Historical Standpoint and Overview of Analytes of Interest

Amphetamine and Methamphetamine

Review of the literature reveals a lengthy history of problems or issues related to investigation of amphetamines. In addition to the analytical challenges, understanding of amphetamine-positive results is often a difficult problem. Excretion of amphetamines is dramatically influenced by the urinary pH, thus making an evaluation of the measured concentrations difficult. In addition, the enantiomeric composition of methamphetamine and amphetamine in the sample is critical information because of the availability of l-methamphetarriine in some over-the-counter nasal inhalers. Although most abused drug is d-enantiomer, racemic mixtures are commonly encountered in the illegal community.

When the presence of amphetamine or methamphetamine is reported, concern for the illegal use of the drugs immediately surfaces. However, an understanding of results must always include the prospective for the use to have been legitimate, which most often translates to use pursuant to medical prescription. Amphetamine- and methamphetamine-containing drugs are prescribed, although not extensively because of their high potential for abuse and quick development of tolerance, although the use of amphetamine for treatment of ADHD has significantly increased the medicinal use of amphetamine.

Amphetamine Analogs (MDA, MDMA, MDEA)

Methylenedioxyamphetamine (MDA) was synthesized in 1910, but not seriously studied for almost 40 years. Several areas where MDA was investigated therapeutically included as a cough suppressant, an ataractic, and an appetite suppressant (Amphedoxamine). It was also studied as a treatment for Parkinson disease, but in fact provoked the disease rather than helping. MDA was used in a study of patients undergoing psychotherapy treatment and reportedly enhanced as measured by various psychometric assessments. The pleasurable central nervous system effects led to major abuse in the 1960s, leading to preparation of the drug in 1970.

Methylene-di-oxy-methamphetamine (MDMA) was first synthesized by Merck in Germany and patented in 1912. Despite the common fallacy that it was developed as an appetite suppressant, that is not true, as it was one of a number of compounds developed as part of a project to develop haemostatic substances. It was illegally manufactured and some abuse was noted in the late l960s. The drug slowly gained fame and was used by more individuals. Its abuse followed the abuse of MDA, which was also being used in the illegal drug community. MDMA held more than a few advantages, including fewer undesirable side effects; the fact that the addition of the methyl group was enough to make it a legal compound, and some psychotherapists felt it was a powerful addition to their treatment. In spite of their objections, MDMA was added in Schedule I in 1985.

It was detached from the schedule for a short period in 1987 because of an administrative error by the Drug Enforcement Administration (DEA) in the initial scheduling process It was placed back on the schedule the following year, where it remains to this day.

The origin and history of 3,4-methylenedioxyethylamphetamine (MDEA) is less well known and recognized. Its development and reason for development is not clearly defined. On scheduling of MDMA, MDEA became more widely used, but did not become an acceptable substitute in the illegal community most probably because of the fact the drug did not have comparable desirable effects, as MDMA did. Shulgin reported the properties of strangely easy communication and positive self-viewing of MDMA as being absent in MDEA. Lack of these effects may explain the reason this drug is not as desirable.

These amphetamine analogs are all in Schedule I, and therefore have no documented medical use. The first to appear in the United States illegal market was MDA, followed by MDMA, which was much preferred by users and gained popularity that remains to this day over the desmethyl analog. MDEA offered no advantages and never gained much popularity, and the 4carbon relative of MDMA, N-methyl 1-(3,4-methylenedioxyphenyl-2butamine) (MBDB), has also not been found to be more popular than MDMA itself. The only one of these drugs that gained a following in the medical community is MDMA, which was used by some psychiatrists who believed the drug added to their capability to take care of some psychiatric conditions by its effects on the patient. These arguments were unproductive when raised as objections to the effort by the DEA to place the drug into Schedule I in the 1980s.

Precursor Compounds

Even though issues like l-methamphetamine containing nasal inhalers confuse the explanation of results, its role and understanding is well known. A more complicating, and less well known, factor in the interpretation of positive results is that of precursor compounds. For purposes of this chapter, the term precursor compound is used to refer to a compound that is metabolized by the body to either amphetamine or methamphetamine. Historically most of the amphetamine precursor drugs were developed as anorectics, attempting to uphold the anorectic effect without the problems of addiction and tolerance seen with amphetamine and methamphetamine.

Drugs shown to be metabolic precursors to methamphetamine and/or amphetamine include amphetamine, benzphetamine, clobenzorex, deprenyl, dimethylamphetarnine, ethylamphetarnine, famprofazone, fencamine, fene~yl~ine, fenproporex, furfenorex , mefenorex, mesocarb, and prenylamine. In addition, another drug converted by the body to amphetamine is lisdexamfetamine. In this case, the drug is specifically designed to be a pro-drug of amphetamine. A pro-drug is designed to be metabolized to the desired active agent compared to precursors that are metabolized to another drug but the administered drug is itself the active agent. That is to say, the production of amphetamine or methamphetamine from these precursor compounds is incidental despite the fact that several, including deprenyl and fenethylline, have had at least part of their activity attributed to amphetamine derived from the drugs rather than from the drugs themselves. These claims have not been demonstrated, however. In the case of lisdexamfetamine, the compound has no pharmacological activity of its own. The purpose is to deliver amphetamine when administered as directed while preventing a common form of abuse since the administered drug has no activity. Although many of these drugs are not universally available throughout the world, one or more of these drugs are available in essentially every part of the world.

Many of these precursor compounds fall in the therapeutic category of anorectics with some degree of effectiveness. Benzphetamine, clobenzorex, ethylamphetamine, fenproporex, furfenorex, and mefenorex all belong to this therapeutic category. These compounds were often developed in an attempt to separate the desired anorectic effect from the typical central nervous system effects produced when using amphetamine or methamphetamine. Those precursor compounds that fall under other various treatment categories are listed below.

Amphetaminil is a psychotropic drug used for the treatment of fatigue, depression, and potency disorders, as well as narcolepsy. It has also been used in an evaluation of the treatment of hyperkinetic children and as an anorectic. In combination with other medications, amphetaminil has also been used as a tonic and in the treatment of hypotension.

Deprenyl is primarily used in the treatment of Parkinson disease and is most often used in combination with L-dopa. Co-administration of deprenyl enhances the activity of L-dopa and decreases unfavorable side effects seen when Adopt is administered alone. At typical therapeutic concentrations, deprenyl functions as a strong monoamine oxidase  inhibitor. The action of deprenyl has, at least in part, been attributed by some investigators to the effects of its metabolites, amphetamine and methamphetamine on the intake of biogenic amines. However, the role these 2 metabolizes play in the action of deprenyl is not universally accepted, as evidenced by conflicting opinion in the literature that methamphetamine and amphetamine are not important for the action of this drug.

The question of action of methamphetamine and amphetamine in this case plays a role in the interpretation of analytical data associated with determination of drug use. The concentrations of methamphetamine and amphetamine are quite low compared to the initial deprenyl administered, and since they are the l-enantiomer of the drugs, it is reasonably argued they do not play any significant role. Amphetamine and methamphetamine are monoamine oxidase inhibitors; however, unlike deprenyl, the action of amphetamine and methamphetamine is more pronounced on the A- rather than B-form of the enzyme. The inhibition caused by amphetamine and methamphetamine is a competitive and reversible phenomenon, but the inhibition of monoamine oxidase caused by deprenyl is not reversible. Their low concentrations, even in long-term deprenyl therapy, is important to understand with respect to analytical test results, which show the presence of methamphetamine and amphetamine and the evaluation of the possibility of use of this drug as opposed to direct use of methamphetamine or amphetamine.

Deprenyl has also been shown to have significant positive effects in the prevention and treatment of Parkinson disease-like symptoms associated with (1-methyl-4-pheny-1,2,3,6-tetrahydropyridine MPTP). This protective effect is attributed to the enzyme inhibitory action that prevents the oxidative conversion of MOP by monoamine oxidase to the more toxic 1-methyl-4-phenylpyridinium (MPP+), which is suspected to be the contributing agent in the MPTP-associated symptoms. This defensive effect of deprenyl can, however, is overwhelmed by high concentrations of MPTP. Other medical uses for deprenyl are described later in this review.

Famprofazone is an antipyretic and analgesic that also has some slight sympathomimetic properties and is found as a component of the multi-ingredient medication. The drug is manufactured in Switzerland and recently in Taiwan.

Fencamine is reported to be a central nervous system stimulant and has been used in the treatment of depression.

Fenethylline is a central nervous system stimulant and is used in the treatment of children with attention deficit disorders. It has also been used in the treatment of narcolepsy. Although it has a significant central stimulant activity, the activity is not identical to that of amphetamine and the side effects associated with this drug are significantly less than those seen with amphetamine. It has also been used as an antidepressant. One of the advantages of this drug is the fact that it does not cause increased blood pressure, often seen when using amphetamine, making it attractive for use in patients with cardiovascular difficulties.

The proposition has been made that the action of fenethylline is first and foremost due to the amphetamine rather than the fenethylline itself. As with deprenyl, there is no debate that amphetamine is a metabolic product of fenethylline, but somewhat whether or not fenethylline has activity of its own. Consequent assessment of pharmacological data by Nickel et al. showed, however, that the activity associated with this drug closely mirrors the plasma concentrations of fenethylline and not amphetamine. Additionally, the pharmacological activities associated with the drug are different from those associated with amphetamine. Remembering that the amphetamine portion of the molecule is racemic, the activity expected to be observed would be less than that expected with an equivalent dose of d-amphetamine. Fenethylline is a schedule I drug in the United States and has no documented valid medical use.

Mefenorex is a sympathomimetic agent with properties similar to amphetamine, but has less effect on the cardiovascular system. It is used as an anorectic adjunct in the short-term treatment of moderate to severe obesity.

Mesocarb is a stimulant that does not have some of the negative side effects of amphetamine. It has been used to counteract the effects of benzodiazepines and has also been reported to augment workload capability and cardiovascular role. It has been shown to significantly increase learning ability and had significant positive influence on the excretion of epinephrine in hyperactive children. It has also been used as a technique to extend tolerance to low temperatures in both cold air (-20 °C) and cold water (O-2.5 °C). Under even these extreme conditions, better overall thermal regulation was noted when the drug was used.

Prenylamine, a coronary vasodilator, is used in the treatment of angina. It also functions as a calcium channel blocker acting as a calcium antagonist. Interestingly, it has also been shown to cause a dose-dependent decrease in anaphylactic histamine release in animals. Recently, prenylamine was also shown to have a significant effect as an anti-tumor agent in the inhibition of cell proliferation in human colon cancer cells.

Lisdexamfetamine is specifically designed as an amphetamine pro-drug. It was developed to provide amphetamine for the treatment of ADHD while limiting the potential for abuse. Amphetamine and the other ADHD drugs suffer from such as grinding up the pills and snorting them to get a rapid high degree of absorption and a pleasurable amphetamine high. Since the drug must be metabolized by the body before the amphetamine is released, this potential abuse is avoided.

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