The Diagnosis and Treatment of Stimulant-Related Emergencies

Background: Stimulants are the most commonly used illegal drugs in Germany, with a lifetime prevalence of 1.2–6.1%. In Germany, cocaine and amphetamines are the most commonly used illegal stimulants. Their use is on the rise and associated with significant morbidity, mortality, and crime. We present an overview of the management of stimulant-related disorders.

Methods: This review is based on publications retrieved from a selective search in scientific databases and AI-supported platforms, with consideration of pertinent guidelines, reviews, meta-analyses, and original papers.

Results: Even in younger persons, stimulant use increases the risk of medical and neurological emergencies such as rhabdomyolysis (for amphetamines: 30.5%, 95% confidence interval [22.6; 38.5]) and stroke (for amphetamines: OR: 4.95 [3.24; 7.55]; for cocaine: OR: 2.33 [1.74; 3.11]). Stimulant intoxication manifests itself with agitation, aggression, or psychotic symptoms. There can also be long-term psychosis, depression, and cognitive impairment. Symptomatic acute treatment may be needed for dehydration, hyperthermia, and agitated states. Agitated patients need de-escalating communication and stimulus shielding and can be adequately treated with benzodiazepines or antipsychotic drugs in 70–90% of cases. The standard treatment for stimulant dependence is withdrawal treatment for several weeks, followed by rehabilitation therapy for several months. No type of pharmacotherapy has yet been approved for this. Cognitive behavioral therapy, contingency management, and exercise have been found to stabilize abstinence.

Conclusion: Stimulant-related emergencies pose a therapeutic challenge because of their varied and unpredictable course and the limited available evidence on abstinence-maintaining treatment. Symptom-oriented treatment in acute situations, supplemented by a multimodal treatment strategy to promote abstinence, is recommended.

Cite this as: Fries A, Christ M, Nickl H, Spreer M, Pilhatsch M, Petzold J: The diagnosis and treatment of stimulant-related emergencies. Dtsch Arztebl Int 2025; 122: 715–21. DOI: 10.3238/arztebl.m2025.0158

Following the legalization of cannabis, cocaine and amphetamines have become the most commonly used illegal substances in Germany (1). In Germany, the lifetime prevalence rates of the use of cocaine and amphetamines are 5.6% and 6.1%, respectively, both exceeding the European average (2, 3). In 2021, about 1.6% of the German population illegally used cocaine (“crack”, “coke“), 1.4% amphetamines (“speed“, “up“) and 0.2% methamphetamine (“crystal“, “meth“) in the last 12 months; the highest prevalence rates were found in the age group 21–24 years, with 4.3% and 3.9% for cocaine and amphetamine, respectively (1). In Germany, methamphetamine is most commonly consumed in the regions bordering Czechia. A sharp increase in use was noted after the Czech Republic joined the Schengen area in 2007 (4).

The absolute inpatient case numbers for cocaine-related treatment tripled to quadrupled between 2014 and 2023, whereas they remained largely stable for (meth)amphetamines (5). In 2023, cocaine-related disorders as the primary diagnosis accounted for 5.1% of the outpatient and 4.5% of the inpatient addiction-specific rehabilitation treatments. For (meth)amphetamine use disorders, the proportions of outpatient and inpatient cases were 5.7% and 6.3%, respectively. The majority of those affected were male, with a gender ratio of approximately 2:1 (6).

According to data from the German Federal Criminal Police Office (Bundeskriminalamt, BKA), 2227 persons died as a result of illegal substance use in Germany in 2023. Cocaine, amphetamine and methamphetamine were involved in 610, 402 and 122 deaths, respectively (e1). In 2023, the mortality rate among inpatients with cocaine-related disorders was 0.1% and with (meth)amphetamine-related disorders 0.06% (5).

The aim of this review

Within the group of stimulants, cocaine, amphetamine and methamphetamine are of particular importance due to their high availability, strong harmful effects and significant potential for dependence. Given the increasing use of stimulants and resulting significance for healthcare provision, this review is intended to provide a basis for the clinical management of stimulant-related emergencies.

Methods

This review is based on publications retrieved from a selective search in scientific databases (Google Scholar, PubMed, Cochrane Library) and AI-supported platforms (Perplexity.ai, Elicit.com) that we conducted from 12 February to 15 August 2025. The search period covered the last 36 years. The search term “stimulant use disorders” was combined with the keywords “pharmacology“, „toxicology“, „epidemiology“, “pathogenesis“, “intoxication“, “withdrawal”, “treatment“, and “harm reduction“. We included guidelines as well as peer-reviewed review articles, meta-analyses, and original articles in English and German (provided an English abstract was available). Supplementary information was obtained from textbooks and epidemiological data collected by relevant authorities. We gave preference to more recent publications of high methodological quality and excluded case reports. The findings were then summarized in a narrative format.

Pharmacology

Cocaine acts by inhibiting the presynaptic reuptake of dopamine, norepinephrine and serotonin in the central nervous system. This increases the levels of these neurotransmitters in the synaptic cleft. Unlike amphetamine and methamphetamine, cocaine also inhibits sodium and potassium channels, resulting in local anesthetic effects and cardiovascular adverse reactions. Depending on the route of administration, the effect sets in after seconds (intravenous, inhalation), a few minutes (nasal) or up to 45 minutes (oral) and lasts for 15–30 minutes (intravenous, inhalation) or 1–4 hours (nasal, oral). When cocaine is used in combination with alcohol, cocaethylene is formed which is more toxic and has a longer duration of action (half-life: 2–2.5 hours) compared to cocaine (half-life: 1–1.5 hours) alone (7).

In the central nervous system, (meth)amphetamine causes a forced release of dopamine, norepinephrine and, to a lesser extent, serotonin into the synaptic cleft. In addition, reuptake into the presynaptic terminal is inhibited in the same way as with cocaine, enhancing signal transmission. Since methamphetamine is more lipophilic than amphetamine, it is capable of crossing the blood-brain barrier more readily (8) (Figure). The onset time is comparable to that of cocaine, with the psychoactive effects of amphetamine lasting 4–6 hours and those of methamphetamine up to 12 hours (4).

Figure

Main mechanisms of action of psychostimulants at the synapse

Biological detection

Stimulants can be detected in saliva and blood for up to 36 hours, in urine for 2–4 days and in hair for months to years, depending on length (4, 9). Rapid saliva tests are used in traffic checks and, if necessary, confirmed by blood tests and monitored by hair analysis over time. In everyday clinical practice, testing is primarily based on urine specimens; if necessary, these can also be used for monitoring purposes by determining the substance-creatinine ratio. Specimen manipulation can be minimized by obtaining urine specimens under observation, measuring specimen temperature (34–38 °C) and determining creatinine levels (> 30 mg/dL). Urine screening is carried out using rapid immunological tests, which are susceptible to cross-reactions, and can be supplemented by forensic confirmatory testing.

Diagnostic criteria for stimulant dependence

As with all addictive disorders, the ICD-10 requires for a diagnosis of stimulant dependence that at least 3 of the following 6 criteria be present repeatedly over a period of at least 12 months, or 3 criteria be present simultaneously for at least 1 month:

• Loss of control
• Craving
• Tolerance development
• Somatic withdrawal syndrome
• Neglect of other interests, and
• Persisting with substance use despite evidence of harmful consequences.

In ICD-11, criteria 1 and 2, 3 and 4 as well as 5 and 6 of ICD-10 are combined to dual criteria. At least 2 dual criteria must be met over a period of at least one year (or one month in case of daily use). Craving is not a mandatory component of the first dual criterion. Combining criteria 1 and 2 appears to be useful, given the clinical overlap of symptoms and the interconnectedness of neurobiological control loops. The criteria 3 and 4 are linked by substance-related neuroadaptation, while the criteria 5 and 6 have the prioritization of substance use in common (eTable) (10).

eTable

Comparison of dependence criteria between ICD-10 and ICD-11; adapted from (10)

Etiopathogenesis of stimulant dependence

A standardized survey of 392 persons revealed hedonistic motives, improved structuring of the day and supposed self-medication as the three main reasons for stimulant use (e2). The findings of a systematic review provided convincing evidence that psychostimulants elicit dopaminergic activity in mesolimbic and cortical pathways which is associated with euphoria, motivation and motor activity (11). A systematic review of 54 studies arrived at the conclusion that single intravenous doses of amphetamines cause motor agitation and psychotic symptoms in persons in good mental health at doses of 20 mg or higher at the latest (12). According to a systematic review of 7387 cases, psychotic episodes are associated with the use of methamphetamine in particular. They usually manifest as auditory hallucinations or paranoia and can last for a prolonged period of time in about 25% of cases, in rare cases even longer than six months (e3).

According to the dual-deficit hypothesis, repeated methamphetamine use results in persistent depletion of serotonin and dopamine stores, clinically manifesting as irritability, depression, exhaustion, and increased craving (e4). The compensatory downregulation of dopamine transporters aggravates these symptoms. Studies using positron emission tomography (PET) imaging of the dorsal striatum found downregulation levels of –21% to –26% compared to healthy controls (e5).

A voxel-based meta-analysis of structural magnetic resonance imaging studies involving 922 persons showed that stimulant-dependent individuals had less gray matter in five brain regions associated with self-perception and self-regulation compared to controls (13). On a functional level, persons with methamphetamine dependence exhibit greater impulsivity compared to healthy persons, i.e., they are less inclined to delay gratification; high effect sizes (Cohen’s d) were found both before (–0.70) and after (–0.86) these patients underwent several weeks of inpatient withdrawal and motivational treatment (14). A systematic metaanalysis of 17 studies with 916 participants showed a negative impact of chronic methamphetamine use on almost all evaluated cognitive domains (e.g., attention, processing speed, learning, memory, motor skills, language, and executive functions), with mean effect sizes (Cohen’s d) between –0.34 and –0.66 (15).

In summary, chronic stimulant use is associated with structural, metabolic and functional changes in certain regions of the central nervous system. These are key to learning and maintaining behavioral changes brought about by successful addiction therapy.

Primary management of stimulant-related emergencies

About 0.5% to 2.6% of patients presenting at emergency departments exhibit agitated or aggressive behavior (16, 17). Occurrence varies between rural and urban areas. Agitation and aggressive behavior are unspecific symptoms which can be caused by stimulant intoxication but may also be due to other life-threatening conditions. In 73% [64.3; 81.7] of patients of a cohort including 100 patients, aggressive behavior was associated with current substance use (e6). Thus, the risk of escalation is high when persons with stimulant use are treated in the emergency department (18). Stimulant intoxication should be considered in patients presenting with typical clinical signs and symptoms, such as sweating, hypertension, tachycardia, restlessness, and psychotic symptoms (Table 1). Serious complications include rhabdomyolysis (associated with amphetamine use: 30.5% [22.6; 38.5]) and cerebrovascular events (e7, e8, e9). In a US cohort of 812 247 hospital discharges in 2003, hemorrhagic stroke was diagnosed in 938 cases and ischemic stroke in 998 cases. Amphetamine use (26 of 3164 cases) was associated with an almost fivefold increase in the risk of hemorrhagic stroke (odds ratio [OR]: 4.95 [3.24; 7.55]). Cocaine use doubled the risk of both hemorrhagic stroke (63 of 14 466 cases; OR: 2.33 [1.74; 3.11]) and ischemic stroke (49 of 14 466 cases; OR: 2.03 [1.48; 2.79]) (e8, e9).

Table 1

Clinical symptoms of a patient presenting to the emergency department suggestive of possible substance use; adapted from (e20). Supplementary information on typical findings (toxidrome) in patients with substance abuse (e21, e22, e23)

Persons in a state of acute intoxication may pose a danger to themselves, others seeking help, medical staff, and property. About half of the staff of an emergency department experienced work-related physical violence over a period of one year (e10). Aggressive behavior is one of the most common causes of injury and psychological trauma among hospital staff (19, 20). Factors associated with an increase in violence in emergency departments, such as overcrowding, waiting times and staff shortages, can be addressed and improved (20) (eBox 1). In addition, education and training of healthcare workers, both theoretical and practical, on aggression prevention is recommended, even though the evidence in support of such an intervention is uncertain according to a systematic Cochrane Review including randomized studies (21). Provisions should be made for an alert system whereby additional staff or security forces can be called in to support the treatment team in such situations which require significant resources (21).

eBox 1

Infrastructure, prevention and preparedness in emergency departments

In the primary management setting, initial treatment is mostly symptomatic, regardless of whether somatic causes or intoxication with psychoactive substances are responsible (22) (Table 2). Treatment intensity is determined by the severity of the aggressive behavior, which is usually associated with the severity of the intoxication. The risk of sudden bursts of violence in untreated cases of stimulant consumption supports the liberal use of medication for sedation in order to reduce sympatho-adrenergic activation (e11). In many cases, acute treatment has to be initiated even if no laboratory results are yet available to confirm the diagnosis.

Table 2

Algorithm for the diagnosis and treatment of agitated/aggressive persons following psychostimulant use; adapted from (22, 34, 35, 36)

Management of withdrawal symptoms

When withdrawing from psychostimulants, the initial “crash” phase begins within 24 hours of last use. It is characterized by exhaustion, anhedonia, dysphoria, anxiety, hypersomnia, sensation of hunger, and craving for stimulants (23). Subject to the type of stimulant used and severity of dependence, some withdrawal symptoms, such as depressive mood and disturbed sleep and concentration, can persist for two to four weeks. They can also turn into a withdrawal phase lasting several months, with cognitive impairment, mood swings, and stimulant craving (23, 24). Although severe withdrawal-related complications are rare, withdrawal symptoms left untreated increase the risk of relapse (23).

Since no medication has yet been approved for the treatment of psychostimulant withdrawal, symptomatic treatment is recommended (24). According to pilot studies, improvements in amphetamine withdrawal-related symptoms were achieved using mirtazapine (15–60 mg/day for 14 days) (e12), modafinil (400 mg/day for 10 days, Cohen’s d: −2.06) (e13) and amineptine (100 mg/day for 14 days, Cohen’s d: −0.27) (e14). The latter was withdrawn from the market due to the risk of abuse. A recent review (23) of randomized controlled trials (RCTs) showed reductions in withdrawal-related craving for stimulants with d-amphetamine (60 mg/day) (e15) and naltrexone (oral, 50 mg/day) treatment for amphetamine dependence (e16) and by subcutaneous depot-naltrexone (d-NTX) preparation (380 mg/3 weeks) in combination with bupropion (450 mg/day) treatment (25) or by repetitive transcranial magnetic stimulation (rTMS) for methamphetamine dependence (e17). The results of three RCTs evaluating topiramate treatment were inconsistent, with some showing positive effects on stimulant craving and the number of abstinent days, while others found a lack of superiority compared to placebo (23).

Some RCTs found improvements in depressive symptoms and irritability in cocaine users with desipramine treatment (e18); however, abstinence and retention rates did not change in meta-analyses (26). Symptoms of depression and anxiety were reduced by neuromodulatory and behavioral interventions, such as intensive exercise and mindfulness training (27). Cognitive function improved with rTMS treatment (RCT) (e17) and modafinil (RCT) (23). Sleep quality improved with rTMS (RCT) and mirtazapine treatment (e13, e17).

Relapse prevention

For relapse prevention, psychosocial interventions are essential. In a meta-analysis, contingency management (eBox 2) proved to be the most effective method (OR: 2.29 [1.62; 3.24]) and superior in combination with cognitive behavioral therapy to cognitive behavioral therapy alone (OR: 2.08 [1.28; 3.33]) (28). The Community Reinforcement Approach (CRA) is yet another effective method, which increased abstinence rates in long-term follow-up studies with the help of positive reinforcements, such as work or social contacts (OR: 2.71 [1.12; 6.54]) (28). In patients with methamphetamine dependence, the highest abstinence rates were achieved using a combination of CRA and contingency management (OR at end of treatment: 2.84 [1.24; 6.51]) (28) and using the multimodal matrix model (27). The matrix model combines elements of cognitive behavioral therapy, contingency management, family education, and self-help groups (24).

eBox 2

Contingency management

No medication is approved for relapse prevention. However, an RCT evaluating the management of methamphetamine dependence found that the combination of naltrexone (380 mg/3 weeks) and bupropion (450 mg/day) increased the objective response rate (≥ 3 of 4 negative urine samples) compared to placebo (13.6% versus 2.5%) (25). This improvement is partly explained by a reduction in depressive symptoms (29). In a follow-up study, this combination increased the rate of negative tests at week 12 by 27.1% [13.2; 41.1] compared to 11.4% [4.1; 18.6] with placebo (e19).

In a meta-analysis of two RCTs, topiramate was found superior to placebo in maintaining cocaine abstinence (pooled relative risk reduction coefficient: 2.56 [1.39; 4.73]) (30). In a Cochrane review including 7 studies with a total of 492 participants, disulfiram, a well-established medication for the management of alcohol dependence, was evaluated for its efficacy in the treatment of cocaine dependence. In a double-blind RCT, it improved cocaine abstinence compared to placebo (weighted mean difference of cocaine-negative samples: 4.50 [2.93; 6.07]); in a non-blinded RCT, it reduced cocaine use compared to naltrexone (weighted mean difference in the number of days of use or similar measurement units: −23.50 [−26.58; −20.42]) (31).

There is insufficient evidence from individual RCTs (26) to support other pharmacological relapse prevention strategies, such as treatment with N-acetylcysteine and antidepressants (mirtazapine, selective serotonin reuptake inhibitors) as well as with prescription-only stimulants.

In summary, it is recommended for relapse prevention that patients remain in therapy programs for several months, followed by aftercare (e.g., in self-help groups). Any simultaneous substitution therapy for opioid dependence should be continued, since discontinuation of substitution therapy could have a detrimental effect on treatment adherence (24). It is also necessary to treat other substance use disorders and comorbid conditions (e.g., depression, attention deficit/hyperactivity disorder) and to address social problems (e.g., homelessness, crime), because, if left untreated, these increase the risk of relapse.

Harm minimization

Reducing stimulant use improves psychosocial and functional results, measured using various indices (e.g., Addiction Severity Index), and increases the chance of favorable treatment outcomes, such as reduced craving and negative drug test results (OR: 2.89 [1.67; 5.02]). For this reason, it is seen as an alternative to abstinence as the goal of treatment (32).

The use of prescription-only stimulants is controversial due to their potential for abuse. A meta-analysis found that treatment with prescription-only stimulants increased the rate of 2–3 week abstinence (relative relapse risk reduction: 1.45 [1.10; 1.92]) and the length of abstinence in days (mean difference: 3.34 [1.06; 5.62]), especially in patients with cocaine dependence. Prescription-only amphetamine was particularly effective (risk reduction: 2.44 [1.66; 3.58]) as well as the administration of prescription stimulants at maximum doses and above (risk reduction: 1.95 [1.38; 2.77]) (33).

Conclusion

Overall, there is limited evidence available on the management of stimulant-related disorders and methodological deficits are common. Despite the large number of studies, there is no convincing evidence to support the effectiveness of pharmacological treatment approaches. Various methods of psychotherapy and exercise therapy have beneficial effects in reducing stimulant use; again, however, the available evidence is limited. Given the similarities in clinical course and management challenges, it seems useful to look at cocaine- and (meth)amphetamine-related disorders collectively. High-quality studies and a stimulant-specific guideline are crucial for improving the provision of care to patients with stimulant-related disorders.

Conflict of interest

MS declared that he received a fee from axunio Pharma GmbH. This fee refers to “consulting fees from parties with a content-related connection to the manuscript “.

The remaining authors declare no conflict of interest.

Manuscript received on 13 May 2025, revised version accepted on 1 September 2025

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
PD Dr. med. univ. Dr. rer. medic. habil. Johannes Petzold

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