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

These are the presentations from 2nd and 3rd year pharmacy students from semester long projects on a recreational drug of their choosing. Each presentations contains what was currently known (as of spring, 2015) about the history, epidemiology, pharmacokinetics, and pharmacodynamics of a recreational drug of their choosing.

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

  1. 1. Drug Abuse & Society (RX 462) Spring 2015 Presentations Instructor: Brian J Piper, PhD
  2. 2. 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
  3. 3. 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/
  4. 4. 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
  5. 5. The Ebers papyrus
  6. 6. 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.
  7. 7. 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 Montagne M. Drugs on the Internet, Part V:Absinthe, Return of the Emerald Mask. Substance Abuse & Misuse. 2013;48:506-512.
  8. 8. Marketing efforts Montagne M. Drugs on the Internet, Part V:Absinthe, Return of the Emerald Mask. Substance Abuse & Misuse. 2013;48:506-512. http://www.absinthes.com/themag/wp-content/uploads/2012/09/Le-Monde-Illustre-1892-Cafe-Scene_mini.jpg
  9. 9. L’heure Verte http://absinthe.com.au/absinthe-history/
  10. 10. 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.
  11. 11. 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.
  12. 12. 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.
  13. 13. Anti-absinthe propaganda http://www.museeabsinthe.com/absintheLIVRES6.htmlhttps://www.pinterest.com/jkmatwood/absinthe-o-combien-je-t-aime-tellement/
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. The Czech Method https://www.youtube.com/watch?v=oQIYH7G007A
  21. 21. 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.
  22. 22. Thujone toxicity Erb A. Die grüne Fee Thujon. Bayerische Julius-Maximilians-Universität Würzburg;2003.
  23. 23. 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.
  24. 24. 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.
  25. 25. 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.
  26. 26. 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 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.
  27. 27. Attention performance was not significantly changed by alcohol or alcohol + low α- thujone 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. Alcohol only Results Alcohol + 10 mg/ml α-thujone T0= 0% BAC T1= 30 minutes post administration T2= 90 minutes post administration
  28. 28. Attention performance was significantly changed by alcohol + high α-thujone 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. Alcohol + 100 mg/ml α-thujone
  29. 29. False alarm reactions were significantly initially increased by 100 mg/L α-thujone 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.
  30. 30. Correct peripheral reaction was significantly reduced by 100 mg/L α-thujone 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.
  31. 31. 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.
  32. 32. Oil of wormwood poisoning case report 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.
  33. 33. Oil of wormwood poisoning case report • 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 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.
  34. 34. 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
  35. 35. 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
  36. 36. Ayahuasca Anonymous
  37. 37. 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
  38. 38. 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.
  39. 39. 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
  40. 40. 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.
  41. 41. 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.
  42. 42. 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
  43. 43. 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.
  44. 44. 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.
  45. 45. 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
  46. 46. 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.
  47. 47. 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.
  48. 48. 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
  49. 49. 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
  50. 50. 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.
  51. 51. 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.
  52. 52. 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.
  53. 53. 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.
  54. 54. 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.
  55. 55. 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.
  56. 56. 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.
  57. 57. 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
  58. 58. 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.
  59. 59. 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
  60. 60. 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.
  61. 61. Butane Anonymous March 31,2015
  62. 62. Objectives • What is Butane? • Discovery and history of Butane • Epidemiology • Methods of inhalation • Effects of inhalation • Dangers of use • Regulations In Maine
  63. 63. 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
  64. 64. Butane1,2 • Used to produce – Ethylene – 1,3,-butadiene • Used as – Refrigerant – Aerosol propellant – Constituent in LPG • Main component of liquid gas lighter refills
  65. 65. 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
  66. 66. 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
  67. 67. Inhalant Most Common in 12-19 Years of Age4
  68. 68. 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
  69. 69. 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
  70. 70. 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
  71. 71. 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
  72. 72. 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
  73. 73. 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
  74. 74. 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
  75. 75. 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
  76. 76. Butane Among Highest Fatality Rate4
  77. 77. Propellants Highest Rate Of Use Compared To Other Categories4
  78. 78. 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
  79. 79. §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) .]
  80. 80. §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) .]
  81. 81. 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.
  82. 82. Overview of e-Cigarettes Brian J. Piper, Ph.D., M.S. School of Pharmacy, Husson University
  83. 83. Goals • What is an e-Cigarette? • History • Pharmacokinetics • Efficacy • Safety
  84. 84. 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
  85. 85. 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
  86. 86. 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
  87. 87. 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.
  88. 88. Tobacco Specific Nitrosamines Cahn & Siegel J Public Health Policy 32 (2011) p. 22.
  89. 89. Relevant? • Formaldehyde = carcinogen • 4 sec • distribution? Jensen et al. New Engl J Med 372 (2015) 392-393.
  90. 90. 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.
  91. 91. 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
  92. 92. 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
  93. 93. 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.
  94. 94. Adverse Events (N = 40) Coponnetto et al. Exp Rev Respir Med 2012: 6(1):63-74.
  95. 95. 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.
  96. 96. 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
  97. 97. 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%) ?
  98. 98. Do e-Cigs aid smoking cessation? • 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.
  99. 99. Do e-Cigs aid smoking cessation? 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 Bullen et al. Lancet 382 (2013) 1629-1637.
  100. 100. Do e-Cigs aid smoking cessation? 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% Bullen et al. Lancet 382 (2013) 1629-1637. * p < .05 versus patch
  101. 101. 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.
  102. 102. Do e-Cigs aid in smoking reduction? • Study completion rates: – A (7.2/7.2 nic): 65% – B (7.2/5.4 nic): 63% – C (0 nic): 55% Caponotto et al. (2013) PLoS One 8(6): e66317.
  103. 103. Do e-Cigs aid in smoking reduction? • 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% Caponotto et al. (2013) PLoS One 8(6): e66317. -----------------------------------------------------
  104. 104. Free Advertising?
  105. 105. Center’s for Disease Control (2013). Morbidity Mortality Weekly Report 62(35), 729-730.
  106. 106. 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.
  107. 107. 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
  108. 108. 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.
  109. 109. 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?
  110. 110. Self-Test • T/F: The nicotine Cmax is equivalent following cigarette and the e-Cig administration.
  111. 111. Hookah Smoking By: Jeremy Bishop
  112. 112. Objectives  History & background  Epidemiology  Social views  Health effects  Pharmacodynamics  Pharmacokinetics  Cessation  Legal issues
  113. 113. Commonly Known As  Hookah  Shisha  Sheesha  Waterpipe  Narghile  Hubble Bubble
  114. 114. 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
  115. 115. 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
  116. 116. 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
  117. 117. 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
  118. 118. Publicity
  119. 119. Health Effects  Associated with increase risk of:  Lung cancer  Altered pulmonary function  Coronary heart disease  Arteriosclerosis  Fetal effects  Infections  Second hand smoke
  120. 120. 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
  121. 121. *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.
  122. 122. 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
  123. 123. Pharmacodynamics  Nicotine:  Binds nicotinic cholinergic receptors  Releases neurotransmitters (dopamine)  Desensitization / Tolerance  Withdrawal:  Increase release of Corticotropin releasing factor  Decreased dopamine activity
  124. 124. Cessation  None targeting hookah smoking  Treat similar to cigarette addiction  Nicotine replacement therapy
  125. 125. Legal side  Cigarettes or smokeless tobacco sale laws  Does not include tobacco used for a hookah  Allows selling to anyone  Flavoring  Smoke free laws
  126. 126. 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.
  127. 127. 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.
  128. 128. HU-210 Kaitlin Kelley & Shannon Mockler
  129. 129. Objectives • Introduction – Overview – AKA – Package Contents • History • Epidemiology • Pharmacokinetics • Pharmacodynamics • 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
  130. 130. 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
  131. 131. 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...
  132. 132. Contents http://www.emcdda.europa.eu/attachements.cfm/att_80086_EN_Spice%20Thematic%20paper%20—%20final%20version.pdf
  133. 133. History Dr. Raphael Mechoulam “Father of Marijuana Research” First synthesized: 1988- Hebrew University, Israel
  134. 134. 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
  135. 135. History http://journal.frontiersin.org/article/10.3389/fnbeh.2011.00060/full
  136. 136. 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
  137. 137. Global Drug Survey 2014 http://www.globaldrugsurvey.com/facts-figures/the-global-drug-survey-2014-findings/
  138. 138. 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
  139. 139. 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
  140. 140. 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
  141. 141. http://www.globaldrugsurvey.com/facts-figures/the-global-drug-survey-2014-findings/
  142. 142. 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
  143. 143. 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
  144. 144. 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
  145. 145. 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
  146. 146. 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
  147. 147. 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-
  148. 148. “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
  149. 149. “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
  150. 150. “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
  151. 151. “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
  152. 152. “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
  153. 153. “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
  154. 154. 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
  155. 155. Social/Life Implications http://www.globaldrugsurvey.com/facts-figures/the-global-drug-survey-2014-findings/
  156. 156. 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
  157. 157. 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
  158. 158. 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.
  159. 159. RX462: Drug Abuse and Society Kris Ravin Ketamine
  160. 160. “Ketamine Tiger” by Marisa Wood Bassett
  161. 161. • History • Notable People • Epidemiology • Ketamine in Medicine and Society • Laws • Pharmacokinetics • Pharmacodynamics • Interactions • Toxicology Outline
  162. 162. • 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
  163. 163. • 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
  164. 164. • 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
  165. 165. • 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
  166. 166. • 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
  167. 167. • 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
  168. 168. • 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
  169. 169. Epidemiology
  170. 170. • 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
  171. 171. • 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
  172. 172. • 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
  173. 173. • 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
  174. 174. • 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
  175. 175. • 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
  176. 176. 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
  177. 177. Pharmacokinetics
  178. 178. • 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
  179. 179. • 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
  180. 180. • 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
  181. 181. • 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
  182. 182. • 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
  183. 183. • 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
  184. 184. Pharmacodynamics
  185. 185. • 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
  186. 186. • 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
  187. 187. • 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
  188. 188. • 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
  189. 189. • 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
  190. 190. • 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
  191. 191. • 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
  192. 192. • 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
  193. 193. Toxicology
  194. 194. • 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
  195. 195. • 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
  196. 196. • 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
  197. 197. • 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
  198. 198. • 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
  199. 199. • 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
  200. 200. • 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
  201. 201. • 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
  202. 202. • 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
  203. 203. • 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
  204. 204. • 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.
  205. 205. Kratom: Mitragyna speciosa Anonymous Husson University Pharm.D. 2016 http://commons.wikimedia.org/wiki/File:Young_Kratom _Tree.JPG
  206. 206. 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
  207. 207. 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
  208. 208. 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/
  209. 209. 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
  210. 210. 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
  211. 211. 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
  212. 212. 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
  213. 213. 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%
  214. 214. 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
  215. 215. 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
  216. 216. Mitragynine Works Through Opioid Receptors10
  217. 217. 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
  218. 218. 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
  219. 219. 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
  220. 220. 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
  221. 221. 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
  222. 222. 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.
  223. 223. Mephedrone RX462: Drug Abuse and Society Clarisse Baba Marcus Guilemette http://www.synchronium.net/2010/01/05/mephedrone-cat/
  224. 224. 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
  225. 225. 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
  226. 226. 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
  227. 227. 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
  228. 228. 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
  229. 229. 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)
  230. 230. 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
  231. 231. Epidemiology 3
  232. 232. Form of Mephedrone Use in High School and College in Scotland 3
  233. 233. Source of Mephedrone Among the 205 Mephedrone Users 3
  234. 234. 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
  235. 235. Demographic Factors Associated with Mephedrone (con.) 4
  236. 236. 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
  237. 237. Methods of Mephedrone Use 5 • 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
  238. 238. Methods of Mephedrone Use 5 • 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
  239. 239. Methods of Mephedrone Use 5 • 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
  240. 240. 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
  241. 241. 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
  242. 242. 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
  243. 243. 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/
  244. 244. 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/
  245. 245. 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
  246. 246. Mephedrone Death-Related Case 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
  247. 247. Mephedrone Death-Related Case 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
  248. 248. 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
  249. 249. 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
  250. 250. 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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