SUBJECT FORENSIC SCIENCE Paper No. and Title PAPER No. 9: Drugs of Abuse MODULE No. 12: Common Stimulants: Amphetamines and Module No. and Title Methamphetamines Module Tag FSC_P9_M12 FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction to Amphetamine 3. Synthesis of Amphetamine and Methamphetamine 4. Use of Amphetamine 5. Fatal Dose 6. Mode of action 7. Signs and Symptoms 8. Withdrawal Symptoms 9. Screening Test 10. Qualitative Analysis 11. Metabolism 12. Designer Amphetamines 13. Medico-legal Aspect 14. Summary FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines 1. Learning Outcomes After studying this module, you will be able to know about- Amphetamines and Methamphetamines Mechanism of Action Amphetamines and Methamphetamines Designer Amphetamines Metabolism of Amphetamines 2. Introduction to Amphetamine Amphetamine (Amfetamine) belongs to the phenylethylamine family with a methyl group substitution in the alpha carbon position. Several substitutions of the phenylethylamine structure are possible, resulting in several amphetamine-like compounds. These compounds collectively known as “amphetamines”, and include Amphetamine Phosphate, Amphetamine Sulphate, Benzphetamine, Chlorphentermine, Clobenzorex Hydrochloride, Dextroamphetamine, Diethylpropion, Mazindol, Methamphetamine, 4-Methylthioamphetamine, Methylphenidate, Pemoline, Phendimetrazine, Phenmetrazine, and Phentermine. Amphetamine was first marketed in the 1930s as “Benzedrine” in over the counter and taken to treat nasal congestion. By 1937 amphetamine was accessible through prescription in tablet form and was used in the treatment of the sleeping disorder Narcolepsy and behavioral syndrome called Minimal Brain Dysfunction (MBD), which nowadays is known as Attention Deficit Hyperactivity Disorder (ADHD). Amphetamine is a stimulant and an appetite suppressant. It excites the Central Nervous System by raising the quantity of various substances in the body. This increase heart rate and blood pressure and reduces craving, besides other effects. Amphetamine, dextroamphetamine and methamphetamine are together denoted as amphetamines. Their chemical properties and action are so alike that even proficient consumers have trouble knowing which drug they have taken. Street names for Amphetamine: Amp, Eye Openers, Road Dope, Sweets, Uppers, Wake Ups, Jelly Bean etc. FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines Derivative of Amphetamines: The derivatives of amphetamines are Methamphetamine, Dextroamphetamine, Fenfluramine, Phentermine, Mephentermine, Methyl phenidate, Synthetic amphetamines („Designer drugs‟) - a. Methylenedioxymeth- amphetamine (MDA or „Love drug‟) b. Methylenedioxyethamphetamine (MDEA or „Ecstasy‟). Amphetamine and methamphetamine are indirect sympathomimetic agents giving rise to release of norepinephrine (noradrenaline) and inhibition of monoamine oxidase. Effects via this action result in hypertension, tachycardia, and inhibition of gut motility. It was this last effect that led to their medical use in treating obesity. However, they are also CNS stimulants and their effect on the CNS soon led to these drugs being abused. Amphetamine (α-methylphenethylamine) and methamphetamine (N-methyl-α- methylphenethylamine) in free-base form are both liquids. Amphetamine is normally produced as amphetamine sulfate, hydrochloride or phosphate and is more commonly abused in Europe than is methamphetamine. Methamphetamine is normally produced as Methamphetamine Hydrochloride and is more popular in North America and Japan than is amphetamine. Street-level amphetamine and methamphetamine are normally submitted to the forensic laboratories as white to off-white powders with relatively low purity (e.g. <20%) but may sometimes occur in tablet form. 3. Synthesis of Amphetamine and Methamphetamine Many methods are available for the licit as well as illicit synthesis of amphetamine, but the Leuckart Reaction has been the most popular. This method is simple, rapid, gives a good yield and does not involve any particularly hazardous chemicals or procedures. It may be considered as a three-step reaction that involves the condensation of Phenyl-2- propanone (P-2-P) with Formamide followed by a hydrolysis of the N- formylamphetamine and finally purification by steam distillation. Methamphetamine can be made by the Leuckart reaction using either Methylamine and Formic Acid or N- methylformamide in the condensation step. FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines Leuckart reaction for the synthesis of amphetamine and methamphetamine Common adulterants for amphetamine include caffeine to increase the stimulant effect and/or to mask low levels of the drug, and sugars (e.g. lactose) used as a diluent. Amphetamine and methamphetamine have isomeric (enantiomeric) forms. Studies have shown that the d-isomer has a more potent effect on the CNS system than the l-isomer and that the d-isomer is eliminated from the body slightly faster than the l-isomer. 4. Use of Amphetamine Some amphetamines have therapeutic uses and are still available as prescription drugs in Western countries but they are not generally available in India (except for Mephentermine). Amphetamine and dextroamphetamine, non-catecholamine sympathomimetic agents, are taken as mixture to treat Attention-Deficit Hyperactivity Disorder (ADHD) or Narcolepsy. They are taken as vasoconstrictors in inhalant therapy to contract nasal mucous membranes in these circumstances as nasal allergies and asthma; now such inhalants have been banned because of their toxicity.4. Action FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines 5. Fatal Dose The fatal dose of amphetamines is highly variable, and whereas death can occur with as diminutive as 1.5 mg/kg of methamphetamine, survival has been recorded with 28 mg/kg. This in fact represents the usual range of amphetamine‟s lethal dose - 150 mg to 2 grams. However, because of tolerance, addicts can tolerate up to 5 grams, or 15 gm/day (smokable methamphetamine). Lethal blood level is said to be around 0.2 mg per 100 ml, though addicts can tolerate much higher levels with hardly any toxic effects. 6. Mode of action The major mechanism of action of amphetamines involves the release of monoamines from storage sites in axon terminals, which leads to increased monoamine concentration in the synaptic cleft. The release of dopamine in the Nucleus Accumbens (NAc) and related structures is responsible for the reinforcing and mood elevating effects of amphetamines. Cardiovascular effects result from the stimulation of release of noradrenaline. The dopamine released into the cytoplasm of neurons undergoes oxidation, resulting in the production of several toxic chemicals (oxygen radicals, peroxides and hydroxyquinones). Amphetamines also have weak Monoamine Oxidase (MAO) inhibiting property, but the significance of this is not clear. The most prominent effects of amphetamines are the catecholamine effects as a result of stimulation of peripheral alpha- and beta-adrenergic receptors. Enhanced concentration of noradrenaline at the locus coeruleus is responsible for the anorexic and stimulating effects, as well as to some extent, for the motor- stimulating effects. The increase in central dopamine (especially in the neostriatum) provokes stereotypical behaviour and some motor effects. The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of GABA-ergic efferent neurons, contributing significantly to the stereotypical behaviour, locomotor effects, and neurotoxicity of amphetamines. The effects of serotonin and dopamine at the mesolimbic system alter perception and induce psychotic manifestations. FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines Amphetamine forms effortlessly absorbed particles that are extremely lipid soluble. The most noticeable monoamine neurotransmitter involved in the effects of the amphetamine is dopamine. Dopamine causes the desirable effects of the drugs, as well as some of the most disturbing psychological effects of the drugs, such as stereotypic behaviors and psychosis. 7. Signs and Symptoms The common signs and symptoms include: Alertness and increased concentration Initial euphoria and more extrovert behaviour Increased talkativeness with rapid speech Increased work capacity with allaying of fatigue Improvement of athletic performance initially followed by further deterioration Stimulation of reticular activating system causing wakefulness and postponement of sleep FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines Hunger is suppressed Tremors Pupils are dilated Tachycardia and hypertension are not so significant High doses produces euphoria, marked excitement, that may progress to mental confusion, delirium, hallucinations and an acute psychotic state Peripheral component of toxicity include vasomotor effects, palpitation, arrhythmias, vomiting, abdominal cramps and vascular collapse Death is uncommon and is usually preceded by convulsions and coma Except that, death due to amphetamine toxicity most commonly results from arrhythmias,