Understanding Methamphetamine: A Review of Its Pharmacological Mechanisms and Chemical Properties in Relation to Addiction

Abstract

Methamphetamine, often called crystal meth, is a synthetic stimulant that impacts both the brain and the central system. The half-life of methamphetamine (MA) varies between 10 and 30 hours, with extended use leading to tolerance development. The United Nations Office on Drugs and Crime (UNODC) indicates that major methamphetamine producers are mainly located in Southeast Asia and North America. This compound was first synthesized in 1919 by the Japanese chemist Akira Ogata, using ephedrine as a starting material. Methamphetamine has two stereoisomers: l- and d- forms. It elevates the extracellular levels of monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine. There are primarily two production methods: 1) extracting or hydrogenating amphetamine or methamphetamine from ephedrine or pseudoephedrine, and 2) synthesizing the drugs using various precursor chemicals. In a report from 1996, the World Health Organization (WHO) stated that over 35 million individuals globally were regular users of methamphetamine, making it the second most widely abused illicit drug after cannabis. The intake of methamphetamine results in elevated blood pressure, increased body temperature, accelerated heart rate, and heightened respiratory rate. Users frequently continue its use due to its rewarding properties, which include feelings of euphoria, reduced fatigue, decreased appetite, enhanced energy, increased libido, and higher self-esteem. Currently, there are no sanctioned pharmacological treatments specifically targeting methamphetamine dependence.

Keywords

Introduction

The illegal psychostimulant substances, which encompass cocaine and amphetamines along with their derivatives, are a highly addictive group of compounds. In recent years, there has been a significant rise in the usage of select drugs from this category[1]. Notably, both methamphetamine (MA) and 3,4-methylenedioxymethamphetamine have gained popularity[2]. Methamphetamine, often known as crystal meth, is a synthetic stimulant that impacts the brain and central nervous system. When smoked or injected, it produces an immediate rush that lasts just a few minutes but is profoundly pleasurable. The half-life of MA varies between 10 to 30 hours, depending on factors like drug purity, urine pH, and the quantity consumed. Similar to other addictive psychoactive substances, long-term use of MA can lead to tolerance, necessitating larger doses to achieve the same high. The sought-after effects of using illicit methamphetamine include feelings of euphoria, reduced appetite and need for sleep, heightened mental alertness and energy, disinhibition, a sense of wellbeing, and increased self-confidence. Methamphetamine can be found in various forms, including pure crystalline hydrochloride salt and pressed tablets[3,4,5].  The United Nations Office on Drugs and Crime (UNODC) indicates that the primary producers of methamphetamine are located in Southeast Asia and North America, where a significant number of users also reside. Amphetamine-like substances rank as the second most commonly misused drugs after cannabis, and the patterns of methamphetamine consumption differ significantly across various global regions[6].

PAST OF METHAMPHETAMINE:

Amphetamine-type stimulants, encompassing both methamphetamine and amphetamine, were created as synthetic replacements for ephedra. Ephedra, derived from the plant Ephedra sinica, has a history of use in traditional Chinese medicine, known as ma huang, spanning over 5,000 years. In 1885, researchers isolated and analysed ephedrine, the active alkaloid in ephedra. It was found to share similarities with epinephrine, which had also been isolated around the early 1900s^[7]. Unlike epinephrine, ephedrine could be administered orally, offered a longer lasting effect, provided more significant and consistent central nervous system (CNS) stimulation, and boasted a wider therapeutic range. Efforts to find a synthetic alternative to ephedrine led to the creation of amphetamine-type stimulants, achieved by altering the ephedrine structure to fulfil pharmaceutical objectives such as CNS stimulation, bronchial dilation, or nasal vasoconstriction^[8]. In 1919, Japanese chemist Akira Ogata first synthesized methamphetamine using ephedrine as a precursor. Initially, the use of amphetamines primarily involved nasal insufflation. In 1932, the pharmaceutical company Smith, Kline, and French introduced the Benzedrine inhaler, intended for treating asthma and nasal congestion. The inhaled amphetamine produced vasoconstriction of the nasal mucosa, reducing mucosal swelling and edema, and the product was initially available without any prescription requirements. In 1959, S. Pfeiffer Company began manufacturing Valo inhalers, each containing 150-200 mg of methamphetamine^[9].

Figure No. 1: Crystals of Methamphetamine^[10]

CHEMISTRY OF METHAMPHETAMINE:

Methamphetamine, also referred to as methamphetamine, N-methylamphetamine, methylamphetamine, and desoxyephedrine, is a psychostimulant belonging to the phenethylamine and amphetamine classes of psychoactive substances. This compound exists in two stereoisomers: the l- and d- forms. D-methamphetamine, known as the dextrorotary enantiomer, possesses a significantly higher potency as a psychostimulant, exhibiting 3-5 times the central nervous system (CNS) activity compared to l-methamphetamine, the levorotary enantiomer. Nonetheless, both enantiomers affect dopamine release and can lead to stereotypy characterized by a continuous, mechanical repetition of speech or movement as well as psychosis when consumed in elevated doses. Illegally, methamphetamine may be obtained as pure d-methamphetamine (dextromethamphetamine) or as a racemic mixture, appearing in either powdered or crystalline forms. The crystalline variant is often referred to as “ice” or “crystal meth.” This form typically indicates a highly purified variant of d-methamphetamine, intended for smoking, producing effects akin to those of intravenous administration. Furthermore, the crystalline form of methamphetamine is furthermore linked to a higher likelihood of dependence compared to lower purity alternatives^[11,12].

PHARMACOLOGY OF METHAMPHETAMINE:

Methamphetamine significantly impacts the brain by increasing extracellular levels of monoamine neurotransmitters, such as dopamine, serotonin, and norepinephrine, primarily by facilitating their release from nerve terminals. The precise mechanisms by which methamphetamine triggers neurotransmitter release remain unclear. However, it seems to involve the movement of neurotransmitters from synaptic vesicles, mediated by the vesicular monoamine transporter VMAT2, to the neuronal cytoplasm, along with the reverse transport of these neurotransmitters through the plasma membrane transporter into the extracellular environment^[13]. The cardiovascular stimulation induced by methamphetamine is largely attributed to the release of norepinephrine from sympathetic nerve endings. While the underlying process that contributes to the alertness associated with methamphetamine and its effectiveness in treating attention-deficit hyperactivity disorder is not fully understood, it likely involves, at least in part, the activation of the brain's noradrenergic neurotransmitter system^[14,13].

Figure No. 2: Structures of Methamphetamine and Amphetamine

Dopamine Antagonists:

First-generation antipsychotics primarily function as antagonists of dopamine D2 receptors. In contrast, newer second-generation antipsychotics also target serotonin receptors. These medications have been considered as prospective treatments for stimulant dependency. An open-label study lasting four weeks investigated the efficacy of risperidone (3, 6 mg per day) in veterans seeking treatment for methamphetamine addiction. The outcomes were assessed through self-reported substance use, urine drug screenings, and monitoring of side effects. Findings indicated a reduction in methamphetamine consumption correlated with the administration of risperidone, which was also reported to be well tolerated^[4].

METHAMPHETAMINE FORMULA:

Production of methamphetamine typically follows two primary methods: 1) extracting or hydrogenating amphetamine or methamphetamine from ephedrine or pseudoephedrine, and 2) synthesizing the drugs using alternative precursor chemicals. Each batch historically yielded approximately 5–10 pounds of methamphetamine. With increasing regulations on these substances, new procedures involving ephedrine and pseudoephedrine have emerged, predominantly using either extraction or hydrogenation techniques. Currently, the majority of illicit laboratories utilize these methods, starting from ephedrine or pseudoephedrine derived from legitimate pharmaceutical products and culminating in the synthesis of methamphetamine through various mixing and filtering processes. Unlike earlier production techniques, modern extraction and synthesis often rely on commonplace chemicals found in household items or agricultural supplies, along with precursors present in over-the-counter medications. The chemical agents required for methamphetamine production via the ephedrine/pseudoephedrine reduction method include ephedrine or pseudoephedrine, hydriodic acid, and red phosphorus. Alternatives to hydriodic acid consist of iodine combined with hypophosphorous acid or anhydrous ammonia alongside sodium; however, the former substitution may generate highly volatile gases and poses an increased risk of combustion or explosion. The traditional P2P production method does not utilize ephedrine or pseudoephedrine but instead employs various other precursor chemicals such as phenyl-2-propanone, aluminium, methylamine, and mercuric chloride, ultimately producing dl-methamphetamine^[8,15]. Utilizing one of the aforementioned methods, two categories of methamphetamine can be synthesized: dextro-Levo-methamphetamine, also known as dl-methamphetamine, and dextro-methamphetamine, referred to as d-methamphetamine. The dl-methamphetamine is synthesized through the traditional P2P method and exhibits lower potency compared to d-methamphetamine, which is produced using the reduction of ephedrine or pseudoephedrine. The d-methamphetamine variant is the most prevalent type currently available in circulation. "Ice" is a specific crystalline form of methamphetamine predominantly found in Hawaii, created by crystallizing powdered methamphetamine in solvents such as methanol or acetone; it possesses a higher purity level than the other two forms and is primarily consumed through smoking^[8,16].

THE MA DISPUTE:

The World Health Organization reported that in 1996, over 35 million individuals globally used methamphetamine (MA) regularly, ranking it as the second most widely abused illicit substance after cannabis. Recent studies suggest that MA represents the fastest-growing illicit drug worldwide. Certain ethnographic groups may face a heightened risk of experiencing MA's adverse effects. The prevalence of MA abuse among the male homosexual and bisexual communities poses significant challenges, particularly due to the increased incidence of high-risk sexual behaviours linked to its use. Furthermore, chronic MA consumption can worsen cognitive impairments associated with HIV^{[17,18,19,20]}. Growing evidence indicates that prenatal exposure to MA leads to pronounced morphological brain changes, which are connected to cognitive deficits. Recreational users often referred to as “ravers” may ingest MA voluntarily or unknowingly alongside other substances, such as MDMA. The drug can be administered through various methods, including smoking (vaporization), snorting, intravenous injection, or oral consumption. Users typically sustain their dependence for under Can $5 daily and experience effects of intoxication lasting from 6 to 16 hours^[21]. A recent qualitative survey revealed that individuals under the influence of MA often feel that the drug helps them regain a sense of normalcy and offers coping mechanisms for trauma and depression; however, it also leads to heightened reactivity. Most participants reported a significant decline in their overall quality of life attributable to MA abuse. The survey found that over 80% of street youth habituated to MA experienced symptoms of MA psychosis, with psychotic manifestations intensifying as the duration of MA use increased. Alarmingly, repeated psychotic episodes may lead to greater treatment resistance, with symptoms becoming less amenable to medication after multiple relapses, and in some instances, residual symptoms that were previously absent may emerge post-relapse. Alongside the psychological complications linked to prolonged MA use, the drug is associated with a range of physical health issues, which include dental decay, infections, heart failure, and malnutrition^[22,23].

SIGNS OF METHAMPHETAMINE USE, MISUSE, AND ADDICTION:

The use of MA elevates blood pressure, body temperature, heart rate, and respiration. Users often continue using MA due to its rewarding effects, which include feelings of euphoria, diminished fatigue, decreased hunger, enhanced energy levels, increased libido, and elevated self-confidence. Conversely, acute negative effects can manifest as abdominal cramps, tremors, elevated body temperature, bruxism (teeth grinding), strokes, and irregular heart rhythms, along with heightened anxiety, insomnia, aggressive behaviour, paranoia, and hallucinations. The immediate effects of MA are influenced by the dosage and method of consumption. When injected or smoked, the effects are swift and intense, often referred to as a “rush,” which is then succeeded by feelings of euphoria, increased energy, alertness, and heightened sexual desire. Users may experience an elevation in heart rate, blood pressure, and respiratory rate, and many may grind their teeth or pick at their skin. The effects can endure for as long as 12 hours. With the development of tolerance, individuals who use MA chronically may resort to repeating doses every few hours during “binging” sessions, potentially leading to symptoms such as paranoia, hallucinations, delusions, mood disturbances, and formication (a sensation of insects crawling on the skin). Following prolonged or heavy MA use, withdrawal syndrome may present, characterized by a dysphoric mood, anhedonia, fatigue, increased appetite, disturbances in sleep, and either slowed or accelerated psychomotor activity. The intensity of withdrawal symptoms is correlated with the duration and severity of recent MA use. Individuals’ dependent on MA have reported that the most severe withdrawal symptoms typically subside within several days to three weeks; however, there are numerous clinical accounts of more subtle symptoms, such as anhedonia, persisting for several months. Apathy has been more commonly reported than depressed mood, indicating that anhedonia may pose a greater challenge than major depressive disorder following the cessation of MA use^[24].

TREATMENT OF METHAMPHETAMINE ADDICTION:

Currently, there are no approved medications specifically for addressing methamphetamine dependency. Existing methods to avert relapse predominantly involve psychosocial strategies^[25]. It is unlikely that a singular medication will demonstrate significant effectiveness in preventing relapse among the majority of methamphetamine users. Given the chronic nature of this condition, the "memories" associated with addiction may be deeply ingrained, potentially leading to actual structural modifications in brain neurons, such as changes to dendritic spine density, which render the addiction resistant to medical treatment. Nonetheless, optimism persists regarding the potential development of new medications targeting various pathways to help individuals maintain abstinence^[26]. Preliminary research indicates that bupropion, which has both dopaminergic and nondopaminergic effects, as well as the opioid receptor antagonist naltrexone, may impact certain cravings associated with amphetamines. More broadly, the demonstrated effectiveness of varenicline in smoking cessation raises hope that a therapeutic model employing a partial agonist a single compound with both agonist and antagonist characteristics might prove beneficial for other forms of addiction. Additionally, the notion of "drug substitution therapy," utilizing low-dose oral amphetamine, has been suggested as a possible treatment for methamphetamine dependency, and initial data, though requiring further validation, lend some support to this idea^[27]. However, significant apprehensions arise regarding the application of an abused substance in treating stimulant dependency. Given that some rehabilitation facilities assert that cognitive impairments can hinder retention in treatment programs, alternative approaches may include the administration of cognitive enhancers during methamphetamine withdrawal and the implementation of deep brain stimulation aimed at temporarily disabling brain regions implicated in addiction and relapse^[28].

CONCLUSION:

MA a synthetic replacement of ephedra. Is the illegal psychostimulant. Compose of cocaine and amphetamine. MA is a highly addictive psychostimulant drug. Although methamphetamine is used in treatment of hyperactivity disorder there are also large number of issues associated with it.  Methamphetamine dependence is a growing problem in various areas of the world. The development of effective treatments for methamphetamine dependence has become a pressing concern. Methamphetamine produces a range of direct effects including subjective euphoria, arousal and psychomotor activation. At higher doses, stimulation of striatal dopamine D2 receptors appears to mediate psychosis. prenatal exposure to MA leads to brain defects which are hazardous to health. According to WHO reports after cannabis methamphetamine is the second largest abused illicit substance. Amidist all of these complications of MA and growing concerns investigations are underway

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