Stimulants, as a group, encompass a wide range of synthetics (amfetamine, methamphetamine, methylphenidate, mephedrone) and naturally derived substances (cocaine and crack, ephedrine, khat) broadly described as sympathomimetic. Ingestion creates characteristic euphoric effects thought to be mediated by release of the monoamines norepinephrine, serotonin and dopamine.1 Cocaine and amfetamine use are the most common with a global prevalence rate of 0.4% and 0.7%, respectively. It is estimated that dependence will develop in 16% of people using cocaine and 11% of those who use amfetamines.2
Acute intoxication and chronic use of these substances can present with cardiovascular symptoms, movement disorders and a range of psychiatric symptoms including agitation, enhanced anxiety, paranoia, panic attacks and psychosis. Associations with violent behaviour, high-risk sexual activity and the injecting of stimulants further underline the implications of stimulant use at the public health level.2, 3, 4
Tolerance and dependence can be expected to develop following regular, long-term use. For patients dependent on stimulants, a withdrawal syndrome of approximately 1 week's duration marked by craving, fatigue, agitation, insomnia and increased appetite can follow on from abstinence.5, 6
Recreationally, patterns of SUD vary from use of a single stimulant, several different stimulants and simultaneous or sequential use of drugs from different classes. Combinations of different drugs may be explored by patients as a means of shaping the overall psychoactive experience.3 Stimulant use among people with opiate use disorder is common and linked to poor engagement with opiate agonist therapy and the increased risk of overdose that follows.7, 8
After decades of research there are, at the time of writing, no pharmacological agents approved in the treatment of SUD.9, 10, 11, 12 It is worth mentioning explicitly that there is also limited evidence to support the prescribing of stimulants themselves (so-called agonist replacement therapy) for patients with SUD.10, 13 There is a need for rigorous, high-quality clinical trials that can overcome the historical methodological challenges.11
Stimulant use for many will be self-limiting without treatment beyond the provision of harm minimisation advice and psychoeducation. For those who use stimulants in combination with alcohol, heroin or GBL, effective treatment of the co-occurring dependency may enable reductions in stimulant use. Successful care of patients dependent on stimulants should involve a comprehensive treatment approach that includes psychosocial interventions that reflect the complexity of factors behind SUD. While a range of therapeutic modalities are recommended, there is particularly good evidence for contingency management.2, 11
For many the route to abstinence is through mutual aid and peer support such as Cocaine Anonymous, Crystal Meth Anonymous or Rational Recovery. Further information on the treatment of cocaine dependence can be found in UK clinical guidelines.14 The limited effective interventions available for SUD have prompted the exploring of other treatment modalities.
There is a small developing evidence base for the potential of interventions based on neuromodulation such as transcranial magnetic stimulation (tMS) in SUD. This is an area of research in its early stages, without consensus on an appropriate cortical target or optimal frequency of TMS.15
An important area of consideration is the management of patients with SUD and suspected or verified attention deficit hyperactivity disorder (ADHD). As might be expected, ADHD is more common in patients with substance use disorder.16 There is limited guidance to support clinicians in making a definitive diagnosis of ADHD in this group of patients or to navigate the risk-benefit balance of commencing treatment with stimulants compared with second-line non-stimulant-based alternatives.17, 18
Cocaine is a naturally derived compound found in the coca plant. Aside from application as a topical anaesthetic, it is primarily used recreationally. Once extracted, cocaine's properties are enhanced when processed into cocaine hydrochloride, a powdered form that is commonly insufflated (snorted). Removal of the hydrochloride creates a water-insoluble base form (freebase) known as ‘crack' that can be smoked. Both forms of cocaine can be injected although as a freebase it must first be dissolved in an acid. An epidemiological study from 2023 suggests an increase in rates of crack injection in both England and Wales.19
Symptoms of withdrawal include depressed mood, agitation and insomnia. These are usually self-limiting. It should be noted that given cocaine's short half-life and the binge nature of cocaine use, many patients essentially detoxify themselves regularly, with no pharmacological therapy. Symptomatic relief such as the short-term use of hypnotics may be helpful in some, but these agents may become agents of dependence themselves for some patients.14
Amfetamine-type substances were first synthesised in the early 20th century initially having a wide range of applications. Currently, their clinical use is restricted to the treatment of ADHD and narcolepsy.20 Amfetamine as a salt, usually amfetamine sulphate, the cathinone mephedrone and the more potent, long-acting methamphetamine are most commonly associated with significant misuse.
Within a recreational context, amfetamine sulphate is known as ‘speed' and mephedrone as ‘drone' or ‘meow meow'; names for methamphetamine include ‘meth', ‘crystal' or ‘tina'. These substances can be ingested as tablets or ‘pills', insufflated as powders and, less commonly, injected or ‘slammed'. Methamphetamine, when in its crystalline form ‘ice', can also be inhaled.
A withdrawal syndrome is common in those who are dependent. Treatment should focus on symptomatic relief, although many symptoms of amfetamine withdrawal (low mood, listlessness, agitation, irritability, fatigue, etc.) are short-lived and may not be amenable to pharmacological treatment. Insomnia can be treated with short courses of hypnotics, again noting the risk of dependence on these agents.1, 9, 11 A 2022 systemic review and meta-analysis observed that mirtazapine may reduce the amount of methamphetamine consumed by patients with methamphetamine use disorder.21
In those who are dependent on opioids and cocaine, the provision of effective substitution therapy for treatment of the opioid dependence with either methadone or buprenorphine can lead to a reduction in cocaine use.14
Psychotic symptoms in association with methamphetamine are related to frequency of use and severity of methamphetamine dependence.22 In many, perhaps most, cases psychotic symptoms can resolve with the resolution of intoxication - i.e. over the course of a day or so. The majority of patients attending an emergency setting with acute psychotic symptoms in the context of very recent methamphetamine use can be managed with simple sedation (e.g. diazepam 5-10mg as needed 4-6 hourly for agitation) and therapeutic rest.23 Some patients, however, may need more intensive treatment in line with the treatment of acute psychosis in Chapter 2.
It should be noted that psychotic symptoms in the context of stimulant use are progressive with continued use - they tend to start earlier in each binge and to last longer. A median of 25% of patients report on-going symptoms 1 month after methamphetamine consumption.24 Psychosis in the context of intoxication is associated with persecutory delusions and tactile hallucinations, while more persistent methamphetamine-associated psychosis is characterised by delusions of persecution and auditory hallucinations and is largely indistinguishable from a primary psychotic disorder.24 In the emergency department it can be difficult to make a clear diagnosis. Between 16% and 38% of patients initially diagnosed with methamphetamine psychosis are later diagnosed as having schizophrenia.24
In the acute setting, another important differential diagnosis in methamphetamine users presenting with agitated psychosis is GBL withdrawal delirium (where stimulant/GBL polysubstance use is prevalent). There is symptomatic overlap between stimulant intoxication - autonomic hyperactivity, agitation, hallucinations - and GBL withdrawal delirium. The latter requires higher doses of benzodiazepines and more prolonged treatment (see ‘GHB and GBL dependence' later in this chapter).
As already stated, in the emergency setting, simple sedation with benzodiazepines for agitation is often sufficient initially. If antipsychotics are indicated, the fourfold increased odds of developing extrapyramidal side effects (EPSEs) in patients who use methamphetamine should be borne in mind.25 Agents with a low propensity to cause EPSEs should be used and there is evidence for efficacy of olanzapine. Aripiprazole may be preferred for rapid tranquillisation as olanzapine and benzodiazepines cannot be co-administered. Haloperidol should not be used because of the risk of dystonia. Early review regarding continuation is important as for most patients their symptoms resolve within 2 or 3 weeks, and there is no evidence to support the benefit of prophylactic prescription of antipsychotics in methamphetamine-related psychosis.26
Anhedonia can be profound in early abstinence from stimulants. For many, low mood will resolve in line with duration of abstinence and supportive psychosocial interventions.19 For those in whom it endures psychological treatments are effective but may be difficult for addiction patients to access because of institutional barriers.2
Antidepressants have primarily been evaluated as treatment for the substance dependence itself, with depression as a secondary outcome. There is some evidence for TCAs in reducing depressive symptoms.27 However, TCAs are not recommended in those with on-going comorbid substance misuse because of their cardiotoxicity.28 There is no evidence to support the use of SSRIs and indeed these are associated with significant interactions with stimulants19 and increased disengagement.2