigue and low mood
• Anxiety, agitation and paranoia
• Sore throat, sore nose
• Nose bleeds
• Nausea, vomiting, stomach pain
http://lifeinthefastlane.com/epistaxis/

LD50 of Mephedrone
• LD50of mephedrone in humans is unknown
• Further studies are needed to confirm
accurate dose range
• From many case reports, death was associated
with an increased dose of mephedrone
combine with either alcohol or other
stimulants
http://www.medical-
institution.com/tag/pharmacology/

Mephedrone Death-Related Case
Reports 7
• A total of four deaths related to the use of mephedrone
• Case 1
• A 49 year old female
• Insufflated 0.5 g of mephedrone obtained from an online
purchase
• Prior to that she consumed alcohol and smoke some cannabis
• 2-4 hours after taking mephedrone she complained of sore
chest and vomited proceed by collapse
• She was taken to the hospital but die later on after many
resuscitation attempted

Reports (con.) 7
• Case 2
• A 19 year old male took an unknown quantity of mephedrone
along with alcohol and ecstasy while attended a party
• Some hours later eye witness reported he was shaking,
sweating and acting strangely
• Despite attempts to revive him when the emergency service
arrived at the scene he was later pronounce dead at the
hospital
• He had suffered from a cardio-respiratory arrest

Reports (con.) 7
• Case 3
• A 55 year old female with a previous history of psychiatric
issues and consistent use of illicit drugs
• Was believed to have consumed alcohol and an unknown
substance one evening
• Many witnesses reported that she was having a hard time
breathing
• She went to bed and was found unresponsive the following
morning
• The emergency services pronounced her dead at the scene

Mephedrone Death-Related
Case Reports (con.) 7
• Case 4
• A 17 year old male
• Was driving at night on a
raining day with friend
under the influence of
mephedrone
• Was driving on the wrong
side of the road
• He eventually collided with
an oncoming car
• He died at the scene
http://silviahartmann.com/poem/challenge-poem-head-on-collision.php

Mephedrone Legislation (USA) 8,9
• Mephedrone is relatively
illegal to consume
• It is NOT illegal to possess
• Legal use of mephedrone: as
garden fertilizer
• State Legislation Across USA
– Michigan banned the drug in
October 2010
– New York made mephedrone
Schedule I in July of 2011
– Ohio made mephedrone illegal
to buy/sell/possess without
license in July of 2011
– Florida has made mephedrone
Schedule I as of July in 2012
http://www.tradeindia.com/fp1006378/Bio-Fertilizers.html

Mephedrone Legislation in Maine 9,10
• Mephedrone is listed as a
Schedule W drug
• Schedule W drugs in Maine
include: cocaine,
amphetamines, methadone,
hallucinogens like LSD,
Barbiturates
• Class D misdemeanor for
possession of mephedrone or
other Schedule W drug with a
$400 fine and could include
probation and time in jail
http://mofga.net/Directories/CommunitySupportedAgricultureinMaine/tabid/268/Defa
ult.aspx

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