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SUBJECT FORENSIC SCIENCE

Paper No. and Title PAPER No. 9: Drugs of Abuse MODULE No. 12: Common : and Module No. and Title 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 3. Synthesis of Amphetamine and 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, , , Hydrochloride, , Diethylpropion, , Methamphetamine, 4-Methylthioamphetamine, , , , , and .

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 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,  ,  Phentermine,  ,  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 (noradrenaline) and inhibition of monoamine oxidase. Effects via this action result in , 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 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- 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 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 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, hyperthermia, or intra-cerebral hemorrhage. In cases of survival, symptoms gradually resolve as the drug is excreted over a period of 24 to 48 hours.

8. Withdrawal Symptoms

Withdrawal after persistent amphetamine abuse may precipitate severe depression and suicide attempts. Anxiety, abdominal cramps, gastroenteritis, headache, diaphoresis, lethargy, and dyspnoea may result. Increased appetite is common.

9. Screening Tests

 MARQUIS REAGENT TEST

Preparation of reagent- To the 1ml of Formaldehyde solution, few drops of conc. Sulphuric Acid is added and stock solution is prepared.

Procedure:  Few drops of sample are placed in spot plate.  Then 2-3 drops of stock solution is poured on the plated

Result: Orange- Red Colour for both amphetamine and methamphetamine.

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines

 SIMON'S REAGENT TEST

Preparation of reagent: Solution A: 20% aqueous Sodium Carbonate solution. Solution B: 50% ethanolic Acetaldehyde solution. Solution C: 1% aqueous Sodium Nitroprusside solution.

Procedure:  Appropriate amount of sample is taken on spot plate  A drop of Solution A is added followed by one drop of Solution B.  Further, few drops of Solution C is added.

Result: Appearance of blue colour indicates the positive tests for the presence of methamphetamine while appearance of slow pink to cherry red colour indicates the presence of amphetamine.

 LIEBERMANN’S TEST

Preparation of reagent: 5 gram of Sodium Nitrite is added in 50 ml. of Sulphuric Acid.

Procedure:  To the sample, reagent is added drop wise.

Result: Red- Orange color indicates the presence of Amphetamines.

 MANDELIN’S REAGENT TEST

Preparation of reagent: 1 gram Ammonium Vanadate is dissolved in 100ml. concentrated Sulfuric Acid.

Procedure:  Appropriate amount of aqueous solution is taken.  Few drops of Mandelin‟s reagent is added

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines

Result: Appearance of green color darkens rapidly indicates the positive test for the presence of amphetamines. On stirring the colour passes through several shades to emerald green and dark reddish brown, which changes to light red-brown on heating.

10. Qualitative Analysis

Amphetamine and methamphetamine can be quantified by HPLC or GC. Normally, if GC is used, the samples are base-extracted into an organic solvent and either run directly or derivatised and then run. Using HPLC there is no need to extract; the sample can be dissolved in a suitable solvent, filtered if necessary and injected. In many cases HPLC is the preferred method for quantitative analysis of amphetamine and methamphetamine.

Following method may be used for the qualitative analysis of Amphetamines:

 THIN LAYER CHOMATOGRAPHY (TLC): Stationary phase : Silica gel G, 250 μm thick impregnated with 0.1M KOH in MeOH and dried Mobile phase : (1) MeOH : 25% Ammonia (100:1.5 v/v) (2) Cyclohexane : : Diethylamine (75:15:10 v/v) Visualisation : Acidified Iodoplatinate Rf values : TA: Amphetamine: 0.43 ; Methamphetamine: 0.31 TB: Amphetamine: 0.15 ; Methamphetamine: 0.28

 GAS CHROMATOGRAPHY (GC):

Using capillary Gas Chromatography (GC), operated under a suitable temperature programme, coupled to a mass spectrometer (GC-MS) the drug components of most samples can be separated and identified.

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines

Besides the above mentioned Instrumental Techniques, following other techniques may be applied for the qualitative analysis of Amphetamines:  High Performance Liquid Chromatography (HPLC)  Fourier Transform Infra- Red Spectroscopy (FTIR)  Ultraviolet - Visible Spectroscopy (UV- VIS)  Mass Spectroscopy (MS)

11. Metabolism

The amphetamines are metabolised by a combination of hydroxylation of the ring and the side-chain carbon atom adjacent to the ring, and removal of the nitrogen. Drugs with alkyl groups on the nitrogen are dealkylated (methamphetamine and Methylenedioxymethylamphetamine (MDMA)) to other active amphetamines (amphetamine and methylenedioxyamphetamine (MDA), respectively; Fig. 2.6). Methylenedioxyethylamphetamine (MDEA) and MDMA are both metabolised to MDA as well as other metabolites.

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines

The methylenedioxyamphetamines are also transformed into dihydroxy compounds (catechols) following opening of the ring. These hydroxy metabolites can be either monomethylated or conjugated with sulphate esters or with glucuronic acid. The side chain of non-N-substituted amphetamines is oxidised to form benzoic acid derivatives (e.g. amphetamine), which are excreted as the glycine conjugate, or the sulphate or Glucoronide conjugate. Amphetamine and methylamphetamine are also oxidised at the β- carbon to form the pharmacologically active analogues.

12. Designer Amphetamines

Designer drugs are congeners of active compounds that have been modified from legitimate pharmaceutical agents, and are used for recreational purposes. Designer drugs are usually stronger and cheaper than the parent compound, and can be easily synthesized in clandestine laboratories. The term “designer drug” does not include new forms or new dosing routes of old drugs (e.g. used in freebase form, i.e. “crack”). It also does not include legal drugs which are abused (e.g. ephedrine, caffeine, , etc.).

The first designer amphetamine to be developed was methylenedioxymethamphetamine (MDMA), which was introduced by E Merck & Co. in Germany in 1914. However, it was never marketed. It was only in the 1970s and early 1980s that it made its appearance as an “underground” drug. Since 1983 it has become increasingly popular among adolescents and college students as a recreational drug to be used during “rave parties”.

The other designer amphetamines quickly followed and are mostly available as gelatin capsules or loose powder for ingestion. They have made their way into India in the late 1990s, and are quite openly abused by college students from affluent families.

13. Medico-legal Aspect

Most deaths from amphetamine are either suicidal or accidental. The popularity of amphetamine as stimulant for the harrying pace and anxieties of modern life has resulted in a number of addicts who might poison themselves from an overdose taken accidently or through mental confusion from automatism or simultaneous ingestion of . Homicidal usage of amphetamines is very rare.

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines

14. Summary

 The original amphetamine, racemic beta-phenylisopropylamine was first synthesized in 1887, and was marketed in 1932 as a nasal (Benzedrine inhaler). Its widespread abuse led to its ban in 1959.

 Methamphetamine abuse began in the 1950s and reached a peak in the 1970s. It used to be referred to as “speed” or “go”. In the late 1980s, a pure preparation of Methamphetamine Hydrochloride made its appearance for the first time in Hawaii where it was referred to as “batu”. It quickly made its way across to the United Kingdom, Australia, Western Europe, and USA, where it became popular by the slang name “ice” or “glass”.

 While “ice” is produced by the ephedrine reduction method and is very pure, occurring as large translucent crystals, a variant produced by an oil-based method is called “crystal” or “crank”, and is a white to yellow crystal product.

 Amphetamines can be taken orally, by injection, by absorption through nasal and buccal membranes; or by heating, inhalation of the vapours, and absorption through the pulmonary alveoli. Inhaled amphetamine is almost immediately absorbed with a rapid onset of effects.

 Amphetamine is a sympathomimetic agent giving rise to release of norepinephrine and inhibition of monoamine oxidase.

 Designer amphetamines are abused by teenagers and young adults for inducing euphoria, facilitating intimacy and verbosity, and heightening sexuality.

 Effects of drug abuse results in hypertension, tachycardia and inhibition of gut motility.

FORENSIC SCIENCE PAPER No. 9: Drugs of Abuse MODULE No.12: Common Stimulants: Amphetamines and Methamphetamines