Amphetamine Withdrawal

Prolonged use of amphetamines induces both physical and psychological dependence that cause symptoms of amphetamine withdrawal upon cessation of intake.

The disease is related to the following processes:  Poison and has an incidence of about  3 / 100.000.

Overview

Amphetamines pertain to the large group of psychoactive drugs, more precisely to those mediating central nervous system stimulation. From a pharmacological point of view, amphetamines act as central sympathomimetics. They bind to distinct receptors and increase extracellular concentrations of the neurotransmitters dopamine, norepinephrine and serotonin in various brain regions. Elevated levels of these neurotransmitters are associated with alertness, agitation, euphoria, hallucinations, reduction of appetite and hypertension.

Alertness and above all euphoria cause psychological dependence on amphetamines. Additionally, prolonged intake of amphetamines induces pharmacodynamic tolerance, i.e., doses need to be constantly increased in order to trigger the desired effect. Pharmacodynamic tolerance is mainly mediated by desensitization of receptors and subsequent decrease of neurotransmitter release. Reduction of receptor density may also play an important role. Pharmacodynamic tolerance is related to physical dependence on these drugs.

Therefore, any reduction of amphetamine doses or cessation of intake causes symptoms of amphetamine withdrawal (AW) [1]. Symptom onset usually occurs within one day after significant dose reduction or discontinuation of amphetamine use. In order to overcome AW, the patient needs to resist the desire to consume amphetamines and has to endure dysphoric moods, irritability, depression, fatigue, sleep disorders and possibly pain. These complaints interfere with life quality and often cause relapses or administration of other drugs to compensate for the lack of amphetamines [2].

According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), in order to be diagnosed with AW, a patient needs to present at least two of the above mentioned symptoms. Symptoms have to be observed in a close temporal connection with reduction or cessation of amphetamine use and cannot be explained by any other pathological condition.

No drugs are approved for AW treatment, and few studies yielded promising results [3] [4].

Etiology

Amphetamines is a rather broad term and may refer to any of the following illegal drugs:

  • Amphetamine ("Speed")
  • Methylenedioxyamphetamine ("Sally", "Sass")
  • Metamphetamine ("Crystal", "Crystal Meth")
  • 3,4-Methylenedioxymethamphetamine ("Ecstasy")
  • Other derivatives of amphetamine

While addiction and AW are generally associated with use of illicit drugs, application of certain amphetamines and derivatives is approved in Europe and the United States for treatment of attention deficit and hyperactivity disorder (ADHD). This applies to dextroamphetamine, for instance.

It has been suggested that both an individual predisposition and environmental factors play key roles in developing drug dependence. Although these are general assumptions, they are most likely applicable to amphetamine abuse. In this context, a family history of drug addiction may be considered a risk factor for amphetamine dependence. However, it is unclear whether this fact results from inherited gene variants or from persisting social surroundings that facilitate access to legal and illegal drugs. While the latter may seem more plausible, inherited alterations of central nervous system signaling cascades may in fact render a person more susceptible to the effects of amphetamines and other drugs.

Psychological disorders are generally considered to increase the risk of drug dependence.

Epidemiology

Abuse and subsequent dependence on amphetamines constitutes a public health concern of increasing importance. While there are regional differences in incidence and prevalence of amphetamine abuse, alarmingly high figures are reported from all continents. According to a survey conducted in the United States in 2006, more than 1% of all respondents had consumed amphetamine, metamphetamine or related drugs during the previous month. In Australia and New Zealand, numbers of amphetamine addicts exceed those of cocaine addicts by far, while the opposite seems to be the case in Africa [5]. Independent of their geographical location, the vast majority of patients that reduce or cease amphetamine administration experience symptoms of AW.

Sex distribution
Age distribution

Pathophysiology

Amphetamines are indirect sympathomimetics that bind to distinct receptors expressed in the central nervous system. They alter extracellular concentrations of monoamines, i.e., of dopamine, norepinephrine, serotonin and other neurotransmitters by impeding re-uptake and increasing release.

Different molecular mechanisms have been identified:

  • Amphetamines and dopamine. Under physiological conditions, dopamine is cleared from the synaptic cleft by reuptake into presynaptic neurons. Reuptake is mediated by dopamine transporter DAT. Now, amphetamines serve as substrates for this transporter and therefore act as competitive inhibitors of DAT. It has also been proposed that amphetamines induce reverse dopamine transport through DAT independent of neurotransmitter release triggered by an action potential [6].
  • Amphetamines and norepinephrine. Presumably, inhibition of reuptake and induction of reverse transport also account for prolonged action of norepinephrine.

Pharmacodynamic tolerance is induced by desensitization of amphetamine receptors. Consequently, equal amounts of amphetamines (or endogenous ligands) are insufficient to trigger neurotransmitter release and higher doses are necessary. After reduction or cessation of amphetamine use, desensitization persists for a few days. Limited excitability of these neurons causes symptoms of AW and since they are part of the reward pathway, AW patients experience dysphoric moods, depression and irritability.

Of note, pharmacodynamic tolerance should not be confused with tachyphylaxis. The latter consists in decreased effectivity of amphetamines administered within short periods of time after those drugs had been used for the last time. Here, neurotransmitter stores are not yet replenished and even though receptors are not yet desensitized, amphetamines will not cause significant increases of extracellular monoamine levels.

Distinct amphetamines may present different affinities to determined molecular targets. Also, desensitization varies with receptors and with ligands. And although symptoms associated with AW result from physical and psychological dependence, the individual experience of withdrawal largely depends on the patient, on the drug they used and on consumption habits.

Prognosis

Prolonged use of amphetamines induces physical and psychological dependence. The former results from reversible receptor desensitization and is self-limiting if patients don't have relapses. However, cognitive function may be partially permanent [7]. Psychological support as well as changes to the patient's social environment may be required to overcome the latter because the desire to feel amphetamine-mediated euphoria may persist even after neurotransmitter balance is regained.

Presentation

The vast majority of amphetamine addicts experience symptoms of AW. According to a study conducted several years ago in the United Kingdom, 86% of 50 current or past amphetamine dependent clients reported irritability, musculoskeletal pain, dysphoric moods or depression and impaired social functioning [1]. Less frequently, fatigue, exhaustion, chills, night sweats, sleeping disorders, nausea and vomiting, headaches and an increased appetite were noted. Here, AW symptoms lasted up to a few weeks.

These observations have been confirmed in other studies [8]. Most severe symptoms occur within a few days after initiation of detoxification and some symptoms may persist for a few weeks. In rare cases, complete resolution of AW complaints could only be achieved within several months.

Because amphetamines act as psychotropic stimulants, cessation of administration may uncover underlying mood disorders and depression. Dysphoric moods are one of the main triggers of relapse. If amphetamines are not available, dependent patients may switch to other drugs. Abuse of cannabis, alcohol and benzodiazepines are very common among patients undergoing AW.

Amphetamines cause erectile dysfunction but generally augment the sexual drive. It is therefore not uncommon to detect symptoms of sexually transmitted diseases in AW patients [9].

Workup

According to the current version of the Diagnostic and Statistical Manual of Mental Disorders, diagnosis of AW is based on the patient's medical history, clinical and psychological examination:

  • Anamnesis should reveal prolonged use of amphetamines and recent reduction or cessation of administration.
  • AW patients feel a strong desire to use amphetamines again.
  • Dysphoric moods are an exclusion criterion for AW.
  • Furthermore, the patient claims at least two of the following symptoms: fatigue, insomnia or hypersomnia, psychomotor agitation or retardation, increased appetite, vivid dreams.
  • These symptoms interfere with day-to-day activities and social functioning and may not be explained by any other pathological condition, substance abuse or withdrawal.

Drug abuse and drug dependence are no longer distinguished clinically and the above given definition holds true for both conditions.

Treatment

Several compounds have been tested for their effectivity in AW, but there is no approved drug for treatment of this condition nor sufficient scientific evidence that would justify such an approval [8].

Amineptine, a tricyclic antidepressant, has been proven to alleviate symptoms resulting from autonomous dysfunction [3]. But while lethargy, fatigue and increased appetite were relieved by administration of amineptine, craving for amphetamines and risk of relapse could not be decreased. Reboxetine, an antidepressant that inhibits reuptake of norepinephrine, has also been proposed as a possible therapeutic approach to AW. This recommendation is based on a small clinical study comprising eleven patients. In ten out of eleven patients, "some beneficial effects withdrawing from amphetamine" were observed [4]. Finally, AW has been treated with mirtazapine, a noradrenergic and serotonergic antidepressant [10]. This compound has initially been found to reduce agitation and anxiety, but not depression. However, a following study could not confirm these results [11].

Psychological therapy may be of greater use than any medication. Both individual therapy, group or family sessions may be helpful. Methods like cognitive behavioral therapy and contingency management may be applied [5].

Prevention

Education is the key to prevent all kinds of drug abuse. There are no specific measures regarding amphetamine dependence unless information about detrimental effects, possible permanent impairment of cognitive function and symptoms associated with AW.

Most amphetamine addicts use other legal and illicit drugs before first administration of amphetamine or related substances. Frequently, drugs are sold and consumed in secondary schools, high schools and colleges. Social pressure may be particularly high in these institutions. Thus, the above mentioned education programs should primarily be addressed to adolescents and young adults. They should be comprehensive and not restricted to amphetamines.

Amphetamine addicts should have the possibility to seek psychological counseling in order to resolve their problems.

Patient Information

Amphetamine is the name of an illicit drug; it is also the name of a group of substances that comprises amphetamine itself ("Speed"), Methylenedioxyamphetamine ("Sally", "Sass"), Metamphetamine ("Crystal", "Crystal Meth") 3,4-Methylenedioxymethamphetamine ("Ecstasy") and other compounds. Prolonged use of these drugs causes physical and psychological dependence and therefore, symptoms corresponding to amphetamine withdrawal (AW) are experienced if doses are drastically reduced or administration of amphetamines is ceased altogether.

Causes

From a pharmacological point of view, amphetamines are psychotropic stimulants that bind to distinct receptors in the central nervous system. Here, they mediate an increase in extracellular concentrations of neurotransmitters like dopamine, norepinephrine and serotonin. These effects cause alertness, agitation, euphoria, hallucinations, reduction of appetite and hypertension.

Over time, amphetamine receptors "get used" to the administrated drug and higher doses become necessary to induce the same effect. This phenomenon is deemed tolerance. If amphetamine use is suddenly stopped, these receptors remain sensitized for a few days or weeks and symptoms of physical dependence manifest.

The above mentioned effect of euphoria is what triggers psychological dependence. Amphetamine addicts crave to experience that effect again and desire to readminister the drug.

Symptoms

Symptoms are most severe within the first few days after initiation of detoxification. They usually comprise:

  • Dysphoric moods, depression
  • Fatigue
  • Sleeping disorders
  • Irritability
  • Increased appetite
  • Vivid, unpleasant dreams
  • Musculoskeletal pain

Diagnosis

AW may be diagnosed if a patient presents dysphoric mood and at least two additional symptoms included in the list given above. These complaints show a close temporal connection to cessation of drug use and can't be explained by other pathological conditions, substance abuse or withdrawal.

Treatment

There is no medical treatment for AW. A few compounds have been tested for their effectivity in this condition, but evidence supporting beneficial effects is scarce. Recommendations are merely based on observations made in very small test groups and therefore, no compound has been approved for AW therapy so far. However, psychological treatment - in form of individual, group or family sessions - may be of great help to overcome amphetamine dependence.

Recognition of amphetamine dependence is the first step in the right direction. Nobody should hesitate to seek professional help.

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References

  1. Cantwell B, McBride AJ. Self detoxication by amphetamine dependent patients: a pilot study. Drug Alcohol Depend. 1998; 49(2):157-163.
  2. Li H, Scholl JL, Tu W, et al. Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal. Eur J Neurosci. 2014; 40(11):3684-3692.
  3. Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: II. A placebo-controlled, randomised, double-blind study of amineptine treatment. Aust N Z J Psychiatry. 1999; 33(1):94-98.
  4. Cox D, Bowers R, McBride A. Reboxetine may be helpful in the treatment of amphetamine withdrawal. Br J Clin Pharmacol. 2004; 58(1):100-101.
  5. Vocci FJ, Montoya ID. Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence. Curr Opin Psychiatry. 2009; 22(3):263-268.
  6. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol. 2007; 47:681-698.
  7. van Holst RJ, Schilt T. Drug-related decrease in neuropsychological functions of abstinent drug users. Curr Drug Abuse Rev. 2011; 4(1):42-56.
  8. Shoptaw SJ, Kao U, Heinzerling K, Ling W. Treatment for amphetamine withdrawal. Cochrane Database Syst Rev. 2009; (2):CD003021.
  9. Hser YI, Liang D, Lan YC, Vicknasingam BK, Chakrabarti A. Drug Abuse, HIV, and HCV in Asian Countries. J Neuroimmune Pharmacol. 2016.
  10. Kongsakon R, Papadopoulos KI, Saguansiritham R. Mirtazapine in amphetamine detoxification: a placebo-controlled pilot study. Int Clin Psychopharmacol. 2005; 20(5):253-256.
  11. Cruickshank CC, Montebello ME, Dyer KR, et al. A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal. Drug Alcohol Rev. 2008; 27(3):326-333.

  • Amphetamine-related presentations to an inner-city tertiary emergency department: a prospective evaluation - SD Gray, DM Fatovich, DL McCoubrie - Medical journal of , 2007 - mja.com.au
  • Of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in - PE Paulson, DM Camp, TE Robinson - Psychopharmacology, 1991 - Springer
  • Of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in - PE Paulson, DM Camp, TE Robinson - Psychopharmacology, 1991 - Springer


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