The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) describes the following 11 amphetamine-related psychiatric disorders:[1]
Amphetamine-induced anxiety disorder
Amphetamine-induced bipolar disorder
Amphetamine-induced depressive disorder
Amphetamine-induced psychotic disorder
Amphetamine-induced sexual dysfunction
Amphetamine-induced sleep disorder
Amphetamine intoxication
Amphetamine intoxication delirium
Amphetamine withdrawal
Amphetamine-induced obsessive-compulsive and related disorder
Unspecified stimulant-related disorder
Either prescription or illegally manufactured amphetamines can induce these disorders. Prescription amphetamines are used frequently in children and adolescents to treat attention deficit hyperactivity disorder (ADHD), and they are the most commonly prescribed medications in children. The dose of Adderall(XR) (dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate) needed to produce toxicity and psychiatric symptoms in a child is as low as 2 mg. A typical dose is 2.5–40 mg/d. In adults, narcolepsy, ADHD of the adult type, and some depression can be treated with amphetamines. Although they are controlled substances, abuse is possible, especially in persons with alcoholism or substance abuse.
The substance 3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational stimulant commonly referred to as ecstasy, which was manufactured legally in the 1980s.[2] MDMA has the desired effects of euphoria, high energy, and social disinhibition lasting 3–6 hours. The drug is often consumed in dance clubs, where users dance vigorously for long periods. The drug sometimes causes toxicity and dehydration, as well as severe hyperthermia. Several other amphetamine derivatives are para-methoxyamphetamine (PMA), 2,5-dimethoxy-4-bromo-amphetamine (DOB), methamphetamine (crystal methamphetamine, crystal meth, or "Tina"), and 3,4-methylenedioxyamphetamine (MDA). Crystal meth is the pure form of methamphetamine and, because of its low melting point, it can be injected.
In a web-based survey of 1,006 individuals who admitted mephedrone use, which is the largest survey to date, results showed that users consider mephedrone's effects to compare best with those of MDMA; the appeal of mephedrone for these individuals is in its availability, low price, and reliable purity.[3]
Khat (Catha edulis Forsk) is the only known organically derived amphetamine. It is produced from the leaves of the Qat tree located throughout East Africa and the Arabian Peninsula. The leaves of the tree are chewed, extracting the active ingredient, cathinone, and producing the desired effects of euphoria and, unlike other amphetamines, anesthesia.
In the midwestern United States, methcathinone, the synthetic form of cathinone, has been produced illegally since 1989, after a student at the University of Michigan stole research documents and began to illegally manufacture the drug. Methcathinone is relatively easy to produce and contains the same chemicals found in over-the-counter (OTC) asthma and cold medicines, paint solvents and thinners, and drain openers (eg, Drano). Its addiction potential is similar to that of crack cocaine.
Amphetamine-related psychiatric disorders are conditions resulting from intoxication or long-term use of amphetamines or amphetamine derivatives. Such disorders can also be experienced during the withdrawal period from amphetamines. The disorders are often self-limiting after cessation, though, in some patients, psychiatric symptoms may last several weeks after discontinuation. Some individuals experience paranoia during withdrawal as well as during sustained use. Amphetamine use may elicit or be associated with the recurrence of other psychiatric disorders. People addicted to amphetamines sometimes decrease their use after experiencing paranoia and auditory and visual hallucinations. Furthermore, amphetamines can be psychologically but not physically addictive.
The symptoms of amphetamine-induced psychiatric disorders can be differentiated from those of related primary psychiatric disorders by time. If symptoms do not resolve within 2 weeks after the amphetamines are discontinued, a primary psychiatric disorder should be suspected. Depending on the severity of symptoms, symptomatic treatment can be delayed to clarify the etiology.
Amphetamine-induced psychosis (delusions and hallucinations) can be differentiated from psychotic disorders when symptoms resolve after amphetamines are discontinued. Symptoms of amphetamine use may be indistinguishable from those associated with the cocaine use. Amphetamines, unlike cocaine, do not cause local anesthesia and have a longer psychoactive duration.
Amphetamine-induced delirium follows a reversible course similar to other causes of delirium, and it is identified by its relationship to amphetamine intoxication. After the delirium subsides, little to no impairment is observed. Delirium is not a condition observed during amphetamine withdrawal.
Mood disorders similar to hypomania and mania can be elicited during intoxication with amphetamines. Depression can occur during withdrawal, and repeated use of amphetamines can produce antidepressant-resistant amphetamine-induced depression. Of interest, low-dose amphetamines can be used as an adjunct in the treatment of depression, especially in patients with medical compromise, lethargy, hypersomnia, low energy, or decreased attention.
Sleep disturbances appear in a fashion similar to mood disorders. During intoxication, sleep can be decreased markedly. In withdrawal, sleep often increases. A disrupted circadian rhythm can result from late or high doses of prescription amphetamines or from chronic or intermittent abuse of amphetamines. Individuals who use prescription amphetamines can easily correct their sleep disturbance by lowering the dose or taking their medication earlier in the day than they have been. Insomnia is the most common adverse effect of prescription amphetamines.
Unspecified stimulant-related disorder is a diagnosis assigned to those who have several psychiatric symptoms associated with amphetamine use but who do not meet the criteria for a specific amphetamine-related psychiatric disorder.
Case study
A 36-year-old male who works as a real estate agent arrives at your office appearing disheveled and slightly agitated. He is guarded, but describes coworkers manipulating his clock to read 9:11 and episodes of police driving by with their sirens on at 4:20. He refuses to open his mail because he recognizes messages targeted at him in the letters. He spends his free time staying up at night, fixing his computer for an "impending apocalypse." On the weekends, he sleeps in until 2 pm and reports low mood and unintentional weight loss of 25 lbs in the last 3 months. When asked about a burn mark on his hand, he admits to "smoking some T." On further questioning he discloses a 5-month period of crystal methamphetamine use.
The pathophysiology of amphetamine-related psychiatric disorders is multifactorial, as amphetamines influence many neural systems. Methamphetamine may induce psychosis through inhibition of the dopamine transporter, resulting in increased dopamine within the synaptic cleft.[4] Similarly, chronic amphetamine use may cause psychiatric symptoms due to inhibition of the dopamine transporter in the striatum and nucleus accumbens. The longer the duration of use, the greater the magnitude of dopamine reduction.
Amphetamine-induced psychosis results after increased use of amphetamines, as observed in binge use or after protracted use. Prescription amphetamines induce the release of dopamine in a dose-dependent manner; low doses of amphetamines deplete large storage vesicles, and high doses deplete small storage vesicles. This increase in dopaminergic activity likely induces psychotic symptoms, as the use of D2-blocking agents (eg, haloperidol) ameliorates symptoms. Amphetamine-induced psychosis has been used as a model to support the dopamine hypothesis of schizophrenia, in which overactivity of dopamine in the limbic system and striatum is associated with psychosis. However, negative symptoms commonly observed in schizophrenia are relatively rare in amphetamine psychosis.
MDMA causes the acute release of serotonin and dopamine and inhibits the reuptake of serotonin. MDMA has neurotoxic properties in animals and, potentially, in humans. Reports suggest that MDMA use is associated with cognitive, neurologic, and behavioral abnormalities, as well as hyperthermia, but these reports are confounded by the association with other factors (eg, heat, exertion, poor diet, other drug use).
Delirium caused by amphetamines may be related to the anticholinergic activity, as observed in different classes of drugs, such as tricyclic antidepressants, benzodiazepines, sedatives, and dopamine-activating drugs. Rapid eye movement during the first phase of sleep is decreased during intoxication, and a rebound elevation of rapid eye movement occurs during withdrawal. This effect eventually alters the circadian rhythm and results in sleep disturbances.
Among people aged 12 years or older in 2020, 0.9% used methamphetamine in the past year. Adolescents aged 12–17 years had the lowest rates of methamphetamine use at 0.1%, while adults aged 26 years and older had the highest rates of use at 1.1%. Of adults aged 12 years or older, 0.3% met criteria for prescription stimulant disorder over the past year.[5]
Psychosis, delirium, mood symptoms, anxiety, insomnia, and sexual dysfunction are considered rare adverse effects of therapeutic doses of prescription amphetamines. These symptomas are more likely to occur with methamphetamine use given the unpredictable composition of substances purchased off the street.
Data about the frequency of amphetamine-related psychiatric disorders are unreliable because of comorbid primary psychiatric illnesses.
International
Methamphetamine was first synthezised in Japan in 1919. During World War II, it was used by both Allied and Axis powers to keep pilots awake during long flights. In the 1940s–1950s, post-war Japan experienced its first meth epidemic as a result of methamphetamine introduction during the war.[6]
Catha edulis, also known as khat,an evergreen plant gathered in many countries in the east African and Arabian Peninsula like Yemen, Ethiopia, Kenya, and Somalia contains the compound cathinone, similar in structure to S-amphetamine. Cathinone metabolizes to norpseudoephedrine and norepherdine in mature leaves, producing many of the stimulant effects of methamphetamine. While Khat increases altertness, it also contributes to oral decay, gastric ulcers, hypertension, and stroke. Prolonged use can lead to dependence, psychotic symptoms, and loss of productivity, which is why the WHO first classified it as a "hazardous and harmful substance" in its Primary Care Geneva report in 2011.[7]
Mortality/Morbidity
The Drug Abuse Warning Network (DAWN) Annual Medical Examiner Data for 2021 showed that 11.2% of all drug-related hospital emergency department visits were associated with methamphetamine use, listed 3rd after alcohol and opioid-related presentations. The South and Western regions of the United States accounted for greater than 70% of all methamphetamine-related ED visits.[8]
In high doses, illicit and prescription amphetamines can produce cardiovascular collapse, myocardial infarction, stroke, seizures, renal failure, ischemic colitis, and hepatotoxicity. Heart attacks, seizures, subarachnoid, intracranial hemorrhage, and strokes may also result in death. The rate of suicide and accidents can increase during periods of toxicity and withdrawal.
In high doses, prescription amphetamines and amphetamine derivatives increase sexual arousal and disinhibition, increasing the risk of exposure to sexually transmitted diseases.
Memory impairment can result after long-term use of high doses of amphetamines because of damage to serotonin-releasing neurons. In the emergency department patients with amphetamine-related disorders are one third more likely than patients with cocaine-related disorders to be transferred to an inpatient psychiatric ward. This difference may partly be because amphetamine withdrawal lasts longer then cocaine withdrawal, and amphetamines are more likely to cause psychotic symptoms than cocaine.
Amphetamine withdrawal is characterized by low mood, increased suicidal ideation, fatigue, increased need for sleep, slowed reaction time, irritability, and vivid and unpleasant dreams. Acute symptoms typically last 1–2 days. Protracted withdrawal may occur and is termed Post-Acute Withdrawl Symptoms (PAWS). It is characterized by impaired short-term memory, inability to concentrate, lack of self control, cravings, and insomnia.[9]
Race-, sex-, and age-related demographics
Methamphetamine-related ED visits in 2021 were most prevalent among White males aged 26–44 years old. White patients accounted for 62.45% of all methamphetamine-associated ED visits, with a greater proportion of men (69%) than women (31%) coming in for methamphetamine-associated sequelae. Together, the South and West regions of the United States accounted for more than 70% of all methamphetamine-related ED visits.[9]
Instruct the patient to abstain from alcohol and illicit drugs, especially because dual diagnosis is a real issue. While abstinence from illicit substances is preferred, harm reduction strategies may be employed to reduce use.
Patients should be in a support group.
Family members should educated about the patient's substance use and triggers so they may provide support.
Refer the patient for psychosocial counseling.
Hospitalize the patient if he or she is suicidal or homicidal.
Refer the patient for substance use counseling.
Helpful Web sites include the following:
Crystal Meth Anonymous
National Institute on Drug Abuse, Methamphetamine Abuse and Addiction
NIDA InfoFacts: Stimulant ADHD Medications - Methylphenidate and Amphetamines
Methamphetamine Drug Facts from National Institute on Drug Abuse
Substance Abuse and Mental Health Services Administration Know the Risks of Meth
Substance Abuse and Mental Health Services Administration Treatment Locator
Amphetamine-related psychiatric disorders can be confused with psychiatric disorders caused by other organic, medical, and psychiatric etiologies. The causes of amphetamine-related psychiatric can be determined through history, physical exam, and preliminary laboratory workup.
The DSM-5-TR provides criteria helpful for determining if the patient is in a state of intoxication or withdrawal. The criteria helps clinicians distinguish disorders occurring during intoxication (eg, psychosis, delirium, mania, anxiety, insomnia) from those occurring during withdrawal (eg, depression, hypersomnia).[1]
Developmental history
The developmental history provides information about the patient's in utero exposure to medications, illicit substances, pathogens, and trauma.
As children, patients may have had prodromal symptoms of psychiatric disorders, such as social isolation, deteriorating school performance, mood liability, amotivation, avolition, anhedonia, sleep disturbances, psychomotor retardation, demoralization, social isolation, and suicidal thoughts and behaviors.
Delinquency, truancy, difficulties in formal education structures, early use of illicit substances and alcohol, oppositional behavior associated with conduct disorder, and early participation in the rave party scene may predispose to the development of amphetamine-related psychiatric disorders.
Psychiatric history
Two issues are emphasized:
Determine whether psychiatric symptoms ever occurred prior to exposure to amphetamines.
Determine whether the patient ever had psychiatric symptoms similar to the present symptoms when taking other illicit substances or medications.
Recent history
The patient's history of amphetamine use is determined by asking the following questions:
When did the patient's amphetamine use start?
How often does the patient use amphetamines?
How much does he or she use?
Via what route does he or she use (inhalational, oral, intravenous)?
Is the patient currently intoxicated or in withdrawal from amphetamines?
Has the patient recently increased his or her amphetamine use or started to binge?
Substance use history
Substances patients may use concurrently with amphetamines:
Alcohol
Marijuana
Cocaine
Lysergic acid diethylamide (LSD)
OTC sympathomimetics
Steroids
Family history
A family history of a psychiatric disorder may suggest a primary psychiatric disorder. A diagnosis of amphetamine-related psychiatric disorder might still be possible if the patient has no family history of psychiatric disorders.
DSM criteria for intoxication and withdrawal
The DSM-5-TR criteria for stimulant intoxication are as follows:
A. Recent use of an amphetamine-type substance, cocaine or other stimulant.
B. Clinically significant problematic behavioral or psychological changes (eg, euphoria or affective blunting; changes in sociability; hypervigilance; interpersonal sensitivity; anxiety, tension, or anger; stereotyped behaviors; impaired judgment) that develop during, or shortly after, use of a stimulant.
C. Two (or more) of the following signs or symptoms, developing during, or shortly after, stimulant use:
Tachycardia or bradycardia
Pupillary dilatation
Elevated or lowered blood pressure
Perspiration or chills
Nausea or vomiting
Evidence of unintentional weight loss
Psychomotor agitation or retardation
Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias
Confusion, seizures, dyskinesias, dystonias, or coma
The signs or symptoms are not attributable to another medical condition, and are not better explained by another mental disorder, including intoxication with another substance.
The DSM-5-TR criteria for stimulant withdrawal are as follows:
A. Cessation of (or reduction in) the prolonged use of an amphetamines, cocaine, or other stimulant compound.
B. Dysphoric mood and two (or more) of the following physiologic changes developing within a few hours to several days after Criterion A:
Fatigue
Vivid, unpleasant dreams
Insomnia or hypersomnia
Increased appetite
Psychomotor retardation or agitation
The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other areas of functioning.
The signs or symptoms are not attributable to another general medical condition, and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.
A full physical, neurologic, and mental status examination should be performed. Initially assess patients for medical stability through assesment of airway, breathing, circulation, and stability of vital signs. Then, assess for degree of danger to ensure safety of yourself and other staff.
During the physical examination, look for signs and symptoms of amphetamine use, including hyperthermia, hypertension, unintentional weight loss, tachypnea, decreased vision, mydriasis, dry mucous membranes and decreased skin turgor due to dehydration, and arrhythmias.
During the neurologic examination, assess the patient for evidence of amphetamine use, including mydriasis, decreased vision, hyperreflexia, parasthesias, and tremors. Pay attention to concerns of headache and focal neurologic deficits as this may represent hemorrhagic stroke from stimulant use.
The mental status exam should focus on identifying delusions, hallucinations, suicidal and homicidal ideation, and insight and judgment. The mental status examination can be very different for intoxication and psychosis.
A mental status expected for a patient with amphetamine intoxication is as follows:[10]
Appearance and behavior: People using methamphetamine chronically may have low BMI, appearing malnourished, disheveled, and diaphoretic. Linear eschars and excoriations may be present near veins of the skin from IV injection. They may exhibit sporadic changes in behavior, alternating between episodes of talkative oversharing and violent behavior.
Speech: Increased, pressured rate
Thought process: Tangential, circumferential
Thought content: Paranoid; no suicidal or homicidal thoughts
Mood: Anxious, hypomanic
Affect: Anxious and tense
Insight and judgment: Poor
Orientation: Alert to person, place, and purpose; perspective of time is disorganized
A mental status expected for a patient with amphetamine psychosis is as follows:[11]
Appearance and behavior: Disheveled, suspicious, paranoid, difficult to engage, poor eye contact
Speech: Decreased rate, rapid
Thought process: Disorganized, guarded and internally preoccupied
Thought content: Paranoid; possible auditory hallucinations; may have suicidal or homicidal thoughts
Mood: Anxious
Affect: Paranoid and fearful
Insight and judgment: Poor
Orientation: Has no concept of purpose, though understands place and person; perspective of time is disorganized
A mental status for a patient withdrawing form amphetamines is as follows:
Complications include an increased risk of the following:
Psychosis
Depression
Anxiety disorder
Sleep disturbance
Memory impairment
Medical complications
Neurologic complications
Other comorbid substance use disorder
Psychosocial impairment
Affect dysregulation and aggression[12]
If amphetamine use and amphetamine-related psychiatric disorders occur in the context of 1 or more personality disorders, the amphetamine-related disorder is more difficult to treat successfully.
Perform ECG to evaluate for cardiac arrhythmias induced by amphetamines. If suspicion for heart failure exxacerbation is high, consider obtaining a transthoracic ECHO (TTE).
Perform EEG to r/o focal or generalized seizure.
Use of the brief psychotic rating scale (BPRS), Beck Depression Scale, and violence and suicide assessment may be helpful as substance use can co-occur with multiple psychiatric comorbidities.
If persistent psychiatric conditions are noted, neuropsychological testing can be beneficial to assess levels of psychosocial and neurologic impairment to guide treatment and placement.
Repeated exposure to amphetamines is theorized to alter the morphology of dendrites in the prefrontal cortex and in the nucleus accumbens. Amphetamines may increase the length of dendrites for longer than 1 month. These alterations may help explain the behavioral cravings and psychosis that long-term abuse of amphetamines produces.
The patient should be monitored closely for recurring psychosis, depression, mania, anxiety, sleep disturbances, and relapse of amphetamine abuse.
Psychiatric and primary care followup care should occur within, at most, 2 weeks of the initial evaluation.
Depending on the complications of amphetamine use, outpatient follow up with a neurologist within 2 weeks of presentation should be considered.
Inpatient care
Admit the patient for observation in the event of mania, severe depression limiting activities of daily living, psychosis, or homicidal ideation.
A patient who is in a state of delirium in combination with psychosis should be instituted on behavioral "delirium precautions". This means maintaining orientation to surroundings, a natural schedule for nutrition, fluids, and sleep, promoting early physical mobility, and minimizing sensory impairements like hearing and vision loss [13]
Initial treatment should include medically stabilizing the patient's condition by assessing their airway, breathing, circulation, and neurologic systems. Because most cases of amphetamine-related psychiatric disorders are self-limiting, detoxification of the substance with time should help relieve symptoms.
Administer oral or IV fluids to provide adequate hydration. Patients who are acutely intoxicated may have had limited oral intake the days they were intoxicated.
Attempt verbal de-escalation prior to the introduction of physical restraints. When physical restraints are needed, re-assess the need for restraints frequently (every 30 min–1 hour) so that people remain in restraints for the minimum amount of time necessary.
If patients cannot be verbally de-escalated, always offer oral medication prior to transitioning to IM medication.
If the patient presents with psychotic symptoms, or he or she is in danger of harming him or herself or others, a high-potency antipsychotic, such as haloperidol (Haldol), olanzapine (Zyprexa), or risperidone (Risperdal) can be used. Obtain an EKG to ensure the patient does not have a prolonged QTc > 500 ms. With all antipsychotics, monitor for extrapyramidal symptoms.
Agitation also can be treated cautiously with oral, IV, or IM benzodiazepines. Lorazepam (Ativan) and chlordiazepoxide (Librium) are commonly used.
Administer naloxone (Narcan) in the event of concurrent opiate toxicity. Use caution to avoid precipitation of acute opioid withdrawal in a patient who has used high doses of opioid on a long-term basis.
Beta-blockers, such as propranolol (Inderal), can be used in the event of tachycardia. They also may be helpful with anxiety or panic.
Psychiatric hospitalization may be necessary when psychosis, aggression, and suicidality cannot be controlled in a less restrictive environment.
Consulting a psychiatrist, substance use treatment counselor, internal medicine physician, neurologist, and social services may be beneficial.
A psychiatrist and substance use treatment counselor can help assess the need for inpatient hospitalization while coordinating outpatient rehabilitation treatment for interested patients.
An internal medicine physician and neurologist can assist with the workup and treatment of medical sequelae of amphetamine use, including non-ischemic cardiomyopathy, endocarditis, and stroke.
Social services can help address social determinants of health like employment, housing and food insecurity, and transportation to help patients attend medical and psychiatric appointments.
If psychiatric conditions persist, causing social and occupational impairment, inpatient treatment may be required.
Medical or neurologic complications require treatment in an inpatient medical or neurologic unit.
Patients intoxicated on amphetamines may exhibit suicidal or homicidal ideation that endangers themselves or others. They should stay in a safe environment and not drive until they are no longer acutely intoxicated.
Compared to people not using amphetamines, those reporting use within the past year were more likely to have comorbid medical multimorbidity, mental illness, and substance use disorders.[14]
People using methamphetamines were more likely to have asthma, bronchitis/COPD, cirrhosis, diabetes, Hep B/C, hypertension, and HIV in comparison to the general population. They were also more likely to have a co-occurring substance use disorder, including alcohol, opioid, cannabis, heroin, cocaine, and sedative use disorders.
Patients who use amphetamines are more likely to have anxiety and depressive disorders than the general population. Female amphetamine users are more likely to have a history of PTSD and intimate partner violence.[15]
Abstinence prevents disorders and is the primary treatment. There are no medications that are routinely prescribed as standard of care or approved by the FDA for the treatment of amphetamine use disorder.
Relapse prevention occurs though patient education, psychotherapy, medical treatment of continuing psychiatric illness (eg, major depression, panic disorder), and attendance at substance abuse meetings.
Four behavioral interventions show improvement in the long-term treatment of amphetamine use disorder. Motivational interviewing, contingency management, community reinforcement, and cognitive behavioral therapy are associated with reduction in the days of stimulant use, the amount of stimulant used per day, and stimulant cravings.[16]
Pharmacotherapy treatments for stimulant use disorder have been attempted with a variety of medications, including, baclofen, gabapentin, sertraline, buproprion, modafinil, dexamphetamine, topiramate, methylphenidate, aripiprazole, and varenicline. No pharmacotherapy has consistently demonstrated efficacious findings.[17]
Several psychiatric conditions can be associated with amphetamine intoxication and withdrawal, all of which may require different management strategies. However, amphetamine-related psychiatric disorders are typically self-limited and usually remit with time.
Amphetamine-related psychiatric disorders occur most often during intoxication; therefore, treatment should focus on controlling medical and psychiatric symptoms while allowing the body to metabolize the substance. Medical therapy involves stabilizing agitation and minimizing psychosis.
If the induced disorders persist and interfere with the patient's social and occupational functioning, treatment should be related to the remaining psychiatric symptoms. Antidepressants, such as sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa), can be used to treat depression. Antimanic agents, such as valproic acid (Depakote), carbamazepine (Tegretol), and lithium carbonate, can be used to treat mania. Anxiety can be treated with nonbenzodiazepine drugs, such as beta-blockers and antimanic agents.
Typical antipsychotics should be used for acute stabilization with the intention of switching to an atypical antipsychotic drug (eg, risperidone, quetiapine, olanzapine, aripiprazole, and ziprasidone) for long-term use to reduce risk of developing extrapyramidal symptoms.
For the purposes of this discussion, specific treatment of amphetamine toxicity is reviewed. For further information, please refer to the articles on Depression, Substance-Induced Mood Disorder, Depressed Type, Bipolar Affective Disorder, Schizophrenia, Anxiety Disorders, and Sleeping Disorders.
Similarly to buprenorphine-naloxone (Suboxone) and methadone for the treatment of opioid use disorder, many pharmacological treatments have been studied for treatment of amphetamine use disorders. Currently, there are no FDA approved medications for the treatment of amphetamine use disorder. The primary medications that have been studied for treatment showed mixed results and limited retention rates, ranging between 30–85%. The most promising pharmacotherapy included bupropion, mirtazapine, aripiprazole, and topiramate.[17]
If psychosis persists after the offending substance is eliminated, use of an atypical antipsychotic (risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) may be considered. No single atypical antipsychotic has been proven to be more beneficial than the others in managing prolonged amphetamine-induced psychosis.
Antimanic agents may be continued if mania persists longer than 2 weeks.
Antidepressants can be useful if depression persists for 2 weeks after withdrawal. Antidepressants alone may not be as effective as other options in amphetamine-induced depression. Medication regimens for treatment-resistant organic mood disorders are the applicable approach.
If anxiety persists longer than 2 weeks, consider the use of nonbenzodiazepine medications. Medications such as beta-blockers, valproic acid, carbamazepine, or gabapentin have shown promise in patients with substance abuse who also have anxiety.
Sleep medication may help patients adjust their circadian rhythm and can be used for approximately 1-2 weeks. If sleep medication is required for long periods, a referral to a sleep clinic is recommended.
Clinicians should select a high-potency antipsychotic that is available in tablet, liquid, and IM forms for administration in emergency situations. Antipsychotics help control psychotic symptoms and provide rapid tranquilization of the agitated and psychotic patient.
Clinical Context:
Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing activity of gamma-aminobutyric acid (GABA) activity, major inhibitory neurotransmitter.
These drugs are primarily used to sedate agitated patients. Availability in PO, IV, and IM forms allowing the drug to be used in emergency situations. Caution must be used in the violent, aggressive patient because benzodiazepines may cause disinhibition.
Clinical Context:
Used to treat concurrent opiate toxicity. Consider in patients with altered mental status due to opiate overdose. Poorly absorbed PO route and should be administered IM or IV. Available in IV, IM, and SC forms. Use caution to avoid precipitating acute opioid withdrawal in patient using opioids long term.
Clinical Context:
Antihypertensive agent useful in psychiatry to treat anxiety and impulse control. Often well tolerated with minimal effect on hemodynamics of blood pressure and pulse.
Propranolol (Inderal) is useful in patients who are agitated, anxious, and hyperarousable because of amphetamines. They are temporarily used until the amphetamine is eliminated from the patient's system. For some patients, anxiety can be prolonged, and nonaddictive beta-blockers may be helpful.
Clinical Context:
Second-generation antipsychotic acting as an antagonist on D2 receptors in the mesolimbic system and 5HT2a serotonin receptors in the frontal cortex. Available in oral, IV, and IM forms for acute agitation and aggression associated with amphetamine intoxication.
Clinical Context:
Second-generation antipsychotic acting as an antagonist on D2 receptors in the mesolimbic system and 5HT2a serotonin receptors in the frontal cortex. Available in oral form for acute agitation and aggression associated with amphetamine intoxication. Has a higher risk of extrapyramidal symptom development than the other second-generation antipsychotic agents.
Clinical Context:
Limited and mixed data showing reduced methamphetamine use, reduced methamphetamine cravings, and decreased engagement in high-risk sexual behaviors in the long-term treatment of amphetamine use disorders. Aripiprazole shows high affinity for D2, D3, 5-HT1A, and 5HT2A receptors and moderate affinity for D4, 5HT2C, 5-HT7, alpha1 adrenergic, and H2 receptors and possesses moderate affinity for the serotonin reuptake transporter. It is thought to be a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, alpha1, and histamine H1 receptors. The most common side effects include headache, nausea, vomiting, insomnia, tremor, and constipation.
Second-generation (novel or atypical) antipsychotics, with the exception of aripiprazole, are dopamine D2 antagonists. They are associated with lower rates of extrapyramidal side effects and tardive dyskinesia than the first-generation antipsychotics are; however, they have higher rates of metabolic side effects and weight gain.
Clinical Context:
Mixed results showing >50% reduction in self-reported meth use during long-term treatment trials. Topiramate is a sulfamate-substituted monosaccharide with broad-spectrum antiepileptic activity that may have state-dependent sodium channel-blocking action, which potentiates the inhibitory activity of GABA. It may block glutamate activity. It is not necessary to monitor topiramate plasma concentrations to optimize therapy.
Clinical Context:
Mixed results showing decreased number of meth-free weeks in patients with low-moderate methampthetamine use disorder. Bupropion inhibits neuronal dopamine reuptake, but it is also a weak blocker of serotonin and norepinephrine reuptake. Bupropion binds to the nicotinic receptor.
Clinical Context:
Mixed results showing decreased meth use as measured by urine toxicology testing and a decrease in high-risk sexual activity. Mirtazapine is an antidepressant that is not chemically related to tricyclics or to any other class of antidepressants. Its primary mechanism of action is antagonism at the central presynaptic alpha-2 receptors. The actions of the drug change as the dose is raised. Mirtazapine exhibits noradrenergic and serotonergic activity.
The mixed serotonergic and noradrenergic drugs have effects on serotonin, norepinephrine, and, in some cases, dopamine, and even on nicotinic acetylcholine systems. Some may exhibit antagonism at the central presynaptic alpha-2 receptors. Because of the empirical nature of psychopharmacology, they may be used as first-line drugs or as follow-up agents when SSRIs fail.
Lorin M Scher, MD, FACLP, Clinical Professor of Psychiatry and Behavioral Sciences, Vice-Chair for Education, Roy T Brophy Endowed Chair, Director, Integrated Behavioral Health Services, Medical Director, Government and Community Relations, UC Davis Health
Disclosure: Nothing to disclose.
Coauthor(s)
Anastasiya "Stacy" Haponyuk, MD, Resident Physician, Combined Internal Medicine and Psychiatry Residency, University of California Health System; Fellow in Clinician Health and Wellbeing, University of California, Davis, School of Medicine/University of California, Irvine, School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Glen L Xiong, MD, Associate Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California, Davis, School of Medicine; Medical Director, Sacramento County Mental Health Treatment Center
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SafelyYou, Blue Cross Blue Shield<br/>book co-editor for: Wolter Kluwer, American Psychiatric Publishing Inc.
Additional Contributors
Amy Barnhorst, MD, Assistant Clinical Professor, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Medical Center; Medical Director of Crisis Services, County of Sacramento
Disclosure: Nothing to disclose.
Michael F Larson, DO, Clinical Instructor, Department of Child and Adolescent Psychiatry, Harvard Medical School; Psychiatrist, Harvard Vanguard Medical Associates and Private Practice
Disclosure: Nothing to disclose.
Acknowledgements
Michael F Larson, DO Clinical Instructor, Department of Child and Adolescent Psychiatry, Harvard Medical School; Psychiatrist, Harvard Vanguard Medical Associates and Private Practice
Michael F Larson, DO is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Child and Adolescent Psychiatry, and American Society of Addiction Medicine
Disclosure: Nothing to disclose.
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