Heidi ChodorowiczHLTH 471April 2nd, 2013

Amphetamine Usage in Adolescents

Introduction

History

Usage – adolescents

Pharmacokinetics

Immediate effects

Pharmacodynamics

Prolonged effects/Neurotoxicity

Discussion

Overview

Introduction: Chemical structure

1. Unsubstituted phenyl ring,

2. 2-C side chain

3. An a-methyl group

4. A primary amino group

Methamphetamine (METH) “Crystal meth”

No amino group (just NH)

Methylphenidate “Ritalin”Chain substituted

Methylenedioxymethamphetamine(MDMDA) “Ecstasy”

Ring substituted

Tyramine & Mescaline Non a-methylated not always

considered an amphetamine

Variations

Used for 1000s of years as plant products: Ephedra China, Middle East, IndiaKhat Kenya, Simalia, Yemen

1887 :Nagajoshi Nagai – first isolated ephedrineLazăr Edeleanu – first synthesized amphetamine

Pharm use1927 by: Gordon Alles stimulant

Illicit drug usage jumped 1950-1970Declined after cocaine Increases Ritalin

History

Adolescent usage

Paglia-Boak, Adlaf & Man, 2011

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

Drugs and Clubs

Measham, 2004

Amphetamine: Oral (slow release Px), IV

Methamphetamine: Oral, IV, or inhalation

MDMA Oral, insufflation (snort)

Lipophilic, therefore:

Metabolized in liver: deamination and hydroxylation: Slow, half-life ≥7 -32 hrs Detection: 24-72 hrs

Pharmacokinetics

Crosses BBB

Psychological: Heightened alertness, concentration, arousal Reduced fatigue, increased energy _______________

Grandosity, self-confidence/esteem, sociability

Behavioural: Locomotor activation, Steroptypy (repetitive movement, posture, or

utterance)

Clinical: Narcolepsy, ADHD, Body weight management

Immediate Effects

Euphoria

Milesi-Hallé et al, 2005

Despite similar concentrations of drug in the body

Lower magnitude of locomotor activity in adolescents

Adolescent differences

Zombeck JA, Gupta T & Rhodes JS. (2009)

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:Stimulate the _____________

nervous system

Pharmacodynamics

For all three transporters, transport was saturablewith increasing neurotransmitter concentration

Verrico, Miller,& Madras, 2007

Sympathetic

System

Neuron origin Neuron Innervation Functions modulated

DA Substantia nigra of midbrain, ventral tegmentum of midbrain

Cortex and parts of limbic system

Motor control, reward centers pleasure, addicition

5-HT Raphe nuclei, midline of brain stem

Most of brain, spinal cord Pain/locomotion, sleep-wake cycle, mood, emotional behaviours

NE Locus coerulus of pons

Cerebreal cortex, thalamus, hypothalamus, olfactory bulb, cerebellum, midbrain, spinal cord

Attention, arousal, sleep cycles, learning, memory, anxiety, pain, mood

Brain Systems affected

Long term/high dose effects

Psychological Physical

Serotonin syndromePsychosomatic disorders, Psychomotor agitation, Paranoia,Amphetamine psychosis 

Tachycardia,Hypertension,Hyperthermia,Seizures,Urinary retentionIntracranial hemorrhage, Myocardial infarction, hyponatremia,Death

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 functioningAbstract, 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

Neurotoxicity

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 fibresLoss of DATsDecreased expression of tyrosine

hydroxylase

Neurotoxicity: DA

McCann, 1998

Clinical trial comparing monkeys treated with MDMA 7 years prior, 2 weeks prior, and a controlSignificant damage to 5-HT

axons at 2 weeksSome 5-HT recovery:

Seldom complete Not in all brain regions

MDMA permanent apoptotic damage to fine serotonergic axons

Neurotoxicity: 5-HT

Caudate nucleus 5-HT immunoreactive axons:Control, 2 weeks post mdma, 7 yrs post mdma

Hatzidimitriou, McCann, & Ricaurte, 1999

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

Neurotoxicity: NE

Fornai et al, 1996

Mice: locomotor sensitization to amphetamine after a single injectionAdolescent mice: higher magnitude

of sensitization

Accelerate dependence courses: shorter time: first use addiction

Adolescents &Addiction risk

Kameda S.R. et al. (2011).

Varied usage profiles, lower comparatively

Immediate effects, prolonged excretion

General catecholamine agonists: DA, 5-HT, NE

Can cause permanent death of neurons, addiction, and sudden death in users

Further research: mechanisms behind neurodegenerative damage

Summary

Questions & Discussion