Stimulant Use Disorder

• For cocaine:
  • In the United States, the estimated prevalence is 0.3% in adults.^[1]
• For amphetamine-type stimulants (prescription stimulants, “crystal meth”):
  • In the United States, the estimated prevalence is 0.2% in adults.^[2]
  • Males are significantly more likely to have intravenous use than females (3:1)
  • Non-prescribed (i.e. - taken from a friend or family member) use of prescription stimulants occurs in up to 9% of children through to high school, and is between 5 to 35% in college-aged individuals.

• Individuals exposed to amphetamine-type stimulants or cocaine can develop stimulant use disorder as rapidly as 1 week, although the onset is not always this rapid.
• In extreme cases, stimulant-induced psychotic disorder can occur, which resembles schizophrenia, with delusions and hallucinations.
• Mental disturbances associated with cocaine use usually resolve within hours to days after cessation of use but can persist for up to 1 month.

• Temporary depressive symptoms may meet criteria for a major depressive episode. Symptoms consistent with panic attacks, social phobia-like behavior, and generalized anxiety-like syndromes are common, as are eating disorders.
• Cocaine users often use alcohol, while amphetamine-type stimulant users often use cannabis.
• Stimulant use disorder is associated with posttraumatic stress disorder (PTSD), antisocial personality disorder, attention-deficit/hyperactivity disorder (ADHD), and gambling disorder.

• Chest pain can be a common symptom during stimulant intoxication. Myocardial infarction, palpitations and arrhythmias have been documented. Sudden death from respiratory arrest, cardiac arrest, and/or stroke have been associated with stimulant use in young and healthy individuals.^[3]
• Depending on the route of use, various medical conditions can develop.^[4]
  • Intranasal users can develop sinusitis, irritation, bleeding of the nasal mucosa, and/or a perforated nasal septum.
  • Individuals who smoke are at increased risk for respiratory problems (e.g. - coughing, bronchitis, and pneumonitis).^[5]
  • Intravenous users can have punctures (“track marks”) most commonly on their forearms, and are at risk for increased HIV infection.
    • Other sexually transmitted diseases, hepatitis, tuberculosis and lung infections are also possible. Weight loss and malnutrition is common in severe stimulant use disorders.^[6]
• In pregnant women, cocaine use is associated with placental blood flow irregularities, abruptio placentae, premature labour and delivery, and an higher risk for low birth weights.^[7]
• In methamphetamine (“crystal meth”) users, cognitive impairment, oral health problems (“meth mouth”), gum disease, tooth decay, and oral sores can occur, due to the toxic effects of smoking the drug and bruxism while intoxicated.^[8]
• Medical problems can develop secondary to adulterants used as “cutting” agents in cocaine.
  • For example, cocaine users who ingest cocaine cut with levamisole (an anti-parasitic primarily used in veterinary care) can develop agranulocytosis and febrile neutropenia.

• Some individuals may use stimulants to control weight or to improve performance in school, work, or athletics.^[9]
• For cocaine use, bipolar disorder, schizophrenia, antisocial personality, and other substance use disorders are risk factors.
• Predictors of cocaine use in teenagers include prenatal cocaine exposure, postnatal cocaine use by parents, exposure to community violence during childhood, unstable home environment, previous psychiatric disorders, and interactions with dealers and users.^[10]
• Stimulant smoking and intravenous use can lead to a rapid progression to severe-levels of stimulant use disorder, which can escalate over weeks to months.^[11]
  • With chronic use, there is a significant decrease in pleasurable effects due to tolerance and a significant increase in dysphoric effects.^[12]

A pattern of amphetamine-type substance, cocaine, or other stimulant use leading to clinically significant impairment or distress, as manifested by at least 2 of the following, occurring within a 12-month period:

1. The stimulant is often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use.
3. A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or recover from its effects.
4. Craving, or a strong desire or urge to use the stimulant.
5. Recurrent stimulant use resulting in a failure to fulfill major role obligations at work, school, or home.
6. Continued stimulant use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the stimulant
7. Important social, occupational, or recreational activities are given up or reduced because of stimulant use.
8. Recurrent stimulant use in situations in which it is physically hazardous.
9. Stimulant use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the stimulant.
10. Tolerance, as defined by either of the following:
    • A. A need for markedly increased amounts of the stimulant to achieve intoxication or desired effect.
    • B. A markedly diminished effect with continued use of the same amount of the stimulant.

      Note: This criterion is not considered to be met for those taking stimulant medications solely under appropriate medical supervision, such as medications for attention-deficit/hyperactivity disorder or narcolepsy.
11. Withdrawal, as manifested by either of the following:
    • A. The characteristic withdrawal syndrome for the stimulant (refer to Criteria A and B of the criteria set for stimulant withdrawal).
    • B. The stimulant (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.

      Note: This criterion is not considered to be met for those taking stimulant medications solely under appropriate medical supervision, such as medications for attention-deficit/hyperactivity disorder or narcolepsy.

• When injected or smoked, stimulants produce an instant feeling of well-being, confidence, and euphoria.^[13]
• Aggressive or violent behaviour, sexual disinhibition, and chaotic behaviour can occur when high doses of stimulants are smoked, ingested, or administered intravenously.
• Severe temporary anxiety similar to panic disorder or generalized anxiety disorder, and paranoid ideation and/or psychotic episodes that resemble schizophrenia may be present with high dose use.^[14]
• There may be paranoid ideation, auditory hallucinations with a clear sensorium, and/or tactile hallucinations, which the individual usually can recognize as a drug effect.
• Depression, suicidal ideation, anhedonia, irritability, emotional lability, and changes in concentration can occur during withdrawal.^[15]

• Cocaine may be consumed in many different preparations, including:
  • Coca leaves, coca paste, cocaine hydrochloride (cocaine powder), and cocaine alkaloids (freebase and crack cocaine)
  • Each preparation has a different potency because of varying levels of purity and speed of onset.
  • In all forms of the substance, however, cocaine remains the active ingredient.
• Cocaine hydrochloride (the classic “powder,” also called “coke,” “blow”) is usually “snorted” through the nostrils
  • It can also be dissolved in water and injected intravenously
  • Effects include euphoria, energy, hyperactivity, tachycardia, constricted blood vessels, dilated pupils, hypertension, and increased body temperature
  • At high doses, it can cause paranoia, irritability, formication (sensation of small insects crawling on [or under] the skin when there is nothing there)
• Mechanism of action: cocaine inhibits reuptake of serotonin, norepinephrine, and dopamine. Specifically, inhibition of the dopamine reuptake transporter (DAT), is responsible for its primary effects, which results in in elevated concentrations of these neurotransmitters in the brain.^[16] (unlike amphetamine and methamphetamine, cocaine does not have any action on vesicles such as VMAT2).^[17]

• Normal cocaine (“powder” form) has a hydrochloride component and a high melting point, which makes it hard to smoke (and thus why it is snorted).
  • If you tried to smoke cocaine powder, it would just melt (it would be like smoking sugar)
• Crack cocaine, other the other hand, is created from mixing cocaine with a base (such as ammonia or baking soda).
  • This technique is called freebasing, and allows it to sublimate at lower temperatures so it can be smoked. The cocaine vapour goes directly into the lungs (which has lots of surface area) and it goes directly to the brain.
  • This method bypasses first-pass metabolism, which makes crack cocaine highly addictive and potent.
• Using crack cocaine with heroin is a practice known as speedballing.

• Amphetamine was first synthesized in 1887.
• Amphetamines and its amphetamine-type stimulants (e.g. - methylphenidate, dextroamphetamine) derivatives are now clinically used in the treatment of narcolepsy and attention deficit hyperactivity disorder.
• These substances may be used/misused orally or intravenously (methamphetamine is also taken by the nasal route).
• The common effects include euphoria, increased energy, alertness, decreased appetite
• At high doses, prescription stimulants can also cause paranoia, dystonia, aggression, and cardiac arrhythmias
• Mechanism of action: amphetamines and methylphenidate block the dopamine transporter (DAT)
  • Amphetamines (but not methylphenidate!) also additionally interact with the vesicular monoamine transporter type 2 (VMAT2), to promote the release of vesicular neurotransmitters.^[18]

• Methamphetamine or N-methylamphetamine (“crystal meth,” “ice,” “crystal,” “crank”) is an illegal stimulant that can be smoked, injected, or taken orally.
• Amphetamine/methamphetamine-type stimulants are longer acting than cocaine and thus are used fewer times per day.
• Mechanism of action: similar to amphetamine, it works by triggering catecholamine (dopamine and other neurotransmitter) release from vesicles and also prevents reuptake of dopamine by inhibiting the dopamine transporter (DAT).^[19]

• Naturally occurring, plant-derived stimulants such as khât also exist and have similar properties.^[20]

• 3,4-Methylenedioxymethamphetamine (commonly known as “MDMA,” “Ecstasy,” “E,” “XTC,” “X”) is a somewhat unique substance in that it is officially classified as a hallucinogen in the DSM-5, but actually has strong stimulant properties and also acts like an amphetamine.
  • Arguments have been made that MDMA should be in its own category of substances.^[21]
• Its effects include openness, empathy, energy, euphoria, enhanced colour perception, and a general sense of well-being.
• Negative effects include restlessness, decreased appetite, altered focus/concentration, dyspnea, paresthesia, hyperhydrosis, and tachycardia.
• At high doses, facial dystonia can develop (“gurning”)
• Mechanism of action: release and re-uptake inhibition of serotonin, dopamine and norepinephrine, and binds to 5-HT2A and alpha-2 receptors
• There is evidence for long-term neurotoxic effects of MDMA use, such as cognitive impairment, impairment in neuroendocrine function, serotonin system dysfunction, and sleep disturbance.
• There many also be adverse effects on brain microvasculature, white matter maturation, and damage to axons.
• Use of MDMA may also decrease functional connectivity between brain regions.^[22]

• Like with all substance use disorders, there is a complex interplay between biological, social, psychological, and cultural factors.
• There may be alterations in secretion patterns of prolactin and downregulation of dopamine receptors from chronic stimulant use.

• Primary mental disorders
  • Stimulant-induced disorders may resemble primary mental disorders (e.g. - major depressive disorder) (see “Stimulant Withdrawal” differential diagnosis). The mental disturbances resulting from the effects of stimulants should be distinguished from the symptoms of schizophrenia, major depressive disorder, bipolar disorder, generalized anxiety disorder, and panic disorder.
• Phencyclidine intoxication
  • Intoxication with phencyclidine (“PCP” or “angel dust”) or synthetic “designer drugs” such as mephedrone (“bath salts”) may cause a similar clinical picture and can only be distinguished from stimulant intoxication by the presence of cocaine or amphetamine-type substance metabolites in a urine or plasma sample.
• Stimulant intoxication and withdrawal
  • Stimulant intoxication and withdrawal are different from the other stimulant-induced disorders (e.g. - anxiety disorder, with onset during intoxication) because the symptoms in the induced disorders predominate the clinical presentation and are severe enough to warrant additional independent clinical attention.^[23]

• Benzoylecgonine, a metabolite of cocaine, typically remains in the urine for 1 to 3 days after a single dose and may be present for 7 to 12 days in chronic users.
• Short-half-life amphetamine-type stimulants such as MDMA (3,4-Methylenedioxymethamphetamine) and methamphetamine can be detected for 1 to 3 days, and potentially up to 4 days depending on dosage and rate of metabolism.
• Hair samples may detect amphetamine-type stimulants for up to 90 days

• Mildly elevated liver function enzymes can be present in intravenous cocaine users or in those with concomitant alcohol use.

• Stopping chronic cocaine use may be associated with electroencephalographic changes, suggesting persistent abnormalities

• Physical findings of other medical conditions (e.g. - weight loss, malnutrition, poor hygiene) may be present.

• Contingency management is the main psychotherapeutic treatment for stimulant use disorders.
• Psychostimulants, N-acetylcysteine, opioid agonists, disulfiram, and antidepressants have been investigated as potential treatments.^[24]
• Mirtazapine 30 mg/day for 12 weeks reduced methamphetamine use by a mean of 7 days out of 28 (vs. 4.8 days with placebo) in a phase 3, double-blind, placebo-controlled RCT ^[25]

• VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders (2015)
• ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder (2024)