Amphetamine usage in adolescents

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  • Illicit substances, prescriptions drugs, and nutracuticals all controlled substances!Canada has a partial ban on dietary supplements containing ephedra with caffeine, however, not a full ban as seen in the US- FDAKhat is regulated under controlled drug and substances act – in which it is illegal to obtain without medical practicionerAMPH as (1) an unsubstituted phenyl ring, (2) atwo-carbon side chain between the phenyl ring and nitrogen,(3) an a-methyl group, and (4) a primary amino groupMethamphetamine--> no secondary amineChain-subsituted amphetamines: methylphenidate (3), and ring substituted amphetamines, such as 3,4-methylenedioxymethamphetamine (MDMA: ecstasy) (4), as well as non-a-methylated phenethylamines, such as tyramine (5) or mescaline (6)
  • Traditionally used to treat asthma and respiratory infections, as an appetite suppressant and to boost athletic performanceLazar = romanian
  • varied usage profiles: more cocaine in NE and EU, but more amphetamines in AsiaCanada: alcohol, cocaine, then methBeauvais F, Jumper-Thurman P & Burnside M. (2008). The changing patterns of drug use among American Indian students over the past 30 years. American Indian & Alaska Native Mental Health Research (Online), 15(2), 15-24.
  • Paglia-Boak A, Adlaf EM, Mann RE. The 2011Ontario student drug use and health survey. CAMH Research Document Series (32):1-34General reduction in usage since 19993.3% of grades 7-12 reported ever using ecstasy in 2011, a decrease from 6% in 2001Methamphetamine usage dropped from 5/1% in 1999 to 1% in 2011
  • spatiality, consumption, commercialisation and control can be illustrated of the patterns of drug use of those attending specific dance clubs. UK clubbers have drug consumption patterns wider in repertoire and greater in frequency and quantity than general young adult population. For example, the lifetime prevalence rate for use of any illicit drug is 12% amongst 16- to 29-year olds in the general population in the 2000 British Crime Survey (Rwhereas the lifetime prevalence rate amongst clubbers ranges from 52% to 81% (Release, 1997), depending on club location, region, music policy and socio-demographic customer base.Measham, F. (2004). Play space: Historical and socio-cultural reflections on drugs, licensed leisure locations, commercialisation and control. International Journal of Drug Policy, 15(5), 337-345.
  • Route of administration affects pharmacokinetics amphetamines can be taken orally (pill) or intravenously, whereas methamphetamines can withstand head and be smoked; which elicits effects much faster, and remains in the system much longer than cocaine, for example. Both drugs have a half-life of approximately 7 hrs, and metabolites of the drugs can be detected within urine for several days.
  • Psychological effects can include euphoria, anxiety, increased libido,alertness, concentration, energy, self-esteem, self-confidence, sociability,irritability, aggression, psychosomatic disorders, psychomotor agitation,grandiosity, repetitive and obsessive behaviors, paranoia, and with chronic and/or high doses, amphetamine psychosis can occur. Occasionally this psychosis can occur at therapeutic doses during chronic therapy as a treatment emergent side effect.[3][10]
  • Zombeck JA, Gupta T & Rhodes JS. (2009). Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice. Psychopharmacology, 201, 589-99. doi:10.1007/s00213-008-1327-0adolescents display reduced locomotor stimulation to methamphetamine,locomotor stimulation was significantly reduced in adolescents versus adults even though concentrations of drug in the brain were similar at all time points. Male, adolescent (PN 30-35) and adult (PN 69-74) C57BL/6J mice were administered an intraperitoneal injection of cocaine (5, 15, 30 mg/kg) or methamphetamine (1, 2, 4 mg/kg) and euthanized 5, 10, 15, 30, 60, 120, or 240 min later. Home cage locomotor activity was recorded by video tracking, and drug concentration levels in brain and blood from the infraorbital sinus were measured using liquid chromatography combined with mass spectroscopy. Results
  • Verrico, CD, Miller, GM, & Madras, BK (2007) MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (2007) 189: 489–503To compare MDMA effects at monoamine transporters with endogenous neurotransmitters, we conducted assays with [3H]DA, [3H]NE, and [3H]5-HT and the human DAT, NET, and SERT. The time course of transport of 5-HT (Gouletet al. 2001), DA (Yatin et al. 2002), and NE had been previously determined and verified (data not shown). [3H] Monoamine transport assays were conducted for 10 min, and affinities (Km) and velocities (Vmax) of [3H]DA for the DAT, [3H]NE for the NET, and [3H]5HT for the SERT were measured. For all three transporters, transport was saturablewith increasing neurotransmitter concentration
  • Silverthorn DU, Ober WC, Garrison CW, Silverthorn AC, Johnson BR. (2009) Human Physiolog: an Integrated approach. 4th edition. Pearson EductionInc, San Fransisco. 312-313
  • King G, Alicata D, Cloak C & Chang L. (2010). Neuropsychological deficits in adolescent methamphetamine abusers. Psychopharmacology, 212, 243-9. doi:10.1007/s00213-010-1949-xDzietko M, Sifringer M, Klaus J, Endesfelder S, Brait D, Hansen HH, et al. (2010). Neurotoxic effects of MDMA (ecstasy) on the developing rodent brain. Developmental Neuroscience, 32, 197-207. doi:10.1159/000313473Maybe make a table – compare amph, meth, mdmanown to induce apop(MDMA,‘Ecstasy’), methamphetamine and D-amphetamine. Biological chemistry, 392(1-2), 103-115totic damage to fine serotonergic fibers in the adult rat brain.
  • McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., & Ricaurte, G. A. (1998). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C] WIN-35,428. The Journal of neuroscience, 18(20), 8417-8422.reductions in the level of DA, decreases in the expression of tyrosine hydroxylase, and a loss of DATs.  Intriguingly, neuroimaging studies have revealed that long-term methamphetamine use in humans can lead to a noticeable reduction in DAT levels, which has been interpreted to indicate a loss in DA fibers. Given that there is a progressive reduction in the density of DA fibers as a function of normal ageing, these data suggest that methamphetamine users may be artificially hastening the deterioration of a neurochemical system important for regulating motor control.
  • Hatzidimitriou, G., McCann, U. D., & Ricaurte, G. A. (1999). Altered serotonin innervation patterns in the forebrain of monkeys treated with (±) 3, 4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. The Journal of Neuroscience, 19(12), 5096-5107.Monkey study: The present results indicate that squirrel monkeys treated with MDMA and evaluated after a 7 year post-drug survival period continue to show altered brain 5-HT innervation patterns. These findings extend previous findings with MDMA (Insel et al., 1989; Ricaurte et al., 1992; Fischer et al., 1995) and other substituted amphetamines (Woolverton et al., 1989; McCann et al., 1994a,b) and suggest that MDMA-induced alterations of brain 5-HT in- nervation in nonhuman primates may be permanent. The present data also indicate that although some 5-HT recovery does take place over the 7 year post-drug period, this recovery is not always complete and does not occur in a number of brain regions.
  • Fornai, F., Torracca, M. T., Bassi, L., D'Errigo, D. A., Scalori, V., & Corsini, G. U. (1996). Norepinephrine loss selectively enhances chronic nigrostriatal dopamine depletion in mice and rats. Brain research, 735(2), 349-353.-pre-treatment with the selective noradrenergic neurotoxin DSP-4 (50 mg/kg, i.p.) enhanced methamphetamine-induced striatal dopamine depletion. -low dose of methamphetamine Sprague-Dawley rats did not decrease striatal dopamine levels when injected alone but produced a significant decrease in striatal dopamine when given to rodents carrying a long-lasting norepinephrine depletion previously induced by DSP-4.
  • Kameda S.R. et al. (2011). Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine. Pharmacology Biochemistry and Behavior, 98, 320-324. adolescents have accelerated dependence courses with shorter times from first exposure to dependenceLabonte et al: 5-HT firing in adulthood was increased in rats that had received Amph (1.5 mg/kg.d) during adolescence. At this regimen, DA firing activity was increased, but not NE firing. Conversely, the highest Amph dose regimen (5.0 mg/kg.d) enhanced NE firing, but not DA or 5-HT firing rates. In the OFT, Amph (1.5 mg/kg.d) significantly increased the total distance travelled, while the other doses were ineffective. Laviola G., Pascucci T. & Pieretti S.. (2001). Striatal dopamine sensitization to D-amphetamine in periadolescent but not in adult rats. Pharmacology Biochemistry and Behavior, 68, 115-124 Important structural and functional changes in brain occur during adolescence and developmental differences in forebrain dopamine systems could mediate a biologic vulnerability to drug addiction during adolescence. Periadolescent male rats are particularly sensitive to psychostimulants that are DAT inhibitors but are not internalized and do not release dopamine. Immaturity of DAT and/or DAT associated signaling systems in adolescence specifically enhances behavioral and dopaminergic responses in adolescence.-walker et al 2010
  • Amphetamine usage in adolescents

    1. 1. Amphetamine Usage inAdolescentsHeidi ChodorowiczHLTH 471April 2nd, 2013
    2. 2. Overview Introduction History Usage – adolescents Pharmacokinetics Immediate effects Pharmacodynamics Prolonged effects/Neurotoxicity Discussion
    3. 3. Introduction: Chemical structure 1. Unsubstituted phenyl ring, 2. 2-C side chain 3. An a-methyl group 4. A primary amino group
    4. 4. Variations Methamphetamine (METH) “Crystal meth”  No amino group (just NH) Methylphenidate “Ritalin”  Chain substituted Methylenedioxymethamphe tamine(MDMDA) “Ecstasy”  Ring substituted Tyramine & Mescaline  Non a-methylated  not always considered an amphetamine
    5. 5. History Used for 1000s of years as plant products:  Ephedra China, Middle East, India  Khat  Kenya, Simalia, Yemen 1887 :  Nagajoshi Nagai – first isolated ephedrine  Lazăr Edeleanu – first synthesized amphetamine Pharm use1927 by:  Gordon Alles stimulant Illicit drug usage jumped 1950-1970  Declined after cocaine  Increases  Ritalin
    6. 6. Adolescent usage Paglia-Boak, Adlaf & Man, 2011
    7. 7. Drugs and Clubs Profressor Mielke briefly mentioned research with a colleague at WLU:  peak in MDMA usage after the nightclub, Beta opened Correlation between night clubs/“rave space” with MDMA etc. Lifetime prevalence of illicit drugs:  UK Clubbers:52-81%  vs. 12% of 16-29 yr olds Measham, 2004
    8. 8. Pharmacokinetics Amphetamine:  Oral (slow release Px), IV Methamphetamine:  Oral, IV, or inhalation MDMA  Oral, insufflation (snort) Lipophilic, therefore:  Crosses BBB Metabolized in liver: deamination and hydroxylation:  Slow, half-life ≥7 -32 hrs  Detection: 24-72 hrs
    9. 9. Immediate Effects Psychological:  Heightened alertness, concentration, arousal  Reduced fatigue, increased energy Euphoria  _______________  Grandosity, self-confidence/esteem, sociability Behavioural:  Locomotor activation,  Steroptypy (repetitive movement, posture, or utterance) Clinical:  Narcolepsy,  ADHD,  Body weight management Milesi-Hallé et al, 2005
    10. 10. Adolescent differences Despite similar concentrations of drug in the body Lower magnitude of locomotor activity in adolescents Zombeck JA, Gupta T & Rhodes JS. (2009)
    11. 11. Pharmacodynamics  Competitive agonists to transporters, increase: 1. Dopamine (DA) 2. Serotonin (5-HT) 3. Norepinephrine (NE)  Inhibit:  Vesiculart monoamine transporters (VMAT)  Monoamine Oxidases (MAO)  Overarching effects: For all three transporters, transport was saturable  Stimulate the Sympathetic _____________ with increasing neurotransmitter concentration nervous system Verrico, Miller,& Madras, 2007
    12. 12. Brain Systems affectedSystem Neuron origin Neuron Innervation Functions modulatedDA Substantia nigra of Cortex and parts of limbic Motor control, midbrain, ventral system reward centers  tegmentum of pleasure, midbrain addicition5-HT Raphe nuclei, Most of brain, spinal cord Pain/locomotion, midline of brain sleep-wake cycle, stem mood, emotional behavioursNE Locus coerulus of Cerebreal cortex, thalamus, Attention, arousal, pons hypothalamus, olfactory sleep cycles, bulb, cerebellum, midbrain, learning, memory, spinal cord anxiety, pain, mood
    13. 13. Long term/high dose effectsPsychological PhysicalSerotonin syndrome Tachycardia,Psychosomatic disorders, Hypertension,Psychomotor agitation, Hyperthermia,Paranoia, Seizures,Amphetamine psychosis Urinary retention Intracranial hemorrhage, Myocardial infarction, hyponatremia, Death
    14. 14. Neurotoxicity Significant, and likely permanent overall damage to the brain King et al, 2010: Adolescents METH usage is inversely correlated with neuropsychological functioning (dose- response):  Executive functioning  Abstract, non-verbal reasoning Dzietko et al, 2010: Adolescents of child bearing age: single injections results in damage to the following areas of neonatal rat brains:  cortex, septum, thalamus, hypothalamus and the cornu ammonis
    15. 15. Neurotoxicity: DA Decrease density of Basal Ganglia:  Caudate nucleus: -23%,-24%  Putamen: -25%-16% Larger decreases in PD  Caudate Nucleus: -47%  Putamen: -68% Reductions in density:  Loss of DA fibres McCann, 1998  Loss of DATs  Decreased expression of tyrosine hydroxylase
    16. 16. Neurotoxicity: 5-HT Clinicaltrial comparing monkeys treated with MDMA 7 years prior, 2 weeks prior, and a control  Significant damage to 5-HT axons at 2 weeks  Some 5-HT recovery:  Seldom complete Caudate nucleus 5-HT immunoreactive axons:  Not in all brain regions Control, 2 weeks post mdma, 7 yrs post mdma MDMA permanent apoptotic Hatzidimitriou, McCann, & Ricaurte, 1999 damage to fine serotonergic axons
    17. 17. Neurotoxicity: NE AMPH use decreases NE over time DA loss more significant with NE loss and meth, than meth alone NE loss:  Enhance neurotoxic damage  Decrease the threshold for neurotoxicity to nigrostriatal DA neurons Fornai et al, 1996
    18. 18. Adolescents &Addiction risk Mice: locomotor sensitization to amphetamine after a single injection  Adolescent mice: higher magnitude of sensitization Accelerate dependence courses:  shorter time: first use  addiction Kameda S.R. et al. (2011).
    19. 19. Summary Varied usage profiles, lower comparatively Immediate effects, prolonged excretion General catecholamine agonists: DA, 5-HT, NE Cancause permanent death of neurons, addiction, and sudden death in users Further research:  mechanisms behind neurodegenerative damage
    20. 20. Questions & Discussion

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