Weight loss pill naltrexone — specifically the naltrexone/bupropion combination (Mysimba) — is a licensed prescription treatment for obesity in the UK, approved by the EMA and recommended under NICE guidance TA494. Naltrexone alone is not licensed for weight management; its benefit arises from its fixed-dose pairing with bupropion, which together act on appetite and reward pathways in the brain. This article explains how the combination works, who may be suitable, how it is taken safely, what side effects to expect, and how to access it through NHS or private services in the UK.

How Naltrexone Works as a Weight Loss Treatment

Naltrexone works as a weight loss treatment only in combination with bupropion (Mysimba), acting on hypothalamic POMC neurones to reduce appetite and on mesolimbic reward pathways to diminish the pleasure of eating calorie-dense foods.

Naltrexone is an opioid receptor antagonist originally developed to support the treatment of alcohol and opioid dependence. In the context of weight management, it is not used as a standalone agent but rather in a fixed-dose combination with bupropion, marketed under the brand name Mysimba in the UK and Europe. This combination product has received approval from the European Medicines Agency (EMA) and is recommended by NICE technology appraisal guidance TA494 as an adjunct to a reduced-calorie diet and increased physical activity — but only when prescribed as part of a specialist weight management service that includes dietary, physical activity, and behavioural support.

The mechanism by which this combination supports weight loss is twofold. Bupropion acts on dopamine and noradrenaline pathways in the hypothalamus, stimulating pro-opiomelanocortin (POMC) neurones to reduce appetite and food cravings. Naltrexone blocks opioid receptors, interrupting the autoinhibitory feedback loop on POMC neurones and reducing the rewarding aspects of eating — particularly the pleasure derived from highly palatable, calorie-dense foods via mesolimbic reward pathways. Together, these actions may help reduce compulsive eating behaviours and overall caloric intake.

It is important to note that naltrexone alone is not licensed as a weight loss treatment in the UK. The weight management benefit is specifically attributed to the naltrexone/bupropion combination (Mysimba). Any use of naltrexone outside this licensed indication would be considered off-label, and patients should be fully informed of this distinction.

The overall effect on body weight is modest. In the pivotal COR (Contrave Obesity Research) clinical trial programme, participants receiving naltrexone/bupropion alongside lifestyle intervention achieved mean weight reductions of approximately 5–9% from baseline over 56 weeks, compared with 1–3% in placebo groups — representing a treatment effect of roughly 3–5% over placebo. This medication is not a replacement for dietary and behavioural change. These findings are reflected in the MHRA/EMC Summary of Product Characteristics (SmPC) for Mysimba and the EMA European Public Assessment Report (EPAR).

Who May Be Suitable for Naltrexone for Weight Management

Mysimba is suitable for adults with a BMI of 30 kg/m² or above, or 27 kg/m² or above with a weight-related comorbidity, following individual clinical assessment; it is contraindicated in those with uncontrolled hypertension, seizure history, eating disorders, or current opioid use.

The naltrexone/bupropion combination (Mysimba) is indicated for adults with a body mass index (BMI) of 30 kg/m² or above, or for those with a BMI of 27 kg/m² or above in the presence of at least one weight-related comorbidity, such as type 2 diabetes, dyslipidaemia, or hypertension. Suitability must be assessed on an individual basis by a qualified healthcare professional, taking into account the patient's full medical history, current medications, and treatment goals.

Age restrictions: Mysimba is not indicated in patients under 18 years of age. It should be used with caution in patients aged 65 years and over, and is not recommended in patients aged 75 years and over, as data in these groups are limited.

Opioid-free interval: Patients must be opioid-free for a minimum of 7–10 days before starting treatment to avoid precipitating acute opioid withdrawal. If there is any uncertainty about recent opioid use, a naloxone challenge test should be considered before initiation, as described in the SmPC.

Certain groups are not suitable for this treatment. Contraindications include:

• Uncontrolled hypertension — bupropion can raise blood pressure and heart rate; note that controlled hypertension may itself be a qualifying comorbidity for eligibility

• A history of seizures, or conditions or concurrent medications that lower the seizure threshold (including abrupt alcohol or benzodiazepine withdrawal, CNS tumours, or severe head trauma)

• Eating disorders such as anorexia nervosa or bulimia nervosa

• Current or recent use of monoamine oxidase inhibitors (MAOIs) — a minimum interval of 14 days must elapse after stopping an MAOI before starting Mysimba

• Pregnancy or breastfeeding (use is contraindicated; women of childbearing potential should use effective contraception)

• Current opioid use or acute opioid withdrawal, as naltrexone will precipitate withdrawal symptoms

• Severe hepatic impairment (contraindicated)

• End-stage renal disease (contraindicated)

• Abrupt discontinuation of alcohol or benzodiazepines (risk of seizures)

Additional cautions apply in the following situations:

• Moderate hepatic impairment or moderate-to-severe renal impairment: the maximum daily dose must be reduced (refer to the SmPC for specific guidance)

• Bipolar disorder or a history of mania or hypomania: bupropion may precipitate a manic episode

• Narrow-angle glaucoma: bupropion may increase intraocular pressure

• Significant cardiovascular disease: careful assessment is required given the potential for blood pressure and heart rate elevation

• Drug interactions: bupropion is a potent CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates with a narrow therapeutic index (e.g., certain antidepressants, antipsychotics, beta-blockers, and antiarrhythmics). Bupropion is itself metabolised by CYP2B6; inhibitors (e.g., ritonavir) or inducers (e.g., efavirenz) of this enzyme may alter bupropion exposure. Caution is also required with other medicines that lower the seizure threshold.

A thorough medication review is essential before initiation. In accordance with NICE TA494, treatment should only be continued beyond 16 weeks if the patient has lost at least 5% of their initial body weight. Patients who do not meet this threshold should have treatment discontinued and alternative strategies explored.

Dosage, Forms and How to Take Naltrexone Safely

Mysimba is a prolonged-release tablet (8 mg naltrexone / 90 mg bupropion) titrated over four weeks to a maximum of two tablets twice daily; tablets must be swallowed whole with food and never crushed or chewed.

In the UK, the licensed weight management product containing naltrexone is available as a prolonged-release oral tablet. Each tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride. The dose is titrated gradually over four weeks to minimise side effects, particularly nausea, which is one of the most commonly reported adverse reactions during initiation.

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The standard titration schedule is as follows:

• Week 1: One tablet each morning

• Week 2: One tablet in the morning and one in the evening

• Week 3: Two tablets in the morning and one in the evening

• Week 4 onwards (maintenance): Two tablets in the morning and two in the evening (maximum daily dose: 32 mg naltrexone / 360 mg bupropion)

Dose adjustments: In patients with moderate hepatic impairment or moderate-to-severe renal impairment, the maximum daily dose should be reduced in accordance with the SmPC. Mysimba is contraindicated in severe hepatic impairment and end-stage renal disease. It is not recommended in patients aged 75 years and over; in those aged 65 and over, use with caution and monitor closely.

Tablets should be swallowed whole and must not be cut, crushed, or chewed, as this alters the release profile and increases the risk of adverse effects, including seizures. They should be taken with food to reduce gastrointestinal discomfort. However, patients should avoid taking a dose with a high-fat meal, as this significantly increases drug absorption and may raise the risk of side effects.

If a dose is missed, patients should skip the missed dose and resume their normal schedule — they should not double up on doses. Alcohol consumption should be minimised during treatment; abrupt cessation of heavy alcohol use should be managed carefully given the associated seizure risk.

Patients should be reminded that naltrexone will block the effects of opioid-based pain relief. If surgery or emergency analgesia is required, all treating clinicians — including anaesthetists and pain specialists — must be informed that the patient is taking this medication. Non-opioid, multimodal analgesia strategies should be planned in advance wherever possible.

Regular follow-up appointments are recommended to monitor blood pressure and heart rate (particularly during dose titration and in the first few months), body weight, and tolerability.

Common and Serious Side Effects to Be Aware Of

The most common side effects of Mysimba are nausea, constipation, headache, and vomiting; serious risks include seizures, elevated blood pressure, and neuropsychiatric symptoms including suicidal ideation.

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As with all medicines, the naltrexone/bupropion combination carries a risk of side effects, and patients should be counselled thoroughly before starting treatment. Frequencies below are aligned with the Mysimba SmPC categories.

Very common side effects (affecting 1 in 10 people or more) include:

• Nausea

• Constipation

• Headache

• Vomiting

Common side effects (affecting between 1 in 100 and 1 in 10 people) include:

• Dizziness

• Dry mouth

• Insomnia or sleep disturbance

• Increased blood pressure or heart rate

• Abdominal discomfort

• Fatigue

Many of these effects are transient and can be managed by ensuring the medication is taken with food and by adhering to the gradual dose titration schedule. Patients should be reassured that nausea typically improves within the first few weeks.

More serious adverse effects require prompt medical attention and may necessitate discontinuation of treatment:

• Elevated blood pressure or heart rate — blood pressure and heart rate should be monitored regularly, particularly during dose titration and in the first few months of treatment

• Seizures — the risk is dose-dependent and is increased by factors that lower the seizure threshold (including abrupt alcohol or benzodiazepine withdrawal, CNS tumours, and severe head injury); patients should report any unusual episodes immediately

• Neuropsychiatric symptoms, including depression, agitation, hostility, anxiety, or suicidal ideation — the MHRA has issued Drug Safety Update guidance highlighting this risk, particularly in patients with a psychiatric history; patients and carers should be advised to seek urgent medical attention if significant mood changes occur

• Mania or hypomania — particularly in patients with a history of bipolar disorder

• Angle-closure glaucoma — patients should seek urgent ophthalmological assessment if they develop eye pain or visual disturbance

• Hepatotoxicity — liver function should be monitored in at-risk individuals

• Hypersensitivity reactions, including skin rash or angioedema

Patients should be advised to contact their GP or seek urgent medical attention if they experience chest pain, significant mood changes, signs of an allergic reaction, new neurological symptoms, or eye pain.

The benefit–risk balance should be reassessed at each follow-up appointment, and treatment should be stopped if there is no meaningful clinical response or if tolerability becomes a concern.

Reporting side effects: Patients and healthcare professionals are encouraged to report any suspected adverse reactions via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or via the Yellow Card app.

Accessing Naltrexone for Weight Loss in the UK

Mysimba is a prescription-only medicine available via GP referral to a specialist weight management service; NHS access varies by Integrated Care Board, and private prescribing must be through a CQC-registered, GMC-regulated provider.

In the UK, the naltrexone/bupropion combination (Mysimba) is a prescription-only medicine (POM) and cannot be purchased over the counter. Access is typically through a GP, specialist obesity clinic, or a registered online prescribing service, provided that a thorough clinical assessment has been completed.

NICE technology appraisal guidance TA494 recommends naltrexone/bupropion as an option for managing overweight and obesity in adults, but only when prescribed as part of a specialist weight management service that includes dietary, physical activity, and behavioural support, and only when the 16-week stopping rule (minimum 5% weight loss from baseline) is applied. Patients seeking NHS access will typically require a referral to a tier 3 or tier 4 weight management service, depending on their clinical complexity.

It is important to note that NHS prescribing of Mysimba is not universally available across all regions. Access depends on local Integrated Care Board (ICB) formulary decisions and commissioning policies, which may vary. Patients should discuss local availability with their GP or specialist team.

For those considering private prescribing, it is essential to use a regulated provider registered with the Care Quality Commission (CQC) and to ensure that any prescriber is registered with the General Medical Council (GMC), General Pharmaceutical Council (GPhC), or another appropriate regulatory body. Patients should be cautious of unregulated online platforms offering weight loss medicines without a proper consultation, as these may not adhere to UK prescribing standards or patient safety requirements.

If you are interested in exploring naltrexone-based weight management treatment, the recommended first step is to speak with your GP, who can assess your eligibility, review your medical history, and refer you to appropriate services if needed. Weight management is most effective when medication is combined with sustained lifestyle changes, and ongoing support from a multidisciplinary team significantly improves long-term outcomes.

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