Drug abuse and society drug presentations: Spring 2013
This presentation is on recreational drugs as part of a elective course for 2nd and 3rd year pharmacy students. The instructions were to include what is known about history, pharmacodynamics, pharmacokinetics including common routes of administration, overdose potential, and recent epidemiology.
The class chose some older agents (peyote, LSD, mushrooms, cocaine), others that have only become more popular recently (bath sats, synthetic cannabinoids), and some medical drugs (methylphenidate, oxycontin).
First used in soldiers and was later released for use in civilians
Ketamine is not widely misused compared to more popular medications among 8, 10 and 12th graders
Racemic mixture with the S+ enantiomer being the more potent and fewer side effectsVariable concentrations – hospitals within EMCC carry 50mg/mL concentration; 10 mL vialsBenzethonium chloride – has been used as a antimicrobial agent in first aid antiseptics; found in comsmetics, toiletries such as mouthwashes, anti-itch ointments, moist towelettes…
Dissociative drug similar to PCP but with milder respiratory depression, less confusion, and violent behaviorPsychotomimetic – mimics symptoms of psychosis; delusions/delirium According to Drug Bank, ketamine is known to not interact with GABA receptors, although there is conflicting information
NMDA antagonist – most important neuropharmacological mechanisms for the analgesic effects of ketamine; S-enantiomer binds more effectively than the R enantiomerOpiate receptors – contribute to analgesic and dysphoric reactionsSympathomimetic effects – enhanced monoaminergic transmission with inhibition of Ach centrally and peripherally may contribute to the anesthetic state/hallucinationsDAT inhibitor – possibly rewarding/reinforcing properties causing users to use ketamine repeatedly
Hydroxylation – addition of a hydroxyl group to make them more water solubleDehydration – to remove the water and make a white powder that can be snorted by drug usersDemethylation – see on the slide that the methyl group is removed from ketamine to form norketamine
Hypotension – b/c ketamine causes increased heart rate; has bronchdilatory effectsPediatric procedures – general anesthesia, procedure-related pain, procedural sedation, when you need a rapid loss of consciousnessVeterinary procedures – sedation before surgery, control pain, relax muscles
At correct dosing regimens, ketamine is not a pschedelic agent; but when used at subanesthetic doses, it does induce profound psychedelic experiences and hallucinations
K-hole – achieved when person consumes an extreme amount of ketamineAssociated with: schizophrenia effects out-of-body experiences feelings of derealization, depersonalization, disorientation vivid hallucinations psychedelic experiences sensations of floating or falling total loss of time perception
Do not have physical dependence properties seen with morphine, heroin or alcohol, it does have psychological addiction similar to cocaineDrug addicts only use about 10-25% of the therapeutic dose therefore they don’t experience the breathing or HR effectsMore issues arise when abusers combine depressants like alcohol, benzos, or other illicit drugsSome withdrawal symptoms can include: flashback aggressive behavior confusionderealization in more severe cases, possibly death
1st synthetic:methcathinone and mephedroneMethcathinone used in Soviet Union in 1930s as antidepressant – quickly became recreationalBupropion used as antidepressant/smoking cessation
Other synthetic cathinones – enhance stimulant and entactogen effectsBeta blockers – counteract tachycardiaZopiclone – produce visual hallucinationDomperidone – counteract stomach painBZDs – counteract anxiety
Sodium oxybate was FDA approved for the treatment of cataplexy as well as for the treatment of symptoms of daytime sleepiness in narcoleptic patients in 2002 and 2005 respectively.
DAWN – Drug Abuse Warning NetworkAAPCC - American Association of Poison Control Centers MtF – Monitoring the Future
Death occurred due to seizures from withdrawal, polysubstance use with other CNS depressants (EtOH) – one person was found in a river, as well as aspiration ultimately resulting in anoxic brain injury. The authors recognize that toxicologic confirmation of GHB is limited as GHB undergoes rapid elimination and becomes undetectable from blood and urine within 6-12 hours respectively. Due to these limitations the number of cases of death due to GHB may be underestimated.
A comparison of total GHB and related congener Exposure and Drug Information cases reported to the California Poison Control System (1999-2003), the American Association of Poison Control Centers (2001-2003), the Drug Abuse Warning Network (DAWN; 1999-2003), and the National Institute for Drug Abuse Monitoring the Future Survey (2000-2003).
Possible pharmacological mechanisms of GHB. Structures of 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), two GHB prodrugs that are metabolized to GHB in vivo. Structures of GABA, GHB (sodium salt), and NCS-382. GABA and GHB are reversibly metabolized in vivo. Three possible pharmacological mechanisms for GHB. GHB is metabolized to GABA, which binds to GABAA and GABAB receptors, GHB binds to GABAB and GHB receptors, and NCS-382 binds to GHB receptors. Selective ligands for GABAA, GABAB, and GHB receptors are shown below the respective depiction of each receptor.
Aspiration in comatose pt can be fatal
Dose of sodium oxybate indicated for narcolepsy
Nowadays produced by heating ammonium nitrate, which forms nitrous oxide gas and water vapor.
8 grams, half a liter
Opioid – naloxone blocked pain relief in animals. Explains effectiveness of etoh/opioid withdrawal.
Ketamine and NOS dangerous in animals – synnergistic (also ethanol, PCP)
NOS oxidizes cobalamin to Co3+. B12 acts as coenz for methionine synthaseMethionine - critical to cellular function, and decreased methionine synthase activity can result in both genetic and protein aberrations
❚ HER-2/neu gene amplification in infiltrating ductal breast cancer detected by fluorescence in situ hybridizationA, HER-2/neu gene amplification demonstrated by theAbbott-Vysis Pathvysion (Vysis, Downers Grove, IL) methodshowing a significant increase in HER-2/neu gene signals(red) compared with chromosome 17 signals (green) withan HER-2/neu gene ratio of 3.9. B, HER-2/neu gene amplification using the Ventana Inform method (Ventana MedicalSystems, Tucson, AZ) showing another breast cancer specimen with an absolute (raw) HER-2/neu gene copy number
Drug abuse and society drug presentations: Spring 2013
RX462 Drug Abuse & SocietyPresentationsBrian J. Piper, Ph.D., M.S.Department of Basic PharmaceuticalSciencespsy391@gmail.com or email@example.com
ContentsDrug Author Slide #LSD Sarah Moore 3 to 29Peyote Anonymous* 30 to 50Amanita Mushrooms Priyank Mandalia 51 to 68Salvia divinorum Anonymous* 69 to 90Ketamine Anonymous* 91 to 112Bath salts Lindsay Pelletier 113 to 137Gamma-hydroxybutyrate (GHB) Anonymous* 138 to 161Nitrous oxide Curtis Cyr 162 to 178K2 or Spice (synthetic cannabinoids) Anonymous* 179 to 198Methylphenidate Anonymous* 199 to 210Cocaine Anonymous* 211 to 229Oxycontin Anonymous* 230 to 263*Name removed at student’s requestEach presenter was instructed to include history, pharmacodynamics, pharmacokinetics includingcommon routes of administration, risk of overdose, and epidemiology.
Hallucinogen10Powerful mental amplifier that has the ability toenhance reality; makes a person incrediblysensitive to their current environment (physical andmental setting).http://www.ugo.com/movies/inception-list
History1• Albert Hoffman (1906-2008)• Psychedelic (“soul-opening”)• Synthetic drug made fromergot alkaloids (fungusfrom rye)• Synthesized in 1938• Illegal in 1967, categorizedas Schedule I drug.http://www.acidprogram.com/albert/hofmann.htmlhttp://www.erowid.org/culture/characters/hofmann_albert/
History2• Carey Grant was a fan ofthe drug, dropping acida few hundred times inthe 1940s.• Very popular in 1960sbefore and after it wasillegal.• CIA used acid as a “mindcontrol drug” for theirMKULTRA experiments.• Paid prostitutes to dosepeople of interest andrecord their admissions.http://badassdigest.com/2012/04/22/when-lsd-was-legal-and-cary-grant-was-tripping/
LSD: My Problem Child3,4• LSD, not LAD German wordfor “acid” is “saeure”.• Originally synthesized as ahemostatic for use afterchildbirth.• Also had good qualities intreating migraines.• 1943, accidental ingestion• 1950s, used the drug as aresearch tool• Greatly improvedpsychotherapy processeshttp://www.botany.hawaii.edu/faculty/wong/BOT135/LECT12.HTM
Epidemiology5• In 2009: 779,000 people age 12 and older haveused LSD at least once in the last 12 months.• 1.2% 8th graders, 1.9% 10th graders and 2.6% 12thgraders have used LSD in the last 12 months.• The perceived risk of harm from using LSD issteadily declining.http://www.drugabuse.gov/drugs-abuse/lsd-acid
SOURCE: University of Michigan, 2008 Monitoring the Future Study02040608010093 94 95 96 97 98 99 00 01 02 03 04 05 06 07 088th Grade 10th Grade 12th GradePercent Perceiving Great Risk of TakingLSD RegularlyDenotes significant differencebetween 2007 and 2008.www.cadca.org/files/Recent_Drug_Trends.pp
LSD Use Outside of U.S.6• Canada: Schedule III drug (requires Rx orlicense)• Most black-market sale of drug is out ofUnited Kingdom.• LSD is ILLEGAL to possess without aspecial license in Belgium, Canada,Greece, the Netherlands, Norway, Russiaand the UK.• Personal possession LEGAL in Mexico (upto 15μg) and Portugal (up to 500μg)http://www.worldpress.org/map.cfm
ACIDBLOTTERCALIFORNIA SUNSHINEDOTSELECTRIC KOOL-AIDStreet Names for LSD9
Psychological Effects of LSD3• Dose: 40-150 mcg per blot• Effects are proportional todose taken, but durationof trip is the sameregardless of dose.• Dreaming, mysticalexperiences• Intense hallucinations• Auditory, visual and tactilehttp://www.world-science.net/othernews/070129_hallucinogen.htmhttp://www.lsdabusehelp.com
PHYSICAL EFFECTS OF LSDhttp://knowingshine.blogspot.com/2010_10_01_archive.html
Pharmacodynamics1,3,12• *Decreases spontaneousfiring, increases excitationand sensory stimulation (NE).• Hyperresponsiveness tovisual, auditory and tactilestimulation.• 5-HT agonists (2A and 2C), byway of inhibiting 5-HTautoreceptors.• Serotonin-like indoleaminegroup, including psylocybinand DMT.• *Locus coeruleus(norepinephrine)—sendsinformation to sensorycortex.• Raphe nuclei (serotonin)—shuts down firing ofserotenergic neurons.http://depositphotos.com/12099293/stock-illustration-LSD-structural-formula.html
Pharmacodynamics13• Genesis of hallucinations.• Affects the way the retinasrespond to stimuli andcarry that informationback to the brain.• No evidence of interactionwith dopamine rewardpathway.• No physical addiction• No withdrawalhttp://www.dericbownds.net/bom99/Ch10/Ch10.htmlhttp://www.sciencedirect.com/science/article/pii/S0378434799001899
Pharmacokinetics11• t1/2= 3 hours• Effects begin within an hourand last 8-12 hours.• Peak happens around 3-5hours.• 80% of drug is taken up insmall intestine and eliminatedby liver and bile.• Only 1-10% is eliminatedunchanged.• The remainder is excreted asmetabolites.• Taking “acid” with other drugs(alcohol, anti-depressants,heroine, cocaine) can causetemporary psychosis.http://www.sciencedirect.com/science/article/pii/S0378434799001899
Gender Differences7,8• Concentrations of LSD in urine following oral administration of a 4-μg/kgdose to a female subject (▵) and a male subject (×).• A study conducted with rats showed male rats who were administered dosesof LSD were more likely to revisit the area of their cage where the LSD wasadministered than female rats.: http://www.sciencedirect.com/science/article/pii/S0378434799001899
Psychological Effects of LSD10• Typical adverse reaction isthe sensation of a “badtrip”, or temporaryepisodes of panic.• Frightening and traumatic• Impossible to detectactual dosage (from thestreet) in blotter paper.• Heat, air and light willdegrade the drug• Flashbacks or reliving of a“trip”• Hallucinogen PersistingPerception Disorder(HPPD)• Trails, halos, shapes,flashes in peripheral vision• Can last for weeks or yearsafter taking the drug.http://furthurtothefuture.blogspot.com/2012/04/why-you-shouldnt-do-lsd.html
Lysergic Acid Diethylamide11• Halucinogen Persisting Perception Disorder(HPPD)• Exacerbations of underlying mental illness• Users may attempt to hurt themselves• May make users feel “invincible”LSD Oral DosagesThreshold 20 μgLight 25-75 μgCommon 50-150 μgStrong 150-400 μgHeavy 400+ μgLD50 (Lethal Dose) 12,000 μghttp://www.erowid.org/chemicals/lsd/lsd_dose.shtml
LSD Use in Healthcare6,14,15• Terminally ill patients• Alcoholism• Narcotic drug addicts• “Model psychosis” forschizophrenia• Sociopaths• Criminal psychopaths• Psychotherapy adjuncthttp://www.lybba.org/blog/mind-over-matter-psychotherapy-for-cancer-care/
Schizophrenia vs. LSD “Trip”16Schizophrenia• Permanent mentalillness• Unpleasant anduncomfortable positivesymptoms• Near completeseparation from realityand lack of control• Physical implications• Resistant to suggestion• Disturbed thinkingLSD “Trip”• Temporaryhallucinations• Pleasant and euphoric• No separation fromreality• No permanent braindamage• Highly suggestable• Altered perception• KEY difference: 2AR-mGluR2 receptorcomplex
Legal Implications17• Using LSD will not get youfederally prosecuted.• Making, trafficking andselling LSD is federallypunishable.• Penalties for traffickingdepend on the amount inquestion.• Possession with intent tosell: 3-15 years in jail,$2,000 - $300,000 fine.• Possession for personaluse: 1-3 years in jail,$1,000 - $20,000 fine.• More than 2 prior offensescan get you put in jail forlife.http://clovisindependent.com/2011/05/09/clovis-woman-45-held-in-store-robbery/handcuffs/
Abuse10• LSD presents no physicaladdiction potential.• Psychological addiction• Tolerance happens veryquickly, often within 3days.• The high dissipatesquickly after tolerancewithout withdrawal,addiction or cravings.• No associations withdopamine rewardpathways.http://drugs.blurtit.com/q3150977.html
Impacts on Life2,11• Neglect personal hygiene• User may attempt to hurthim or herself due to a“bad trip”.• Some users report thatthe drug SAVED theirmarriage (Clare BoothLuce).• Some report that it wasthe cause of their divorce(Cary Grant).• Some users reportenhancement of personalrelationships.http://www.marmalade-skies.co.uk/beatles.htm
REFERENCES1. Hunt, Jenny. "Your Brain on Drugs: LSD." Palm Partners Recovery Center. Palm Partners Drug Rehab Center, 01 Jan 2013. Web. 23 Feb 2013.<http://www.drugs-forum.com/forum/showwiki.php?title=Lsd >.2. Faraci, Devin. "When LSD Was Legal (And Cary Grant Was Tripping)." Badass Digest. Badass Digest, 22 Apr 2012. Web. 23 Feb 2013.<http://badassdigest.com/2012/04/22/when-lsd-was-legal-and-cary-grant-was-tripping/>.3. "LSD: A Psychedelic Hyperdimension." Understanding Drugs. GaianXaos, n.d. Web. 23 Feb 2013. <http://www.gaianxaos.com/lsd.htm>.4. Hoffman, Albert. LSD: My Problem Child. New York, NY: McGraw-Hill Book Company, 1980. eBook. <http://www.psychedelic-library.org/child1.htm>.5. "LSD (Acid)." National Institute on Drug Abuse: The Science of Drug Abuse and Addiction. National Institute on Health, n.d. Web. 11 Mar 2013.<http://www.drugabuse.gov/drugs-abuse/lsd-acid >.6. "LSD Today." The Substance. Ventura Film SA, n.d. Web. 11 Mar 2013. <http://www.thesubstance-themovie.com/about/about_page6/ >.7. Reuschel, S. et al. Recent advances in chromatographic and mass spectrometric methods for determination of LSD and its metabolites inphysiological specimens. The Journal of Chromatography B: Biomedical Sciences and Applications. 1999; 733: 145-159.8. Elis, Lee. Sex Differences: Summarizing More Than a Century of Scientific Research. New York, NY: Psychology Press, 2008. 569. Print.9. "What Is An Hallucinogen?." The Truth About LSD. Foundation for a Drug-Free World, n.d. Web. 11 Mar 2013.<http://www.drugfreeworld.org/drugfacts/lsd/street-names-for-lsd.html>.10. "LSD Dangers." TheGoodDrugsGuide.com. TheGoodDrugsGuide.com, n.d. Web. 11 Mar 2013.<http://www.thegooddrugsguide.com/lsd/dangers.htm >.11. "Myth Debunking: LSD Does Not Stay In Your Body Forever." The Vaults of Erowid. Erowid, n.d. Web. 11 Mar 2013.<http://www.erowid.org/chemicals/lsd/lsd_myth1.shtml >.12. "How Drugs Cause Hallucinations." World Science. World Science, 3 Aug 2010. Web. 11 Mar 2013. <http://www.world-science.net/othernews/070129_hallucinogen.htm >.13. Hunt, Jenny. "Your Brain on Drugs: LSD." Palm Partners Blog. Palm Partners Recovery Center, 30 Jan 2013. Web. 11 Mar 2013.<http://blog.palmpartners.com/your-brain-on-drugs-lsd/ >.14. "LSD Breakthrough for mental health patients." The Journal of Thelemic Sciences. The Journal of Thelemic Sciences, 24 Feb 2008. Web. 11 Mar2013. <http://thelemicstudies.com/?q=node/16 >.
References15. Szalavitz, Maia. "LSD May Help Treat Alcoholism." Time Magazine: Health and Family. Time Inc., 09 Mar 2012. Web. 11Mar 2013. http://healthland.time.com/2012/03/09/lsd-may-help-treat-alcoholism/ .16. Aron, Paul. "Hallucinogens and Schizophrenia." . N.p.. Web. 11 Mar 2013.<http://www.users.totalise.co.uk/~paul.aron/Hallucinogens.pdf >.17. LaMance, Ken. "LSD: Penalties for Sale and Possession." Legal Match. LegalMatch.com, 09 Nov 2011. Web. 13 Mar2013. <http://www.legalmatch.com/law-library/article/lsd-penalties-for-sale-and-possession.html >.
What is Peyote?1,4,8• Is a small, green, and spineless cactus foundprimarily in northern Mexico and southwesternUnited States called Lophophora williamsii• Primary active ingredient making peyote ahallucinogen is Mescaline– Many other compounds present• Hallucinogens produce a feeling ofseparation from one’s body– Can last from minutes to hours
History1,3• Used for thousands of years by indigenous peoples of Northand South America (Mexico and some North American tribes)– Shamans of Huichol in Mexico• 1638 – Hernandez gave peyote its’ first scientific name Peyotlzacatensis• 1840 – Lemaire used Echinocactus williamsii• 1894 – Then Coulter namned it Lophophora williamsii
History (cont’d)1• North American tribes adopted peyote in thelate 19th century• The use in religious ceremonies has evolvedwith time to be used primarily in the NativeAmerican Churchhttp://theesperanzaproject.org/tag/wirikuta/
Cultivation1,7,8• The top or “button” of the plant is removedand dried, powdered, or made into a tea• Usually the dried top is chewed andswallowed where it is absorbedgastrointestinally– Typical dose is 6-12 buttons– Less commonly smoked• Purpose is to induce religious visions
Epidemiology5• Difficult to determine exact percentages, but is not common• Generally abuse, if it occurs, happens more frequently in native Americans• A retrospective chart review of the California Poison Control System(CPCS) electronic database for cases from 1997-2008 was performed– 31 patients in 12 years• Most young, male patients who took peyote orally• 26 received medical treatment in emergency room• Mild to moderate effects lasting <24 hours– Concluded that overdose is uncommon, considered mild-moderate, andunlikely to result in death
Epidemiology (cont’d)9• Investigated illicit (ie. nonceremonial) peyote use in AmericanIndians (AIs)– 89 AI adolescents in a tribally operated residential substance abusetreatment program (RSATP) from 1998-2001– Most were male, from single parents homes, with low self-esteem– 10 reported illicit use of peyote• 8 used once or twice in their lifetime• Concluded peyote use is low in AI adolescents with priorsubstance abuse problems
Pharmacodynamics1• Physical (Amphetamine-like effects)– Increased heart rate– Increased blood pressure– Dilated Pupils• Psychological (LSD-like)– Time and space distortion– “feel outside themselves”• Other– Nausea– Vomiting– Euphoria• Larger Doses– Increase sensitivity to sensory images– Flashes color– Geometric patterns
Pharmacokinetics4,7• Rapidly absorbed from the G.I. tract• Onset: 30 minutes – 2 hours• Peak Serum Concentrations: 2 – 4 hours• Peak Effect: 4 – 6 hours• Symptoms Last: ~6 - 12 hours• Not bound to albumin• Large volume of distribution• Hepatic metabolism with 60% excreted unchanged in theurine
Mechanism of Action &Drug Interactions4,7• Mechanism– Generally not known– Amphetamine-like– Peyote is a exogenous phenylethylamines• Ex. Endogenous phenylalkaloids are norepinephrine and dopamine• Drug Interactions (Stimulants)– Nicotine– Cocaine– Sympathomimetic amines,– Amphetamines
Toxicology1, 4, 10• Peyote (mescaline) has no reported cases of death due to overdose• Dose– 3 - 5 mg/kg (All effects can lead to self-inflicted or accidental injury)• Psychic effects and visual hallucinations• Anxiety• Paranoia• Fear• Emotional Instability– >20 mg/kg• Hypertension• Bradycardia• Respiratory Depression• Death• Treatment– Symptomatic– Benzodiazepines or antipyschotics(Ex. droperidol)
Law1• Peyote is considered a schedule 1 substance inthe United States under the ControlledSubstances Act and therefore is illegal topossess or use• However, it has been legalized to use in nativeAmerican rituals under an exemption in thelaw (to protect religious use for NativeAmerican Church members)• Canada – Peyote is classified as a schedule 3substance
Law (cont’d)• TITLE 21 - FOOD AND DRUGS• CHAPTER II—DRUG ENFORCEMENT ADMINISTRATION• DEPARTMENT OF JUSTICE• PART 1307: MISCELLANEOUS• Special Exempt Persons• Sec. 1307.31 Native American Church.• The listing of peyote as a controlled substance in Schedule I does not applyto the nondrug use of peyote in bona fide religious ceremonies of theNative American Church, and members of the Native American Church sousing peyote are exempt from registration. Any person who manufacturespeyote for or distributes peyote to the Native American Church, however,is required to obtain registration annually and to comply with all otherrequirements of law.
Long Term Effects4,6• Not completely known• Tolerance to peyote– Cross tolerance to LSD and psilocybin• Study with 3 groups of Navajo Native Americans– Members of Native American Church with regular consumption– People with past alcohol abuse (sober <2 months)– Minimal use of peyote• We administered the Rand Mental Health Inventory (RMHI), and ten standardneuropsychological tests of memory and attentional/executive functions.• Concluded no long term effects on either peyote groups but there were foralcoholic patients
Mescaline-Like Drugs1• Other plants– San Pedro Cactus– Peruvian Torch Cactus• Artificially Produced– DOM– MDA– DMA– MDMA• Spices– Nutmeg(myristicin and elemicin)http://www.herbalfire.com/peruvian-torch-cactus-trichocereus-peruvianus.html
References• 1. Kuhn C, Swartzwelder S, Wilson W. Buzzed. 3rd edition. 90-105.• 2. “Peyote”. Natural Medicines Comprehensive Database. Accessed from AccessPharmacy April 8, 2013• 3. Kapadia G and Fayez M. Peyote Constitutents: Chemistry, Biogenesis, and Biological Effects. Journal of PharmaceuticalSciences. December 1970;59(12):1699-1727. Accessed April 8, 2013.• 4. Plants-Peyote/Mescaline. Micromedex. Accessed April 8, 2013.• 5. Carstairs S, Cantrell F. Peyote and mescaline exposures: a 12-year review of a statewide poison center database. ClinicalToxicology (15563650) [serial online]. April 2010;48(4):350-353. Available from: Academic Search Complete, Ipswich, MA.Accessed April 9, 2013.• 6. Halpern J, Sherwood A, Hudson J, et al. Psychological and Cognitive Effects of Long-Term Peyote Use Among NativeAmericans. Biological Psychiatry. 15 October 2005;58(8):624-631. Accessed April 8, 2013• 7. Delgado J, Traub S, & Grayzel J. Intoxication from LSD and other common hallucinogens. Up to Date. Reviewed June 15,2011. Accessed April 8, 2013.• 8. Babu KM. Chapter 82. Hallucinogens. In: Babu KM, ed. Goldfranks Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=6522465. Accessed April 9, 2013.• 9. Fickenscher A, Novins D, & Manson S. Illicit peyote use among American Indian adolescents in substance abusetreatment: a preliminary investigation. Subst Use Misuse. 2006;41(8):1139-54. Accessed April 8,2013.• 10. Kelsey F. The Pharmacology of Peyote. Department of physiology and pharmacology state university of south dakota.June 1959. Accessed April 8, 2013
Amanita muscaria1,2http://www.geog.ucsb.edu/img/news/2011/1024px-Amanita_muscaria_3_vliegenzwammen_op_rij.jpg• Amanitai: Mount Amanus in northernSyria• Musca: Latin word for fly• It is commonly referred to as fly agaric• Medieval belief that it repelled flies,• Alternative hypothesis proposesthat the term “fly” refers not to insects,but the delirium resulting fromconsumption of the fungus.
History3• 1200 BCE: Multiple indications in religious literature wide-spread Asia• 1291: Fresco in France depicts Adam and Eve standing beside a Tree ofknowledge• 1960 – 65: Appears in United states urban subcultures• 1968: R. Gordon Wasson proposed the fly agaric was in fact the Somatalked about in the ancient Rig Veda texts of India• 1980s: Several books and scientific journal articles appear describingmodern and traditional use as an inebriant across the globe
History (Cont.)3• Jul 20-23, 2000: Consciousness Technologies• Aug 23-26, 2001: Telluride Mushroom Festival;encourage individuals in expanding theirknowledge regarding diverse species and theircultivation• 2002: Clark Heinrich argues a key role of A.Muscaria in many world religions includingHindusin, Judaism and Christianity• Dec 5-6, 2009: Mycological Society of SanFrancisco Annual Fungus Fair
Description4,5• Wide variety among the species;• Var. muscaria: the typical red-and-white spotted variety;Siberian origin, which spreaded outward across Asia,Europe and North America• Var. flavivolvata: red w/ yellow to yellowish-white wartsfound from southern Alaska down through RockyMountains• The cap is covered with numerous small white to yellowpyramid-shaped warts; As the fungus grows, the red colourappears through the broken veil and the warts become lessprominent• Fully grown cap is usually around 8–20 cm (3–8 in) indiameterhttp://www.flickr.com/photos/blackdiamondimages/21178136/in/set-72157601716027470
Fun Facts6,7• Deaths head• Fly agaric• The woodpecker of Mars• Price: Dried A. muscaria averages around ~$52 perounce on ethnobotanical vendor web sites.Psychoactive amanitas are rarely found in undergroundmarkets.• Law: Amanita mushrooms and their active ingredientsare uncontrolled in the United States and in mostcountries. If sold for consumption as a food or drug,sales are regulated by the FDA in the US.http://tinyurl.com/ccosc3k
Fun Facts8Administration Methods:• Simmering a few mature dried caps in waterfor a half hour and then drinking the teaslowly over a period of a couple of hours• Tear off little pieces of dried cap and roll theminto little pills; swallow these withoutchewing, with as little water as possible• Some claims that it can be smoked as well
Amanita MuscariaDosage and PK9• Light: 1 - 5 g (1 medium cap)• Common: 5 - 10 g (1 - 3 medium caps)• Strong: 10 - 30 g (2 - 6 medium caps)• Onset : 30 - 120 minutesPeak : 1 - 2 hoursDuration : 5 - 10 hours (higher doses seem to lastlonger)
Pharmacokinetics10• Absorption: A. muscaria from the gastro-intestinaltract seems to be rapid. However, the exact rate andthe proportion of absorption is still unknown.• Distribution: Muscimol and ibotenic acid, cross theBBB. Neither muscimol nor ibotenic acid is removedfrom the receptor by the GABA or glutamate activeuptake system.• Half-life: Ibotenic acid and muscimol detected in urinewithin one hour after the ingestion. Peak excretion ofibotenic acid occurs two hours after ingestion.
Pharmacodynamics10,11• The primary active chemicals known in Amanita muscaria :Muscimol, Ibotenic Acid, Muscazone, and Muscarine.• Muscimol: Primary action is at GABA receptor sites as apotent GABA-A agonist; active in several parts of the brainincluding the cerebral cortex, hippocampus, andcerebellum.– Psychoactive dose of muscimol is around 10-15 mg; LD50 in miceand rats respectively 3.8 mg/kg SC and 45 mg/kg orally• Ibotenic Acid: The current view is that some Ibotenic Aciddoes cross the blood brain barrier unchanged. Ibotenic acidis structurally similar to the stimulatory neurotransmitterglutamic acid.
Pharmacodynamics10,11• Muscarine: Affect acetylcholine levels and acts atmuscarinic receptors.– While the levels of muscarine in A. muscaria are quitelow (.002% - .003% by dry weight), some of theeffects of A. muscaria are characteristic of cholinergicinvolvement.• Muscazone: The existence of ibotenic acid isomermuscazone in some A. muscaria may clue to thebiosynthesis of ibotenic acid. Possible breakdownproduct of Ibotenic Acid and Ott describes it as apossible "artifact of isolation procedures" whichis "of dubious psychoactivity".
Acute Poisoning12• Drowsiness• Confusion• Dizziness• Ataxia• Euphoria• Hangover (sameday)• Delirium• Visual and auditorydisturbances with hallucinations• Muscle cramps and spasms• Gastrointestinal disturbancesand convulsions may alsobe seen• Increased salivation andPrespiration• Death (rare)
Clinical Effects12,13• Cardiovascular: Pulse and B.P. are usually normal. One caseof patient developing cardiac fibrillation• Respiratory: Over-dose can cause respiratory depression• CNS: Depression and stimulation might alternate.Symptoms begin with drowsiness followed by confusion,with dizziness, euphoria resembling alcohol intoxicationand proceeds to illusions or manic excitement– Periods of excitement may alternate with periods ofsomnolence– Illusions are misinterpretation of sensory stimuli such aschanges in color vision
Clinical Effects12,13• Musculoskeletal: Muscle twitching,fasciculation and spasms• Gastrointestinal: Dyspepsia and vomiting• Metabolic: Light or milddehydration may be observed• Meiosis as well as mydriasishttp://www.funnyjunk.com/funny_pictures/3132057/MARIO+S+MUSHROOMS/
Toxicity Management14• Treatment of signs and symptoms of intoxication• Supportive care• Administration of activated charcoal, most effectivewithin an hour of ingestion• No specific antidote
History1• First noted by Jean Johnson in 1938, he heard of use bythe Mazatec Indians (Mexico).• Mazatecs made tea with the leaves or chewed theleaves to “predict the future”• Gordon Wasson found salvia while researchinghallucinogenic mushrooms. He was not allowed tobring the plant back to the U.S.• The first plant wasn’t acquired until 1962 by GordonWasson and Albert Hofman. They described salvia as aless desirable substitute for mushrooms.• The plant can grow up to 1.5 meters tall
Street names2• Maria Pastora• Sage of the Seers• Diviner’s Sage• Sally-D• Magic Mint• The use of street names is not commonbecause of it being legal in many states, and itis easily purchased online.
Methods of administration1• The active ingredient is salvinorin A, manymethods can be used to get this substanceinto the body.• Smoking (pipe, bong, joint)- extreme effectslast a maximum of 15 minutes (most common)• Chewed (quid)- effects last 1-2 hours• Vaporized• Consumed in a tea (traditional)
Genius mind of the abusers3• Using the leaves directly off of the plant wouldbe considered a 1X strength. People havemade ways to extract the salvinorin A toincrease the concentrations.• 5X- 100X• 100X means that 1 gram of salvia has theamount of salvinorin A as 100 grams.
Recipe4• 1) crush 90g of leaves• 2) add rubbing alcohol (solvent)• 3) let sit for 16 hours• 4) evaporate solvent• 5) add solvent, let stand for 5 minutes,remove top 2/3 of mixture and discard (x5)• 6) combine extract with 10g of leaves• 7) you just made 10X salvia
Epidemiology5,6• 2.8% of a group study reported using salvia atleast once in their life.• 6.1% of people between the ages of 18 and 25reported usage.• Almost 20% admitted doing “risky” behavior suchas selling illegal items, stealing, carrying firearms,fighting with intent to seriously injure.• At risk- white, male, heavy drinkers, frat guys.• 83% increase between 2006 and 2008.
Pharmacodynamics8• MOA: Selective to the kappa opioid receptor.• No 5-HT2a activity.• Study done in mice shows lower DA levels inthe nucleus accumbens.• Originally thought there could be anti-depressant properties.• Mice showed depressive characteristics whileon salvia.
Pharmacokinetics8• Salvinorin A is degraded in the GI, if contactwith mucosa membranes doesn’t occur, theeffects will not be seen.• Metabolized into Salvinorin B• Excreted renally• T1/2- 56.6 minutes• A study in rats showed peak effects occurringat 5-15 minutes, and the effects wore off bythe 2 hour mark.
Toxicity2• Little information as this drug is relatively newin terms of recreational use.• Zero deaths from over dose have beenrecorded.• AAPCC has received 35 calls due to adverseeffects.• LD50- 340mg/kg• Naloxone may be an antidote; however it isnot FDA approved
Experiences• “I was looking at my trip-sitter, and he had turned into an alien-like form.He looked a lot like himself, only gray, and no nose, or ears, or hair. All Icould manage to say was, wtf man.. wtf man.. over and over and overagain, apparently throughout the entire trip. Seconds after thatrealization, I (apparently) had gotten stuck in the curtain I was sittingagainst it. In my mind, I had become the wall”• “I felt like I was being ripped in half by a thousand little men”• “I tried to stand up, but instead just fell over a bed. At that point, I becamethe floor, and started thinking about how lame life is to be a floor.”• Most people said it was something they would not do again.
References• 1) "Salvia Divinorum | CESAR." Salvia Divinorum | CESAR.University of Maryland, 2006. Web. 4 Apr.2013.http://www.cesar.umd.edu/cesar/drugs/salvia.asp• 2) "SALVIA DIVINORUM AND SALVINORIN A." Drug EnforcementAdministration. N.p., July 2012.Web.http://www.deadiversion.usdoj.gov/drug_chem_info/salvia_d.pdf• 3) "The Salvia Dream." The-salvia-dream. Salvia DreamingCreations, 2007. Web. http://www.the-salvia-dream.com/salvialeaves.html• 4) "How To Make Salvia Divinorum Extract." Synchronium. N.p.,2008. Web. 04 Apr. 2013.http://www.synchronium.net/2008/12/22/how-to-make-salvia-divinorum-extract/
References cont.• 5) Perron BE, Ahmedani BK, Vaughn MG, Glass JE, Abdon A, Wu LT. Useof Salvia divinorum in a nationally representative sample. Am J DrugAlcohol Abuse. 2012;38(1):108-13.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408869/+• 6) Muscari, Mary E. "What Are the Effects of Salvia Use inAdolescents?" Medscape. N.p., 4 Apr. 2011. Web. 08 Apr.2013.http://www.medscape.com/viewarticle/739840_2• 7) "Monitoring the Future." National Institute on Drug Abuse, 2011.Web. 8 Apr.2013.http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2011.pdf• 8) Erowid. "Erowid Salvia Divinorum Vault: Basics." Erowid SalviaDivinorum Vault: Basics. N.p., 2000. Web. 08 Apr. 2013.http://www.erowid.org/plants/salvia/salvia_basics.shtml
History¹• 1962: First developed in the United States• 1966: Patented by Parke-Davis• 1967: Dispensed by underground chemistsfrom Michigan• 1970: During the Vietman war, ketamine wasused as an anesthetic & FDA approvedthe use in children and the elderly• 1978: FDA reported abuse of ketamine
History (cont’d);• 1980s & 1990s: Recreational use of ketaminebecame the popular way• 1997: NY passed a law prohibitingsale/possession of ketamine• 1999: DEA named ketamine a schedule IIIdrug & became illegal to possess forrecreational and nonmedical purposes
Slang terms³• Bump• Cat killer• Cat valium• Green• Jet• Honey oil• Kit Kat• Purple• Special K• Special la CokeImages retrieved from: http://drug-effects.us/what-is-ketamine, http://news24now.com/ketamine-crazy300000-risk-death-by-taking-horse-sedative/1328
Epidemiology of Recreational Use>• First reported abuse was of medicalprofessionals• Associated with the “post-rave” clubbing andyouth dance culture– “club drug” alongside ecstasy, cocaine, or GHB• Most common in East and South-East Asia– Possibly due to low price
Epidemiology (cont’d)>• Four main groups commonly abusing ketamine– Regular drug users– Gay club/party scene– Heroin users– Self-exploratory people
Data retrieved from: http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2011.pdf
Chemical Structure²• 2-(o-chlorophenyl)-2-(methylamino) cyclohexanone (hydrochloride)• Molecular Weight: 238 g/mol• Racemic mixture• Prepared in many concentrations– 10 mg/mL– 50 mg/mL– 100 mg/mL• Benzethonium chloride asthe preservativeImages retrieved from: http://greggordon.org/edu/ivanes/ketamine3.htm &http://www.sunshinecoasthealthcentre.ca/hallucinogens.html
Pharmacodynamics?• Rapid acting general anesthetic, hallucinogen,psychotomimetic• Not well understood– Block NMDA receptors?– Interact with opiate receptors?– Sympathomimetic effects?– Dopamine uptake inhibitor?• Known that ketamine does NOT interact with GABAreceptors, unlike many anesthetics
Pharmacodynamics (cont’d)@• NMDA antagonist– Associated with analgesic effects– 10 to 50 times less potent in blocking NMDA receptorscompared to PCP• Opiate receptors– Analgesia and dysphoric effects• Sympathomimetic effects– Enhanced central and peripheral monoaminergictransmission• Dopamine uptake inhibitor– Elevates DA levels
Pharmacokinetics<A• Elimination half life: 2 to 3 hours• Bioavailability– Intramuscular – 93%– Intranasal – 25 to 50%– Oral – 20 ± 7%– Clearance: 12 to 17 ml/kg/min• Metabolized to norketamine by:– Hydroxylation– Conjugation– Dehydration– DemethylationImage retrieved from: http://www.anesthesia2000.com/General/Pharmacokinetics/kinobj4.htm
Pharmacokinetics (cont’d)@ B• Metabolized to norketamine by CYP3A4 withminor contributes from CYP2B6 and CYP2C9isoforms– N-demethylation• Inhibitors of these CYP450 isoenzymes coulddecrease the rate at which ketamine iseliminated
Pharmacokinetics (Cont’d)<• The therapeutic range for ketamine is 0.7to 2.2 mcg/mL with awakening occurringbelow 0.5 mcg/mL• Usually dosed on a 2.0 mg/kg basisImage retrieved from: http://greggordon.org/edu/ivanes/ketamine4.htm
Clinical Use@• Anesthetizing patients who are at risk forhypotension, bronchospasm and in pediatricprocedures• Produces a hypnotic state unlike otheranesthetics– Profound analgesia– Unresponsiveness to commands– Amnesia• Given to patients with tolerance to opioids• Primarily used in veterinary procedures
Recreational UseC;:• As a psychedelic agent• Can be injected, snorted, orally ingested, orrectally administered– Heated to remove the water and form a white powder• Can be added to tobacco or marijuana cigarettesand smoked for entry– Similar to PCPImage retrieved from: http://frontpsych.com/2011/12/01/the-ten-best-psychedelic-albums-of-2011/
Recreational Use (cont’d)C• Recreational dosing– Intramuscular – 25 to 50 mg– Snorting – 30 to 75 mg– Oral – 75 to 300 mg• Effects– Dreamy effect– “K-hole”– Drowsiness– Perceptual distortions
Psychological Effect¹¹¹²• Decreased awareness of environment in whichthey are in• Sedation• “Dream-like” state• Vivid dreams• Increased distractibility• Disorientation• Uncommunicative• Hallucination, impaired thoughts, out-of-bodyexperiences, delirium
Duration of “high”>• Effects are seen:– within seconds when smoked– 1 to 5 minutes when injected– 5 to 10 minutes when snorted• Effects last:– 30 to 45 minutes when injected– 45 to 60 minutes when snorted– 1 to 2 hours when ingested/smoked
Toxicology?;=• Wide margin of safety– Several times been administered 10-times theappropriate dose with complete recovery• Respiratory depression may occur with OD or toorapid rate of administration– May require use of ventilator• Withdrawal symptoms may be seen with chronicuse of ketamine
Toxicology (cont’d);:• “Daily intravenous injections in rats of fivetimes the average human intravenous doseand intramuscular injections in dogs at fourtimes the average human intramuscular dosedemonstrated excellent tolerance for as longas 6 weeks”.• “Twice weekly anesthetic sessions of one,three, or six hours’ duration in monkeys over afour- to six-week period were well tolerated”.
References1. Lankenau SE, Clatts MC. Ketamine Injection among High Risk Youth: PreliminaryFindings from New York City. J Drug Issues. 2002;32(3):893-905.2. Gordon, G. MD. Ketamine fromhttp://greggordon.org/edu/ivanes/ketamine2.htm. February 12, 2012.3. Center for Substance Abuse Research. Ketamine. University of Maryland.Updated on May 2, 2005. http://www.cesar.umd.edu/cesar/drugs/ketamine.asp4. Kalsi, S., Wood, D., & Dargan, P. (2011). The epidemiology and patterns of acuteand chronic toxicity associated with recreational ketamine use.Emerging HealthThreats Journal, 4. doi:10.3402/ehtj.v4i0.71075. Drug Bank. Ketamine. Updated on February 8, 2013.http://www.drugbank.ca/drugs/DB01221#transporters6. Patel PM, Patel HH, Roth DM. Chapter 19. General Anesthetics and TherapeuticGases. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilmans ThePharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011.http://www.accesspharmacy.com/content.aspx?aID=16664636. Accessed April20, 2013.7. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo:Thomson Healthcare. Updated periodically.
References (cont’d)8. Adams VHA. The mechanisms of action of ketamine. Anaesthes Reanim1998;23(3):60-3.9. National Highway Traffic Safety Administration. Drugs and Human PerformanceFact Sheets. Ketamine.http://www.nhtsa.gov/people/injury/research/job185drugs/ketamine.htm10. DailyMed. Ketamine Hydrochloride.http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bb912318-2e22-4469-b0a2-774803ee1bb8#nlm34088-511. Grant IS, Nimmo WS, Clements JA. (1981) Pharmacokinetics and analgesic effectsof i.m. and oral ketamine. Br J Anaesthes 1981;53(8):805-10.12. Curran HV, Morgan CA. Cognitive, dissociative and psychotogenic effects ofketamine in recreational users on the night of drug use and 3 days later.Addiction 2000;95(4):575-90.13. Trevor A.J., Katzung B.G., Kruidering-Hall M.M., Masters S.B. (2013). Chapter 25.General Anesthetics. In A.J. Trevor, B.G. Katzung, M.M. Kruidering-Hall, S.B.Masters (Eds), Katzung & Trevors Pharmacology: Examination & Board Review,10e. Retrieved April 21, 2013 fromhttp://www.accesspharmacy.com/content.aspx?aID=56981944.
Overview1• Not the bath salts you use in your tub!• Designer drug that contains substitutedcathinones• Methylenedioxypyrovalerone (MDPV),mephedrone & methylone most commonly used• Classified as Schedule I substance in October2011
• Cathinone: found naturally inthe plant Catha edulis (khat)– Beta-keto analog of amphetamine• 1st synthetic cathinonessynthesized in late 1920s• Limited therapeutic use due toserious side effects• Emerged as popular designerdrugs of abuse in 2000sHistory2Photo From:http://www.botanypictures.com/plantimages/catha%20edulis%2004%20NL%20uithof%20greenhouse.jpg
• Most popular between ages of 20 and 295– Reports between ages <6 to 59 years of age• Mephedrone drug of choice in Europe2• MDPV drug of choice in United States2• 20115– 6,138 bath salt calls reported to AAPCC• Jan to July 20116– 87 bath salt calls from Maine to Northern NewEngland Poison Center• 20125– 2,654 bath salt calls reported to AAPCCEpidemiology
020406080100120140Sept 2012 Oct 2012 Nov 2012 Dec 2012 Jan 2013 Feb 2013AAPCC Reported Bath Salt ExposuresNumber of ExposuresPelletier. Adapted from:http://www.aapcc.org/alerts/bath-salts/.
• White or brown crystalline powder• Sold in small foil or plastic packets• “Not for human consumption”Appearance1Photo From:http://www.cnn.com/video/crime/2011/02/16/feyerick.bath.salt.drugs.cnn.640x360.jpgPhoto From:http://blogs.riverfronttimes.com/dailyrft/bath-salts-drug.jpg
• Most Common Routes– Insufflation (snorting)– Ingestion• Other Routes– Inhalation– Sublingual– Rectal Administration– Intravenous– IntramuscularRoutes of Administration2Photo From:http://www.tokeofthetown.com/2012/06/07/BathSaltsDetail.jpg
• Cocaine• Amphetamines• Methamphetamines• Caffeine• Hallucinogenes• Kratom• Other syntheticcathinones• AlcoholDrugs Used with Bath Salts2 Beta Blockers Zopiclone Pregabalin Famotidine Omeprazole Domperidone Opiates Cannabis Benzodiazepines
• Like other stimulants, bath salts Inhibitmonoamine uptake transporters leading toincreased concentrations of catecholamines(DA, 5HT, NE) in synapses• Less able to cross blood-brain barriercompared to amphetamines due to beta-ketogroup which increases polarityMechanism of Action2Figures From:http://www.nature.com/npp/journal/v38/n4/fig_tab/npp2012204f1.html
MDPV Effects on Catecholamines7Figure From:http://www.nature.com/npp/journal/v38/n4/fig_tab/npp2012204f2.html
• MDPV found to be 10 times more potent than cocainein producing:– Locomotor activation– Tachycardia– Hypertension• MDPV shown to be a monoamine transporter blocker• Increased potency and selectivity for catecholaminescompared with cocaine• Robust stimulation of dopamine transmission helpsexplain adverse effects seen in humans anddemonstrates serious potential for abuseMDPV Study7
• Typical dose of MDPV ranges from 5 to 30 mg• Tolerance reported with doses >200 mg in a singlesession• Withdrawal syndrome has been reported after abruptcessation following long-term use– Depression– Anergia– Anhedonia– Anxiety– Sleep Disorders– Fatigue– CravingsTolerance and Dependence2
• No treatment available to reverse effects ofbath salts• Main goal: protect patient from harm andfrom doing harm to others• Local hospitals using midazolam– Provides sedation and relieves anxiety• Ketamine also used in extreme cases• Patients with excited delirium placed intomedically induced sleepTreatment8
• Limited data on number of deaths resultingfrom bath salts due to concurrent drug use2• Mephedrone Related Deaths2– Blood concentration = 0.13 to 22 mg/L• MDPV Related Death9– Urine concentration = 670 ng/mL– Blood concentration = 82 ng/mLFatalities
Legislation1• October 2011: U.S. DrugEnforcement Administration places emergency banon MDPV,medphedrone & methylone• July 2012: Legislation signed making mephedroneand MDPV permanently illegal• After United Kingdom banned mephedrone in2010, naphyrone quickly replaced itPhoto From:http://tothemaximusblog.org/wp-content/uploads/2012/07/url.jpeg
• Bangor man arrested after running around andyelling at people on Center Street in Bangor• Claimed to be on bath salts and wanted to get offthem• Charges: disorderly conduct, criminal mischief &resisting arrest• Stops breathing while in jail• Resuscitated and brought to hospital• Ultimately dies at hospitalLocal Stories – 1st Death10
• 19 year-old male brought to Pen Bay MedicalCenter to “get clean”• Causes $30,000 worth of damage to special careunit after becoming agitated• Pen Bay increases police presence as a result• Protocol change: extreme cases sent to EMMCLocal Stories – Pen Bay Incident11
• “Jesse” – 10 year opiate user looking for new wayto get “high”• Found bath salts “everywhere” in Bangor• Injected bath salts and spent 3 hours searchingfor four leaf clovers• Didn’t sleep for 12 days straight• Went from 140 pounds to 105 pounds• Arrested for drug paraphernalia• Considers bath salts to be most destructive drughe’s ever doneLocal Stories – Former User12
• Four people arrested in January 2013 afterlargest bath salt bust in Maine• 24 ½ pounds of bath salts seized• Estimated street value of $1.7 million• Mailed to Maine from ChinaLocal Stories – Hermon Bust13
1. Drug Facts: Synthetic Cathinones (“Bath Salts”). National Institute on Drug AbuseWeb site. http://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts. Accessed March 13, 2013.2. Coppola M, Mondola R. Synthetic Cathinones: Chemistry, pharmacology andtoxicology of a new class of designer drugs of abuse marketed as “bath salts” or“plant food”. Toxicology Letters. 2012;211(2):144-149.3. Messages From the Director. National Institute on Drug Abuse Web site.http://www.drugabuse.gov/about-nida/directors-page/messages-director/2011/02/bath-salts-emerging-dangerous-products. Accessed March13, 2013.4. Bath Salts. The Partnership at DrugFree.Org Web site.http://www.drugfree.org/drug-guide/bath-salts. Accessed March 13, 2013.5. Bath Salts. American Association of Poison Control Centers Web site.http://www.aapcc.org/alerts/bath-salts/. Accessed March 13, 2013.6. Bath salts and K2 in Maine. Alcoholism & Drug Abuse Weekly [serial online]. August29, 2011;23(33):7-8. Available from: Academic Search Complete, Ipswich, MA.Accessed March 13, 2013.7. Baumann M, Partilla J, Schindler C, et al. Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive BathSalts Products. Neuropsychopharmacology. March 2013;38(4):552-562.References
8. EMMC developed bath salts protocol by trial and error. Bangor Daily News Website. http://bangordailynews.com/2012/01/06/health/emmc-developed-bath-salts-protocol-by-trial-and-error/. Accessed March 13, 2013.9. Murray B, Murphy C, Beuhler M. Death Following Recreational Use of DesignerDrug Bath Salts Containing 3,4-Methylenedioxypyrovalerone (MDPV). JournalOf Medical Toxicology [serial online]. March 2012;8(1):69-75. Available from:Academic Search Complete, Ipswich, MA. Accessed March 13, 2013.10. Bangor bath salts user first confirmed death in Maine, medical examiner’s officesays. Bangor Daily News Web site.http://bangordailynews.com/2012/01/11/news/bangor/bangor-bath-salts-user-first-confirmed-death-in-maine-from-the-drug-medical-examiners-office-says/?ref=search. Accessed March13, 2013.11. Pen Bay hospital increases police presence to deal with violent patients.Bangor Daily News Web site.http://bangordailynews.com/2011/11/04/news/midcoast/rockport-police-increase-watch-at-pen-bay-due-to-bath-salts/?ref=relatedBox. Accessed March 13, 2013.12. Bath Salts: A Former User’s Story. WABI TV 5 Web site. (http://www.wabi.tv/news/25141/bath-salts-a-former-users-story). Accessed March 13, 2013.13. Judge revokes bail of man charged in state’s largest bath salts seizure. Bangor Daily News Website. http://bangordailynews.com/2013/02/22/news/bangor/judge-revokes-bail-of-man-charged-in-states-largest-bath-salts-seizure/?ref=search. Accessed March 13, 2013.References (Cont’d)
γ-Hydroxybutyrate (GHB)AnonymousDrug Abuse and SocietyImage: http://www.watchdocumentary.tv/rave-on-the-rave-culture-of-the-late-eighties-still-affects-the-world-today/
Overview of Topics• History• Epidemiology• Pharmacokinetics• Pharmacodynamics• Toxicology• Prescription vs Non-Prescription Use• Expectations for Future Use (my opinion)Image: http://onwardstate.com/2012/01/25/psma-rave-to-hit-alumni-hall/
History 1, 2, 3• Synthesized in 1960 by Dr Henry-Marie Laborit– Analogue for GABA• Originally used for its anesthetic properties• 1970’s– Underwent investigational new drug testing fornarcolepsy and other sleep disturbances• 1980’s/90’s– Used by body builders– Became a popular “club drug”Image: www.chemheritage.org/discover/online
History (Cont.) 1, 3• 1990– FDA banned non-prescription useof GHB• sexual assault AKA “date rape”– Chemical Precursors• γ-butyrolactone (GBL)• 1,4-butanediol (1,4-BD)• 2000– DEA classified GHB and precursors as schedule Isubstances• Illegal to buy, possess, or distribute without a DEA license– Prescription sodium oxybate (Xyrem) listed asschedulle III agentImage: http://jjie.org/kindergartner-placed-handcuffs-arrested-after-tantrum-class/82440
Epidemiology 1, 4• National statistics show increased use in theUS during the 90’s• Use has declined since 2000– DAWN:• 64% increase 1999-2000, 33% decrease 2000-2001, nochange 2001-2002, then 44% decrease in 2003• 1,861 ED visits in 2005 vs 2,340 in 2004– AAPCC:• 485 cases in 2006 vs 1,386 in 2002– MtF:• College students: 29% decrease in use in 2003• 8th, 10th, 12th grade: 0.5-1.5%
Epidemiology (Cont.) 1, 5• Outside the US:– Increase use has been reported in Europe• Denmark, Sweden, and Norway– Also, Australia• Number of GHB-related ambulance calls increased 4%per month from 2001 to 2005http://www.worldpress.org/map.cfm
Trends in Use and Abuse 4• 5 year study (1999-2003) analyzing data fromCalifornia Poison Control System– 1,331 cases– 55% men– Proportion of women increased 38% to 60% in 1999 to 2003– No statistically significant difference between men and women– Mean age 27±9 years– Death in 11% of cases– Self-reported co-ingestion ofethanol, MDMA, amphetamines, cocaine, marijuana, benzodiazepines, etc. in 21% of cases
Trends in Use and Abuse (Cont.) 4Anderson IB, Kim SY, Dyer JE et al. Trends in γ-Hydroxybutyrate (GHB) and Related Drug Intoxication: 1999 to 2003. Annals of EmergencyMedicine. 2006
Trends in Use and Abuse (Cont.) 4• 76% decrease in exposure toGHB observed from baseline– Decrease in cases of abuse– Significant increase in cases ofmalicious intent (“date rape”)• 87% involved females• 43% involved co-ingestion withethanol• 47% occurred at a nightclub, bar, or similar venueImage: http://www.envisioncounsellingcentre.com/date-rape-drugs.html
Pharmacokinetics6, 7• Street Names– “G”, “Liquid Ecstasy,” “Scoop,” “Easy Lay,” “GeorgiaHome Boy,” “Grievous Bodily Harm,” “Liquid X,”“Goop,” “Gib,” “Soap,” and “Nitro”• May be produced using industrial chemicals– Kits used to be sold on the internet• Routes of Administration:– IV liquid for anesthesia– PO• Clear liquid• White powder (dissolved in water)• Tablet or capsulehttp://www.harvarddapa.org/drug-ipedia/sedatives/ghb/
Pharmacokinetics (Cont.) 6, 7• PO Administration– Often of salty powder dissolved in water• Strength often unknown = increased risk of OD• Salty taste that is masked by flavored or alcoholic beverage– Clinical effects within 15-30 min• Peak 20-60 minutes• DDI– Additive Effects• CNS depressants and alcohol– Increased Toxicity• Protease Inhibitors due to CYP450 inhibitionImage: http://www.csus.edu/alcohol/predatory_drugs.html
Pharmacodynamics 7, 8• Structurally similar to GABA– Has effects on sleep-wake cycle, bodytemperature, cerebral glucose metabolism andmemory (amnesia)• Occurs endogenously and exogenously• Endogenous GHB– Neurotransmitter or neuromodulator• Receptors– GHB receptors (endogenous and exogenous)• Hippocampus, cortex, limbic system, and thalamus– GABAB receptors (exogenous only)• Cerebral cortex, cerebellum, and thalamus
Pharmacodynamics (Cont.) 7, 8• Receptor Stimulation– GHB Receptor: Increased synthesis of DA via tyrosinehydroxylase• Striatum and cortex– GABAB Receptor: Activation of Ca2+ and G-proteincoupled Kir channels leads to decreases in DA releaseand ACh concentration• Responsible for producing CNS depressant effects• GHB Precursors– GBL converted to GHB by γ-lactonase– 1, 4-BD concerted to GHB by aldehyde dehydrogenase
MOA of GHB and its Precursors 8Carter L, Koek W, France C. Behavioral analyses of GHB: Receptor mechanisms. Pharmacology & Therapeutics. 2009; 121 (1): 100-114.
Tolerance and Dependence 1, 9• Case Reports– Occurs after q 2-4 hour administration over 2months-4 years with daily doses > 10 g• Rat Studies– Tolerance observed after 6 days of receiving GHBevery 3 hours• Mechanisms of tolerance– Increased GHB metabolism– Reduction in CNS sensitivity
Withdrawal 1, 7, 10• Withdrawal s/s– Insomnia, cramps, n/v, paranoia, hallucinations, tremor, anxiety, HTN, tachycardia, and seizuresWojtowicz J, Yarema M, Wax P. Withdrawal from gamma-hydroxybutyrate,1,4-butanediol and gamma-butyrolactone: a case report andsystematic review. CJEM: Canadian Journal Of Emergency Medicine. 2008; 10 (1): 69-74.
Toxicology 1, 11• S/s of Toxicity– CNS depression/coma, respiratorydepression, salivation, vomiting, myoclonus, death– Salivation and vomiting aspiration• Recovery– Occurs in 6-8 hours following OD• No harm unless aspiration or hypoxia has occurred• Narrow Therapeutic Window– Made smaller with co-ingestion of other CNSdepressants (EtOH) = increased risk of OD
Toxicology (Cont.) 11, 12• LD50– Rats: 1.7 g/kg– Dogs: 3.3 g/kg– Death occurs due to respiratory depression• Treatment– Supportive Care• IV NS prn hypotension• Intubation (with or without adjunctive etomidate) ifsevere respiratory depression present• Atropine if severe bradycardia (often not needed)Image: http://www.mastersext.com/pest-control-rats.html
Treatment (Cont.) 1, 12• Not indicated for treatment– Activated Charcoal• GHB undergoes rapid absorption from GI tract• May increase n/v = increased risk of aspiration• Antidote– Many candidates, but no evidence– AEDs (clonazepam, PHT, phenobarbital, and diazepam)do not reverse coma– GABA receptor antagonist (flumazenil) does notreverse respiratory depression– Others: physostigmine (increased seizures), naloxone(no evidence of clinical improvement)
Illicit vs Prescription GHB 13Illicit GHB Sodium Oxybate• Production and sale notregulated– Purity and strength notguaranteed– One capful of liquid maycontain 5 g of GHB• Much higher rate of abuse• GHB notoriously used forsexual assault (“date rape”)– Negative attention frommedia and law enforcement– US, Europe, and Australia• Production follows GoodManufacturing Practices– Dose is exactly 500 mg/mL– Pt takes 4.5-9 g nightly usingcalibrated device• Abuse much lower due toextensive risk managementprogram– Xyrem Success Program:Physician and patient registrythat limits distribution• Sexual assault: Much lower– Involves physician assaulting apatientImage: http://fmcfsme.com/drug_sodiumoxybate.php
Expectations for Future Use• My Opinion– With increased public awareness of the dangers ofGHB use and abuse via the media and lawenforcement, I predict that the use of GHB willcontinue to decline (at least in the US)http://www.addiction-treatment.com/research/ghb/
References1. Farmer BM. Chapter 80. -Hydroxybutyric Acid. In: Farmer BM, ed. Goldfranks ToxicologicEmergencies. 9th ed. New York: McGraw-Hill; 2011.http://www.accesspharmacy.com/content.aspx?aID=6522118. Accessed March 13, 2013.2. Andresen H, Stimpfl T, Sprys N et al. Liquid Ecstacy – A significant Drug Problem. DeutschesArzteblatt International. 2008; 105 (36): 599-603.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680564/. Accessed March 14, 20133. Wood D, Warren-Gash C, Dargan P, et al. Medical and legal confusion surrounding gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD).QJM: An International Journal of Medicine. 2008; 101 (1): 23-29.http://qjmed.oxfordjournals.org/content/101/1/23.long. Accessed March 14, 2013.4. Anderson IB, Kim SY, Dyer JE et al. Trends in γ-Hydroxybutyrate (GHB) and Related DrugIntoxication: 1999 to 2003. Annals of Emergency Medicine. 2006; 47 (2): 177-183.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246009/. Accessed March 14, 20135. Dietze PM, Cvetkovski S, Baratt MJ, Clemens S. Patterns and incidence of γ-hydroxybutyrate(GHB)-related ambulance attendances in Melbourne, Victoria. The Medical Journal of Australia.2008; 188 (12): 709-711. https://www.mja.com.au/journal/2008/188/12/patterns-and-incidence-hydroxybutyrate-ghb-related-ambulance-attendances. Accessed March 14, 20136. Gahlinger PM. Club Drugs: MDMA, Gamma-Hydroxybutyrate (GHB), Rohypnol, and Ketamine.American Family Physician. 2004; 69 (11): 2619-2627.http://www.aafp.org/afp/2004/0601/p2619.html. Accessed March 14, 20137. Curry SC, Mills KC, Ruha A, OConnor AD. Chapter 13. Neurotransmitters and Neuromodulators. In:Curry SC, Mills KC, Ruha A, OConnor AD, eds. Goldfranks Toxicologic Emergencies. 9th ed. NewYork: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=6504366. AccessedMarch 14, 2013.
References (Cont.)8. Carter L, Koek W, France C. Behavioral analyses of GHB: Receptor mechanisms. Pharmacology &Therapeutics. 2009; 121 (1): 100-114. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631377/.Accessed March 14, 20119. Chakraborty K, Neogi R, Basu D. Club drugs: review of the rave with a note of concern for theIndian scenario. Indian Journal Of Medical Research. 2011; 133 (6): 594-604.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135986/. Accessed March 14, 201310. Wojtowicz J, Yarema M, Wax P. Withdrawal from gamma-hydroxybutyrate,1,4-butanediol andgamma-butyrolactone: a case report and systematic review. CJEM: Canadian Journal OfEmergency Medicine. 2008; 10 (1): 69-74. http://www.cjem-online.ca/v10/n1/p69. AccessedMarch 14, 201311. Doweiko HE. Concepts of Chemical Dependency. 8th ed. Cengage Learning. 2011: 498-499.http://books.google.com/books?id=61WtimqNyVIC&pg=PA498&lpg=PA498&dq=LD50+of+GHB&source=bl&ots=TYdSabVOY&sig=lem2jC13oM2SDYrjMtiYwhBarJs&hl=en&sa=X&ei=8V5DUbnpDqfE4AP3n4DQCg&ved=0CEwQ6AEwAw#v=onepage&q=LD50%20of%20GHB&f=false. Accessed March14, 201312. Mason PE, Kerns WP. Gamma Hydroxybutryic Acid (GHB) Intoxication. Academic EmergencyMedicine. 2008; 9 (7): 730-739. http://onlinelibrary.wiley.com/doi/10.1197/aemj.9.7.730/pdf.Accessed March 14, 201313. Carter L, Pardi D, Gorsline J, Griffiths R. Illicit gamma-hydroxybutyrate (GHB) and pharmaceuticalsodium oxybate (Xyrem®): Differences in characteristics and misuse. Drug & Alcohol Dependence.2009; 104 (1/2): 1-10. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713368/. Accessed March14, 2013
History1,2• Discovered by Joseph Priestly in 1772– Heated iron filings with nitric acid• 1799 – Humphrey Davy experimentations. Coined theterm ‘laughing gas’• 1800-1840 nitrous available to the public for a fee atcarnivals and medicine shows• 1845- Dr. Horace Wells demonstrated dental applicationof nitrous for anesthesia• 1863- nitrous used regularly in dentistry by Dr. GardnerColton• 1880- Anesthesia (chloroform, ether, nitrous) generallyaccepted for surgery and dentistry
Nitrous Uses1,2,3• Adjunct anesthetic and analgesic in dentistry and surgery• Oxidizer to increase power in motor racing and rocketry(contains sulfur dioxide)• Food additive– Canned whipped cream– Cooking sprays– Potato chips• Treatment of alcohol withdrawal?
Mechanism of Action1,4• Not completely understood• GABA inhibition• Opioid agonist• NMDA inhibition
Pharmacodynamics1• Analgesia• Anesthesia• Anxiolytic• Euphoria• Noxious feeling after• Tolerance• May be habit forming
Pharmacokinetics5,8• Onset of action (inhalation)= 2-5 minutes• T½ = 5 minutes• Blood/gas partition coefficient = 0.47• Excreted unchanged by the lungs, minimally through the skin• Very little (0.004%) metabolized• Toxicology - LC50 = 160 mg/m3 (rat)
Nitrous Risks1• Risk of overdose very low– Lack of oxygen is major risk– Gas delivery related injury– Toxicity if combined with other NMDA antagonists– Accidents (driving, standing)– Very little effects on:• Respiration• Brain blood flow• Liver, kidney, GI
Long Term Nitrous Risks4• B12 deficiency– May lead to destruction of nerve fibers– Numbness, tingling– Methionine synthase inhibited– Neurologic/genotoxic/hematologic effects• Immune effects• Megaloblastic anemia• Myocardial effects – increased homocysteine• At occupational exposure limits (OEL), no conclusive evidenceof toxicities
Occupational Hazard4,6• Long term exposure to NOS by medical staff may have healtheffects– Congenital abnormalities, spontaneous abortion– Decreased fertility– Pernicious anemia– Neuropathies
Epidemiology9• Monitored 50 midwives, environmental concentration andbreath tests– 15 had levels below OEL(UK)– 35 showed high exposure (28 very high exposure)
Study on NO in adolescents11• Residents (N = 723) of Missouri Division of Youth Serviceswere assessed with standardized psychosocial measures– Lifetime prevalence of use= 15.8%• Used whipped cream chargers= 57.0%• Used whipped cream cans = 38.6%• Other methods = 39.5%– Mostly white, male, small town– Psychiatric disorders, polydrug use, and temperamentalfearlessness were correlated with NO use
The Law• Regulated by the FDA• Possession is not illegal, but selling for human consumptioncan be prosecuted• Illegal in many states to use recreationally and to sell to aminor• Available over-the-counter in kitchen stores and head shops
Maine Law12• Unlawful use or possession of inhalants• 1. Prohibited acts. A person may not intentionally or knowingly:– A. Inhale, ingest, apply or smell the gases, vapors or fumes of anygas, hazardous inhalant, substance containing a volatile chemical orsubstance containing a chemical material capable of releasing toxicvapors or fumes for the purpose of causingintoxication, euphoria, inebriation, excitement, stupefaction or thedulling of that persons brain or nervous system– B. Possess any gas, hazardous inhalant, substance containing a volatilechemical or substance containing a chemical material capable ofreleasing toxic vapors with the intent to violate paragraph A.• 2. Exclusions. Nothing in this section applies to the inhalation ofanesthesia for medical or dental purposes or the inhalation of the vaporsor fumes of an alcoholic beverage, the sale and consumption of which isauthorized by law.
References1. Kuhn, C., Swartzwelder, S., and Wilson, W. (2003). Buzzed: the straight facts about the most used and abuseddrugs from alcohol to ecstasy. The Duke University Medical Center. New York, NY: W.W. Norton & Company.2. Keys TE. "The_Development_of_Anesthesia". Anesthesiology. 1941;2: 552–574.3. Gillman M.A, Lichtigfeld, F.J. Enlarged double-blind randomised trial of benzodiazepines against psychotropicanalgesic nitrous oxide for alcohol withdrawal, Addictive Behaviors, Volume 29, Issue 6, August 2004, Pages1183–11874. Sanders RD, Weimann J, Maze M. “Biologic effects of nitrous oxide: a mechanistic and toxicologic review.”Anesthesiology. 2008 Oct;109(4):707-22.5. Browne DR, Rochford J, OConnell U, Jones JG. The incidence of postoperative atelectasis in the dependent lungfollowing thoracotomy: the value of added nitrogen. Br J Anaesth. Apr 1970;42(4):340-6.6. Sethi NK, Mullin P, Torgovnick J, Capasso G. Nitrous oxide "whippit" abuse presenting with cobalamin responsivepsychosis. J Med Toxicol. Jun 2006;2(2):71-4.7. Nitrous Oxide. Erowid. http://www.erowid.org/chemicals/nitrous/. Accessed 3/26/13.8. Nitrous Oxide Material Safety Data Sheet. Hynote Gas. http://www.hynotegas.com/Laughing%20Gas-MSDS.pdf.Accessed 3/26/13.9. Henderson KA, Matthews IP. “Biological monitoring of midwives exposure to N2O using the Bio-VOC breathsampler”Journal of Exposure Analysis and Environmental Epidemiology . 2002;12: 309–312.10. Monitoring The Future. Table 1. http://www.monitoringthefuture.org/data/12data/pr12t1.pdf. Accessed3/20/13.11. Garland EL, Howard MO, Perron BE. “Nitrous Oxide Inhalation Among Adolescents: Prevalence, Correlates, andCo-Occurrence with Volatile Solvent Inhalation.” J Psychoactive Drugs. 2009 December; 41(4): 337–347.12. Maine Legislature. Title 22: HEALTH AND WELFARE Subtitle 2: HEALTH Part 5: FOODS AND DRUGS Chapter 558http://www.mainelegislature.org/legis/statutes/22/title22sec2383-C.html
• History• Epidemiology• Pharmacokinetics• Pharmacodynamics• Legal ImplicationsOverview of Topics
John W. Hoffman synthesized in the 80s• JWH-018• JWH-073Pfizer developed in 1980s• CP47,497Hebrew University Israel in 1988• HU-210• HU-211History5www.clemson.edu
• 2000- Used as Incensed• 2002-THC Pharm• 2004- Used recreationally in Europe• 2008- Used started in the U.S.• 2009-2010- DEA temporarily listed the 5synthetic cannabinoids as controlledsubstance• 2011- Listed Schedule 1History1,7
Street Names1• Black Mamba• Zombie World• Bad to the Bone• Blaze• Fire and Ice• Dark Night• Earthquake• Berry Blend• The Moon and G-Force http://www.forbes.com
• Report of Death• 19 yo male went out with his friends partying.They reported smoking marijuana and k2.Becomes disoriented and returned home later inthe evening. Was found dead in bed the followingmorning. No anatomic cause of death• Toxicology report. (cardiac)THC 13ng/mlJWH 0.71ng/mlCase10
• A 19-year-old man was brought to the ED by paramedics for possibleseizure. The patients mother heard him scream, and then ran to his roomto find him "hallucinating," swinging his fists and having the appearanceof being frightened. Subsequently the mother described seizure-likeactivity, followed by "foaming at the mouth," cyanosis, andunresponsiveness. Approximately 20 min earlier he had returned homeafter smoking "K2" with a friend. His mother stated that he had beensmoking this substance for 2 months. Paramedics initially found thepatient lying prone, but he soon became combative, requiring four-pointrestraints. Pre-hospital pulse was recorded as 220 beats/min. On arrival inthe ED, he appeared somnolent and had a pulse rate of 180 beats/min.The patient had a history of heavy cannabis abuse and had recently losthis job due to a positive urine drug screen for THC metabolites. He wasadmitted to the hospital and had an uneventful course. His urine drugscreen was positive for THC (184.7 ng/mL). He was discharged on thesecond hospital day.Case10
1. Paul Cary. Spice, K2 and the Problem of Synthetic Cannabinoids. National Drug Court Resource Center. July 14, 2010.http://www.ndcrc.org/sites/default/files/PDF/NDCRC%20Spice%20and%20Problem%20of%20Cannabinoids.pdf2. NMS Labs. K2 and the Synthetic Cannabinoids: Pharmacology, Effects, and Chemical Analyses. September 10, 2010. WebApril 22, 2013-http://www.slideshare.net/nmslabs/k2-and-synthetic-cannabinoids-pharmacology-effectschemical-analysis3. Drug Fact Sheet. K2 or Spice. Drug Enforcement Administration. Web April 22, 2013.http://www.justice.gov/dea/druginfo/drug_data_sheets/K2_Spice.pdf4. American Association of Poison Control Centers. Synthetic Marijuana. March 13, 2013. Web April 22, 2013.5. Clemson University :: Department of Chemistry". Clemson.edu. Retrieved 2010-08-23.6. Xingdi Hu, Brian A. Primack, et al. College students and use of k2: an emerging drug of abuse in young persons. 2011 july.[PubMed]7. Office of National Drug Control Policy. Synthetic Drugs (a.k.a. K2, Spice, Bath Salts, etc.). The White House. Web-April24, 2013.8. Gefährlicher Kick mit Spice (German). Web-April 24, 20139. National Library of Medicine. Cannabicyclohexanol. Toxicological Data Network. Retrieve fromhttp://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+8002. April 24, 2013.10. NMS LabK2 and the Synthetic Cannabinoids: Pharmacology, Effects and Chemical Analysis. January 18, 2011.http://www.slideshare.net/nmslabs/k2-and-synthetic-cannabinoids-pharmacology-effectschemical-analysis.11. Barry E. Gustin. “Spices” and Synthetic Cannabinoids. Toxicology Consultant.http://www.toxicologyexpert.net/index.php/Dr.-Gustin-s-Blog/qspicesq-and-synthetic-cannabinoids.htmlReference
History1,2,3• Synthesized in 1944 in Basel, Switzerland by chemist LeandroPanizzon• Patented in 1954 for treating psychological disorders• First marketed by Ciba-Geigy Pharmaceutical Company as Ritalin• First used in 1955 to reverse drug induced coma.• FDA approved in 1955 and introduced in the United states in 1956• Initially approved to treat a variety of conditions includingnarcolepsy, low blood pressure, depression, senilebehavior, lethargy, and Mohr’s syndrome• 1980’s ADHD recognized as childhood syndrome – sales ofmethylphenidate increased• 1980’s – 1990 lawsuits filed due to negative side effects
Methylphenidate Overview1,2,4• Central nervous system stimulant– Amphetamine related• FDA approved for the treatmentof attention deficit/ hyperactivitydisorder (ADHD) and narcolepsy• Schedule II controlled substance• Typical dose for ADHD 10-60mgdaily ; not to exceed 72mg daily• Currently available from NovartisPharmaceuticalsImage:http://www.wcdtf.org/education/drugs
Methylphenidate overview5• Administration– Immediate release – Solution, tablets, capsules, chewabletablets– Extended release – Solution, tablets, capsules, transdermalpatch• Brand Names– Concerta– Metadate ER, CD– Methylin, ER– Ritalin, LA, SR– Daytrana (transdermal)• Black Box Warnings:– High potential for abuse and dependenceImage:www.daytrana.com
Chemical Components3• Chemical Name: α-phenyl-2-piperidineacetic• Molecular Formula: C14H19NO2• Molar Mass: 233.3 g/mol• Composition: C(72.1%) H(8.2%) N(6%)O(13.7%)• Melting Point 35°C, 224° for hydrochloridesalt• Piperidine derivative• First Synthesized from benzyl cyanide and 2-chloropyridine• Concerta approved in 2000• Ritalin LA approved in 2002Image:http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---R/Ritalin-or-Methylphenidate.htm
Pharmacodynamics1,2,3• Mechanism of Action– Dopamine(primary)– Norepinephrine– Serotonin(minor)• Pharmacodynamics:– Racemic mixturecomprised of d- and l-isomer– d-isomer more activethan l-isomer
Abuse6,7,12• Similar effects to cocaine when taken in normal or slightly higher than prescribeddoses– “High” feeling and euphoria– Appetite Suppression– wakefulness– heightened alertness– impairment of voluntary movements– headaches– irregular or rapid heart rate– Nausea and vomiting– drowsiness• Common routes of administration when abused– Orally – even the transdermal patch– Intravenously– Intranasally• Commonly abused by college students– concentration– alertness
Abuse & Toxicology9,10,11,12• LD50 in mice: 190mg/kg• Effects at higher doses:– Exhilaration and excitation– Dilation of pupils– Confusion– Hallucinations, paranoia, delirum– Increased blood pressure andpulse rate– Dry mouth– Vomiting– Fever, sweating, flushing– Seizures, coma– Anxiety, restlessness, agitation– Excessive repetition of movementsand meaningless tasks, muscletwitching• American Association ofPoison Control Centers’Toxic ExposureSurveillance Systemdatabase for deaths fromingestion ofmethylphenidate from2000 to 2005: 2• Patients reporting topoison center over 2year period: 289
Monitoring the Future8• Use and Availabilityof Amphetamines• “uppers, speed, Adderall, Ritalin, etc.”Trends in Annual Prevalence of Use of Ritalin (%)
References1. Morton AW, Stockton GG. Methylphenidate abuse and psychiatric side effects. Primary Care Companion to the Journal of ClinicalPsychiatry 2000;2(5):159-1642. Concerta prescribing information. Janssen Pharmaceuticals, Inc. March 20123. Myers RL. Methylphenidate (Ritalin). In: The 100 Most Important Chemical Compounds: A Reference Guide. Westport, CT: GreenwoodPublishing Group; 2007:178-1804. National Institute of Health: National Institute on Drug Abuse. Drug facts: stimulant ADHD medications – methylphenidate andamphetamines. http://www.drugabuse.gov/publications/drugfacts/stimulant-adhd-medications-methylphenidate-amphetamines.Updated 20095. Micromedex Healthcare Series. Greenwood Village, Colo: Thomson Healthcare. Updated periodically6. Sembower MA, et al. Surveillance of diversion and nonmedical use of extended-release prescription amphetamine and oralmethylphenidate in the United States. Journal of Addictive Diseases 2013;32:26-387. University of Maryland: Center for Substance Abuse Research. Ritalin. http://www.cesar.umd.edu/cesar/drugs/ritalin.asp. Updated 20058. Johnston, LD, O’Malley, PM, Bachman JG, & Schulenberg JE. Monitoring the Future national results on adolescent drug use: Overview ofkey findings, 2011. Ann Arbor: Institute for Social Research, The University of Michigan. 20129. Bruggisser M, Bodmer M, Liechti ME. Severe toxicity due to injection but not oral or nasal abuse of methylphenidate tablets. SwissMedical Weekly 2011;141:w1326710. Klampfl K, et al. Case report: intoxication with high dose of long-acting methylphenidate (Concerta) in a suicidal 14-year-old girl. ADHDAttention Deficit Hyperactivity Disorder 2010;2:221-22411. Ozdemir E, Karaman MG, Yurteri N, Erdogan A. A case of suicide attempt with long-acting methyphenidate (Concerta). ADHD AttentionDeficit Hyperactivity Disorder 2010;2:103-10512. Vastag B, et al. Pay Attention: Ritalin acts much like cocaine. Journal of the American Medical Association 1998;286(8):905-906.
History of Cocaine 1• Cocaine is contained in the leaves ofErythroxylum coca.• Grows abundantly in Colombia, Peru, Bolivia, theWest Indies, and Indonesia.• In the 6th century, the inhabitants of Peruchewed or sucked on the leaves for social andreligious reasons.• In the 1100s, the Incas used cocaine-filled salivaas local anesthesia for ritual trephinations of theskull.
History of Cocaine 1,2• Albert Niemann isolated cocaine as the active ingredient ofthe plant in 1860.• Karl Koller introduced cocaine as an effective localanesthetic for eye surgery.• Sigmund Freud, wrote extensively on the psychoactiveproperties of cocaine.• Merck, main cocaine producer in Europe, increasedproduction from less than 0.75 pounds in 1883 to morethan 150,000 pounds in 1886.• Recreational cocaine use was legal in the United States until1914.• The first cocaine-associated myocardial infarction wasreported in the United States in 1982.
Epidemiology 2• Recreational use of cocaine remains a significantproblem.• It is estimated that, almost 34 million Americanshave used cocaine at least once, with 1.7 millionof those dependent or addicted.• European Union statistics estimate that cocainehas been used at least once by more than 12million Europeans, representing almost 4% of alladults.
Epidemiology 3• NSDUH estimates that in 2008 there were 1.9 millioncurrent (past-month) cocaine users.• Approximately 359,000 were current crack users.• Adults aged 18 to 25 years have a higher rate of currentcocaine use.• Men report higher rates of current cocaine use thanwomen.• Data from the 2008 Drug Abuse Warning Network(DAWN) report showed that cocaine was involved in482,188 of the nearly 2 million visits to emergencydepartments for drug misuse or abuse.
Common routes of administration 2• Oral• Intranasal• Intravenous• Inhalation• Bioavailability exceeds 90% with intravenous andsmoked cocaine.• It is approximately 80% following nasal application.• Data for ingested cocaine and application to othermucus membranes such as the urethra, vagina, orrectum are inadequately documented.
Interactions 4• Ethanol• Heroin• Opiates• Antidepressant/antipsychotic medications• Antihistamine data showed that there may berelationship between increased toxicity ???
Pharmacodynamics 5,6• Pharmacologic effect of cocaine occurs in CNS.• Cocaine blocks reuptake of catecholamineneurotransmitters:-norepinephrine-dopamine-serotonin
Tolerance, Dependence, and Withdrawal 7• Sensitization is shown in animal studies and manifested asbehavioral hyperactivity.• In human, the euphoric effect typically is not subject tosensitization.• Most chronic users become desensitized and, overtime, require more cocaine to obtaineuphoria, i.e., tolerance develops.• Chronic users go through frequent periods of withdrawal.• Cocaine Withdrawal Symptoms and Signs :- dysphoria, depression, sleepiness, fatigue andbradycardia.
• Overdoses with cocaine commonly result infatalities from:-arrhythmias.-seizures, or respiratory depression.-cardiac toxicity.-severe hypertensive episodes.• No specific antidote is available.Toxicology 8
Agents used by health professionals 9• IV diazepam• IV propranolol• Others approaches include:-Individual and group psychotherapy.-family therapy, and peer group assistanceprograms.
Societal Perspective of Cocaine 10• Some people in the society believe that, cocaineaddicts and users are:-deviants-criminals• Cocaine is illegal but can be use for medicalpurpose.
• Ear procedures• Nose procedures• Throat proceduresClinical use of cocaine 11
• Constricts blood vessels• Dilates pupils• Increases body temperature ,heart rate, andblood pressure.• Headaches and gastrointestinal problem• Decrease appetite• HIV/AIDS and other blood-borne diseasesImpact of Cocaine on Health and Life12
Outline• Structure of oxycontin• History and Background• Epidemiology• Mechanism of action• Pharmacokinetics• Pharmacodynamics• Tolerance and withdrawal• Toxicology• Legal consequences• Impact of abuse of this drug on the user’s life and health• Treatment for abuse.• Conclusion
StructureThe chemical name is 4,5ɑ-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.source:http://app.purduepharma.com/xmlpublishing/pi.aspx?id=o
History and Background of Oxycontin1• Oxycontin is an opioid analgesic.• Synthesized from opium-derived thebaine.• Used to treat moderate to severe pain.• Oxycontin is a controlled-release form of oxycodone.• Oxycontin was created by scientists from Germany in 1916after the pharmaceutical firms stopped the production ofheroin as a drug to cure all diseases.• The clinical use of the drug was documented in 1917, a yearafter its development.• The first medications in Europe that contained Oxycodonewere Eucodol, Eukodol, and Dinarkon (Seppala et al. 12).
History and Background of Oxycontin1• The drug was initially thought to be more safe, lessaddictive, and more effective at treating pain than heroin.• In the United States, oxycodone was first introduced to themarket in early May of 1938.• Although it is not easy to establish the exact year of thedevelopment and release of Oxycontin, it is believed thatthe drug was originally prescribed during the early 1990s.• In 1995, a Stamford Connecticut pharmaceutical firm calledPurdue Pharm began producing the drug.• The ingredient in the drug was, however, was not new atall.
History and Background of Oxycontin1• Prior to the release of Oxycontin, oxycodone had beenaround for over six decades.– However, the formulation and delivery of the drug was new.• Prior to the introduction of Oxycontin, a number ofpainkillers were used to ease the suffering of individualswith severe pain as a result of cancer or surgery recovery.– Patients were advised by doctors to keep pain relievers in theirbloodstream at all times to stave off the pain.– The challenge was that painkillers, including morphine, onlyrelieved a person’s pain for an average time of 2-3 hours.– This entailed that people had to take several pills every day tokeep their plasma concentration at an effective level.• Oxycontin was able to solve this problem by distributing itsactive ingredient over a 12 hour period (Seppala et al. 15).
Epidemiology2,3• Epidemiology refers to “the study of the determinantsand distribution of health-associated events orstates, and the use of this study to the control ofillnesses and other health-related problems.”• Oxycontin doses start low and are progressivelyincreased as an individual’s tolerance to opioids builds.• However, how much Oxycontin is too much?– This largely depends on various personal factors includingage, medical condition, present exposure to opioids, andother medications taken by individual.• There are people who are at higher risk of adverseevents from the drug, which can be explained bylooking at the precautions of using the drug.