Case-based learning: stimulant-induced psychosis associated with ADHD pharmacotherapy

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterised by pervasive inattention and/or hyperactivity, as well as impulsivity that impairs functioning. Pharmacological treatment is effective for many patients. It is commonly centred around psychostimulants and atomoxetine, if the patient has a history of illicit substance use, which is not in remission, or is unable to tolerate psychostimulants^​1​. This medication choice is widely supported by national guidelines, such as the British Association for Psychopharmacology (BAP) guidelines^​1​ and National Institute for Health and Care Excellence (NICE)^​2​ guidelines, and international guidelines, such as ‘The World Federation of ADHD international consensus statement’^​3​. Most adverse effects of stimulants are mild to moderate — for example, appetite suppression, insomnia and irritability. However, rare but serious psychiatric adverse effects, including new-onset psychotic or manic symptoms, are recognised in regulatory warnings and clinical literature^4-9. 

Stimulant-induced psychosis (SIP) is an uncommon but clinically significant adverse effect of ADHD pharmacotherapy. It most often presents with hallucinations and/or delusions temporally associated with therapeutic exposure to methylphenidate or amphetamine-based stimulants and is not better accounted for by an alternative diagnosis such as delirium, intoxication with another substance or the onset/relapse of a primary psychotic disorder^​4–9​. This aligns with the broader diagnostic concept of substance/medication-induced psychotic disorder, which requires a temporal association, and the exposure is capable of producing psychosis^​10​.  

SIP may occur in individuals without any prior personal or family history of psychotic illness. Population data suggest that new-onset psychosis occurs in a small minority of patients initiated on stimulants. The findings of a study published in 2019 revealed that in a large cohort of adolescents and young adults, psychosis occurred in around 1 in 660 patients, with higher risk in those prescribed amphetamine compared with methylphenidate^​4​. The results of a study, published in 2024, also showed higher odds of psychotic symptom reporting with amphetamines versus methylphenidate, while no association with atomoxetine was found in the same dataset^​6​.

The findings of a 2025 Icelandic nationwide cohort study revealed that 0.38% of adults initiating ADHD medication were hospitalised for first-onset psychosis or mania within one year, which supports a small but clinically meaningful risk of severe presentations requiring inpatient care^​7​. An FDA-linked analysis, published in 2009, showed psychotic/manic events in stimulant-exposed children across trials and post-marketing reports. Hallucinations in children often involved visual/tactile phenomena, such as insects, snakes or worms, and typically resolved after discontinuation, according to the analysis^​8​.

Risk is increased by high stimulant doses, rapid escalation, sleep deprivation and concomitant substance use, particularly cannabis and other illicit stimulants, such as cocaine, co-prescribed medicines with psychotogenic potential — for example, systemic corticosteroids — as well as underlying vulnerability (i.e. personal or family history of psychosis or bipolar disorder)^​4–7​. 

When hallucinations, delusions, marked paranoia or disorganised behaviour emerge in a patient treated for ADHD, clinicians must consider a broad differential diagnosis and act promptly to mitigate risk^​1–3​. Pharmacists, across primary care, secondary care and mental health services, are well placed to identify early-warning symptoms, construct a high-quality medicines timeline — including formulation switches, adherence patterns and co-exposures — advise on urgent escalation and pharmacological intervention, as well as reinforcing patient counselling and monitoring in shared-care arrangements.

This article uses three practical cases to support pharmacists in recognising SIP, escalating appropriately, contributing to multidisciplinary management and counselling patients to reduce recurrence risk.

Which drugs can cause stimulant-induced psychosis?

Prescribed ADHD medicines, such as methylphenidate (all formulations) and amphetamine derivatives, including lisdexamfetamine and dexamfetamine, can cause SIP^​4,7​.

Illicit stimulants — for example, cocaine, methamphetamine and non-prescribed amphetamines — are well-recognised precipitants of psychosis and may coexist with prescribed stimulant therapy. Intoxication, withdrawal and polysubstance exposure can both mimic SIP and amplify risk when combined with prescribed stimulants, which can be critical for differential diagnosis^​9,10​. 

Suggested mechanism underpinning stimulant-induced psychosis

While still debated, the leading model for the mechanism underpinning SIP is excess dopaminergic signalling in mesolimbic pathways^​4​. In this model, psychotic symptoms are thought to arise from excessive mesolimbic dopamine signalling, which confers aberrant salience on otherwise neutral stimuli.

Stimulants improve ADHD symptoms partly by increasing catecholaminergic signalling in prefrontal circuits, but they also increase subcortical dopamine. Amphetamines increase synaptic dopamine — both through transporter effects and dopamine release — whereas methylphenidate primarily inhibits reuptake. This mechanistic distinction is often cited as biologically plausible support for the higher psychosis risk observed with amphetamines^​4,6​. 

Dose matters — at higher levels of exposure, compensatory mechanisms may be overwhelmed, increasing the likelihood of psychotic symptoms, particularly in individuals with underlying vulnerability (e.g. genetic, developmental, or owing to sleep deprivation or substance use). However, product information and regulatory communications describe the possibility of treatment-emergent psychotic or manic symptoms at usual doses, including in those without prior psychiatric history^​4,5,8​.

Risk factors and vulnerability states

SIP is multifactorial: patient vulnerability interacts with dopaminergic exposure, dose dynamics and contextual precipitants (see Table^{​2,4–11​}).

Table: Risk factors for stimulant-induced psychosis

Clinical presentation: symptoms, onset and duration

SIP ranges from transient perceptual disturbances to frank psychosis, which is characterised by delusions, hallucinations, impaired reality testing and associated behavioural disturbance. Presentations can be indistinguishable from primary psychotic disorders at the point of first contact^​9,10​. Typical symptoms include:

• Hallucinations (e.g. auditory, visual, tactile). In children, visual/tactile hallucinations involving insects, snakes or worms are repeatedly reported and were prominent in FDA-reviewed paediatric cases;
• Delusions and paranoia, often persecutory or referential;
• Agitation, anxiety, insomnia and behavioural change, sometimes with manic-like features (e.g. elevated mood, pressured speech, disinhibition)^​4,5,8​.

Symptoms may emerge shortly after initiation or dose increase; however, episodes can also arise after weeks to months of stable dosing, especially when other precipitants develop (e.g. sleep loss, substance co-use, intercurrent illness, medication changes). Many cases resolve within days to around a week after discontinuation of the stimulant, although persistence should prompt reassessment for a primary psychotic or mood disorder or other medical causes^​8–10​. 

Red-flag symptoms

Command hallucinations, severe agitation, suicidality, threats or violence, marked disorganisation, inability to self-care, safeguarding concerns or suspected intoxication/delirium are all red-flag symptoms that require urgent escalation to emergency medical services, such as A&E. Guidance for psychosis and schizophrenia management emphasises timely assessment and access to specialist services^​9,10​.

Differential diagnosis 

Attribution of symptoms to SIP is primarily a clinical judgement based on constructing an accurate chronology of symptom onset, stimulant exposure, dose changes, intoxication or withdrawal, and resolution after cessation. A detailed prescribed, over the counter and illicit drug history, supported where possible by collateral information, is essential. Before attributing symptoms to SIP, clinicians must exclude important differentials, including primary psychotic disorders, bipolar disorder or mania, psychosis related to other substances or withdrawal states, delirium or medical causes, and psychosis induced by other medicines, such as systemic corticosteroids or anticholinergic over-the-counter preparations^​9,10​.
 

Management 

Management prioritises patient safety, urgent assessment, exclusion of alternative causes, including substance intoxication, delirium and primary psychotic disorders, and prompt discontinuation of the suspected offending stimulant. Short-term antipsychotic treatment may be required in severe or persistent cases, consistent with established psychosis management guidance. Ongoing ADHD care after SIP requires careful risk–benefit appraisal, consideration of non-stimulant options and, where rechallenge is considered, specialist oversight, low-dose slow titration and close monitoring, as relapse on rechallenge has been reported^{​9,10,12​}.

The following framework can be used by pharmacists for the management of SIP associated with ADHD pharmacotherapy:

1. Recognise and triage — treat new hallucinations, delusions, marked paranoia, severe agitation or manic-like activation as urgent in anyone taking ADHD medication and consider SIP as a differential diagnosis. Assess immediate risk (e.g. self-harm, harm to others, inability to self-care), arrange a same-day medical/mental health assessment and use local crisis/urgent care pathways consistent with NICE CG178 (adults) or NICE CG155 (children and young people)^​9,10​.
2. Construct a robust medicines and exposure timeline — document the stimulant name, formulation, dose, recent changes, adherence, early refills, “top-ups” and any product switches. Co-prescribed medicines (particularly corticosteroids); OTC sympathomimetics; alcohol and recreational drug use. The MHRA warns that modified-release methylphenidate products differ and switching may change effects and adverse effects^​11​.
3. Support immediate clinical actions — clinicians commonly discontinue the suspected stimulant while urgent assessment occurs, reflecting regulatory warnings and the typical resolution of symptoms after cessation. Pharmacists should support safe discontinuation communication, ensure clarity on what has been stopped and advise against unsupervised dose manipulation^​8​.
4. Facilitate differential diagnosis and referral — ensure that primary psychosis, bipolar disorder/mania, substance-induced states and delirium/medical causes are considered; support appropriate referral to crisis teams, early intervention in psychosis services, or liaison psychiatry where indicated, in line with NICE psychosis guidance^​9,10​.
5. Plan longer-term ADHD care safely — If ongoing pharmacotherapy is needed, encourage specialist review. Consider non-stimulants, psychosocial interventions and, if rechallenge is considered, insist on low-dose slow titration and close monitoring. Evidence indicates higher risk with amphetamine compared with methylphenidate and a dose–response relationship for prescription amphetamines^​4,5​. 

Case part one: psychotic symptoms recognised in an ADHD medication review

During a routine shared-care medicines review, a GP-based pharmacist meets patient A, a 24-year-old adult prescribed modified-release methylphenidate 54mg each morning, commenced 18 months earlier after completion of specialist titration. His prescription is supported by his GP through a shared care policy. The patient reports that ADHD symptoms were initially well controlled, but over the past ten days, there has been worsening insomnia “with only two to three hours sleep per night”, anxiety and a sense of being “over-stimulated”. The patient describes hearing a voice commenting on them when alone and believes neighbours are observing them through walls. There is no disclosed prior psychiatric history. Current medicines include the methylphenidate and sertraline 100mg daily. The patient also reports weekend cannabis use that has increased recently to try and address insomnia, as well as recent use of an OTC decongestant for a viral upper respiratory tract infection.

On examination, the pharmacist observes pressured speech, marked distress and guardedness. The patient denies alcohol intoxication but is equivocal when asked about additional substances. The described experiences are consistent with possible psychotic symptoms.

Immediate steps 

1. Rapid risk triage — assess suicidal ideation, risk of harm to others, safeguarding, capacity and whether the patient can safely return home. If risk is deemed high, then emergency services should be contacted;
2. Same-day escalation — contact the GP/clinical supervisor and arrange urgent assessment. Where risk is high, advise emergency department attendance or crisis team involvement in line with local urgent mental health pathways and NICE-aligned principles for timely assessment of psychosis;
3. Do not leave the patient unsupported if acutely distressed — with consent, involve a trusted relative/friend, or arrange supervised waiting;
4. Document and communicate a medicines timeline — stimulant dose, any missed doses or “top-ups”, formulation changes and co-exposures (e.g. cannabis, OTC sympathomimetics)^​9–11​.

What to avoid

The pharmacist should avoid reassurance that symptoms are “definitely medication-related” — premature attribution risks missed diagnoses — and avoid disputing the factual accuracy of delusional beliefs. Instead, acknowledge the person’s distress and focus on safety and engagement, as well as avoid advising unsupervised medication changes beyond urgent escalation, particularly where risk assessment is incomplete.

Case study part two: management of the patient (urgent care/secondary care interface)

Patient A is reviewed the same day by the GP and referred to the local urgent mental health/crisis service for assessment. The location of where the patient will be managed is determined by this assessment. For example, if the patient has severe agitation, suicidality, inability to self-care, safeguarding concerns or suspected intoxication/delirium, assessment in the emergency department and possible admission may be required. Patient A was assessed in A&E and the associated psychiatric liaison team^​9,10​. 

Immediate management decisions

Patient A was advised to immediately discontinue the stimulant while assessment proceeds. Discontinuation is consistent with regulatory and clinical evidence that psychotic symptoms can be treatment-emergent and often remit after cessation^​8–10​.
 
Collateral history a full medicines reconciliation, including OTC agents, corticosteroids, any stimulant over prescribing or formulation switches, a physical examination and appropriate investigations — for example, toxicology where indicated and infection/metabolic screening if delirium is possible — excluded any other possible causes for patient A’s current presentation. 
 
In terms of symptomatic treatment, where psychosis is severe or persistent, urgent mental health services may initiate short-term antipsychotic medication alongside supportive care and safety planning, which is consistent with established psychosis management guidance, emphasising antipsychotic use (with psychological interventions) in acute psychosis.

Differential diagnosis considerations and how they influence care

If psychotic symptoms persist after stimulant cessation, or if there are features more suggestive of a primary psychotic disorder — for example, pro-dromal symptoms predating stimulant exposure, disorganised thought, negative symptoms and functional decline — or bipolar disorder — for example, pre-existing mood disorder — longer-term psychiatric treatment and follow-up are indicated, and the episode should not be simplistically attributed to SIP. Substance use may shift management towards detoxification support, safeguarding and relapse prevention, as well as complicate attribution^​9,10​.

Case study part three: restarting ADHD medication and next steps

Six weeks later, patient A’s hallucinations and paranoia have fully resolved. Collateral information identifies a period of escalating insomnia, increased caffeine intake, weekend cannabis use and occasional “top-ups” of methylphenidate using leftover tablets. The crisis team records the episode as most consistent with a medication/substance-associated psychotic episode. Nevertheless, it recommends ongoing vigilance. Patient A reports significant impairment from untreated ADHD and requests pharmacological treatment.

Considerations for rechallenge

Rechallenge should be regarded as a specialist decision, requiring a structured risk–benefit appraisal and informed consent. The literature describes recurrence of psychosis in some patients on re-exposure. Therefore, when rechallenge is attempted, it should be cautious, slow and closely monitored. When risk is judged to be elevated — for example, ongoing cannabis use, previous severe episode, strong family history — non-stimulant options and robust non-pharmacological support should be prioritised^​12​.

In the case of patient A, who admitted that cannabis use is unlikely to reduce dramatically, a decision was made to consider a trial of the non-stimulant atomoxetine. Psychoeducation on the risks of cannabis-induced psychosis was given^​2,9​.

When a stimulant is reintroduced, common risk-mitigation strategies include:

• Address modifiable risks first: sleep stabilisation, substance use intervention, and clear agreements about adherence (e.g. no dose escalation; no “top-ups”);
• Start low and titrate slowly, with frequent early contact;
• Consider whether to use methylphenidate rather than an amphetamine in higher-risk patients, as cohort and pharmacovigilance data suggest higher risk/signals with amphetamines;
• Avoid unnecessary formulation switching. If a long-acting methylphenidate preparation is used, maintain consistency because switching can change exposure and adverse effects^{​2,4,6,9,11​}. 

Monitoring going forward

During titration and the first months after re-initiation, monitoring should explicitly include sleep quality, anxiety/activation, perceptual disturbances, emerging paranoia, substance use and adherence. The Icelandic cohort analysis supports the need for ongoing follow-up after initiation or re-prescribing, given that a minority of severe episodes occur within the first year^​7​. 

Patient counselling points

Explain that psychotic symptoms are rare but serious; advise immediate cessation of driving/operating machinery and urgent contact with services if hallucinations, delusional beliefs, severe insomnia or marked agitation occur. Reinforce abstinence from cannabis and illicit stimulants, avoidance of unsupervised dose changes, and disclosure of OTC products and corticosteroid courses to prescribers/pharmacists^​9,10​.