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. 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
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. 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
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. 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. Brain Systems affected
System Neuron origin Neuron Innervation Functions
modulated
DA Substantia nigra of Cortex and parts of limbic Motor control,
midbrain, ventral system reward centers
tegmentum of pleasure,
midbrain addicition
5-HT Raphe nuclei, Most of brain, spinal cord Pain/locomotion,
midline of brain sleep-wake cycle,
stem mood, emotional
behaviours
NE Locus coerulus of Cerebreal cortex, thalamus, Attention, arousal,
pons hypothalamus, olfactory sleep cycles,
bulb, cerebellum, midbrain, learning, memory,
spinal cord anxiety, pain,
mood
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. 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. 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. 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. 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. 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
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
