Bupropion

• 1. Introduction

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  Bupropion, sold under the brand name Wellbutrin among others, was prescribed more than 30 million times in the United States in 2023. That made it the seventeenth most commonly prescribed medication in the country and the third most common antidepressant. The World Health Organization also lists it among its Essential Medicines. Doctors use bupropion to treat major depressive disorder and seasonal affective disorder, and to help people quit smoking. It is a tablet taken by mouth. For a drug so familiar, its inner workings remain strangely uncertain. Its effect on dopamine is weak, and how much that matters is contested. This documentary follows the questions that surround it. How does it differ from the antidepressants it is so often compared with? What does it actually do in the brain? And what happened when its makers, regulators and prescribers disagreed about what the pill was for?

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• 2. Withdrawn and Returned

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  Nariman Mehta, who worked at Burroughs Wellcome, invented bupropion in 1969. The company is now known as GlaxoSmithKline. The US patent was granted in 1974. On the 30th of December 1985, the US Food and Drug Administration approved the drug as an antidepressant, and it went on sale as Wellbutrin.

  In 1986, the drug was pulled from the market. Seizures had occurred often enough at the first recommended dose of 400-600 mg a day to force its withdrawal. Later work showed that the risk depended strongly on the dose. Bupropion came back in 1989, with the maximum daily dose lowered to 450 mg.

  Wellbutrin SR arrived in 1996, a sustained-release tablet taken twice a day rather than three times. The next year, 1997, the FDA approved the drug as a smoking cessation aid under the name Zyban. In 2000 its generic name changed from amfebutamone to bupropion. Wellbutrin XL, a hard-shelled tablet taken once a day, was approved in 2003, and in 2006 it gained approval for seasonal affective disorder. Both SR and XL are sold as generics in the United States and Canada.

  Sanofi-Aventis brought Aplenzin to market after FDA approval in April 2008. It is an extended-release tablet for once-daily use, and it contains the hydrobromide salt instead of the hydrochloride used in other versions. Approval rested on its bioequivalence with Wellbutrin XL. Bupropion now also appears in pairings. Contrave combines naltrexone with bupropion for obesity, and Auvelity combines dextromethorphan with bupropion for depression. The FDA approved the latter in 2022 as a rapid-acting treatment for major depressive disorder.

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• 3. Unusual Among Antidepressants

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  Among participants with recurring seasonal affective disorder, 15% of those taking bupropion through autumn and winter had a major depressive episode, against 27% on placebo. That result sits inside a broader picture that is more modest. Overall, the evidence supports bupropion over placebo for depression, and guidelines consistently list it as an option for adults with major depressive disorder. Some guidelines support it as a first choice, though advice for treatment-resistant depression is limited. Some peer-reviewed studies rate the evidence quality as low, and some meta-analyses find at most a small effect. Its effectiveness appears similar to that of other antidepressants. It also improves depression in bipolar disorder, with a risk of triggering an affective switch that resembles other antidepressants.

  Its rate of sexual side effects is no different from placebo, which sets it apart from most antidepressants. The majority of studies saw significant weight loss rather than weight gain. It does not cause the sleepiness that other antidepressants can produce. It also beats selective serotonin reuptake inhibitors, known as SSRIs, at easing hypersomnia and fatigue in depressed patients. For anxious depression, it does not worsen anxiety, contrary to common belief. It matches SSRIs when anxiety is low or moderate, while SSRIs hold a modest edge in response rates when anxiety is high.

  When an SSRI alone fails, adding bupropion is a common next step, and clinical trials support it. It appears less effective than adding the antipsychotic aripiprazole.

  Studies even suggest that bupropion can relieve sexual dysfunction caused by SSRIs. A 2022 systematic review and meta-analysis examined bupropion for low sexual desire in women. It found the drug appeared effective in a dose-dependent way, though the data were limited. Small studies of bupropion, or bupropion with trazodone, in non-depressed women with hypoactive sexual desire disorder point the same direction. The International Society for the Study of Women's Sexual Health says it can be considered off-label for that condition, despite limited safety and efficacy data.

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• 4. Quitting Smoking and Beyond

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  A course of bupropion for quitting smoking lasts seven to twelve weeks, and the patient stops using tobacco about ten days in. The drug eases nicotine craving and withdrawal symptoms such as depressed mood, irritability, difficulty concentrating and increased appetite. It also slows the weight gain that often follows quitting in the first weeks, although that effect fades with time.

  The results fade too. Abstinence from tobacco falls from 37% at three months to 20% at one year. Six months after treatment, bupropion raises the odds of quitting about 1.6-fold compared with placebo. That matches nicotine replacement therapy and falls short of varenicline. Combining bupropion with nicotine replacement does not improve quit rates. In children and adolescents it offers no significant benefit, and evidence for pregnant women is insufficient.

  For long-term weight gain treated over six to twelve months, bupropion produced an average loss of 2.7 kg compared with placebo. That is not much different from the loss seen with sibutramine or orlistat.

  In the United States, attention deficit hyperactivity disorder is not an approved use, and the American Academy of Pediatrics left bupropion out of its 2019 guideline on the condition. Systematic reviews say it may work, but the trials were small and prone to bias. Like atomoxetine, it takes several weeks to act. Stimulants such as amphetamine and methylphenidate work immediately.

  Cocaine dependence does not respond to bupropion, though it shows promise for reducing use of and cravings for amphetamine-type stimulants. Because it lowers the inflammatory signal tumor necrosis factor alpha, people have suggested it for inflammatory bowel disease, psoriasis and other autoimmune conditions, but clinical evidence is very thin. It is not proven for chronic low back pain. Clinicians have used it for apathy, abulia and akinetic mutism, and in animal models it increased effort and improved motivation, but trials show only limited benefit. It may help with excessive daytime sleepiness and narcolepsy, and it has been used for orthostatic hypotension and postural orthostatic tachycardia syndrome.

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• 5. A Puzzling Mechanism

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  About 20% of the brain's dopamine transporters are occupied by bupropion and its metabolites at 300 mg a day, according to several PET scan studies. The range of means runs from about 14 to 26%. Methylphenidate, another drug in this class, is thought to occupy more than 50% at therapeutic doses. After a single 150 mg dose of bupropion, one PET study detected no measurable dopamine release. These findings raise doubt about how much dopamine matters to its benefits. The label describes it as a norepinephrine-dopamine reuptake inhibitor that also blocks several nicotinic acetylcholine receptors. It does not release norepinephrine or dopamine.

  Most of the pharmacological action comes from metabolites called hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion. They circulate at levels comparable to bupropion or far higher, so bupropion can reasonably be described as a prodrug of them. In humans, oral bupropion yields hydroxybupropion at levels 16-fold higher than bupropion itself. Hydroxybupropion binds more strongly to the norepinephrine transporter, so the drug may act more as a norepinephrine reuptake inhibitor than a dopamine one. Its clinical effects fit that idea. Unlike atomoxetine and reboxetine, though, it does not alter the tyramine pressor response, a marker of norepinephrine reuptake inhibition. Rodent experiments suggest a role for the sigma-1 receptor, but no human binding data seem to exist.

  After a dose is swallowed, plasma levels peak at about 1.5 hours. Sustained-release and extended-release tablets push the peak to 3 hours and 5 hours. Absolute bioavailability is presumed low, at 5-20%, and the XL tablet delivers 68% of the SR tablet. Metabolism varies enormously. Two people taking the same amount can end up with effective doses that differ by as much as 5.5 times. The drug follows two phases, with an initial redistribution of about 1 hour and a slower phase of 12-30 hours. That pattern may explain why a quick high makes abuse unfeasible.

  Species matter too. In rats, oral bupropion produces bupropion levels 3.4-fold higher than hydroxybupropion, the reverse of the human pattern. Rodents show stimulant-like and reinforcing effects, and monkeys self-administer it intravenously, while oral doses in people show little of this.

  Chemically, bupropion is an aminoketone from the family of substituted cathinones and phenethylamines, also named 3-chloro-N-tert-butylcathinone. It has the formula C13H18ClNO and a molecular weight of 239.74 g/mol. The tablets contain a racemic mixture of two mirror-image forms that rapidly interconvert in the body. Two chemical steps from 3'-chloro-propiophenone make it: brominate the carbon beside the ketone, replace the bromine with t-butylamine, then treat with hydrochloric acid. Overall yield is 75-85%.

  Related compounds include hydroxybupropion, radafaxine and manifaxine, all reuptake inhibitors like bupropion. Strip the tert-butyl group or swap in a methyl group, and the result, 3-chlorocathinone or 3-chloromethcathinone, becomes a potent releasing agent for serotonin, norepinephrine and dopamine. Those two have appeared as designer drugs. A cyclopropyl version, called PAL-433, was investigated for cocaine dependence.

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• 6. Seizures and Warnings

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  At 300 to 450 mg a day of the immediate-release form, about 0.4% of patients have a seizure. At the higher-than-recommended 600 mg, the rate climbs almost tenfold. Unprovoked seizures occur in 0.07 to 0.09% of the general population, and most other antidepressants carry 0 to 0.5% at recommended doses. The FDA label bars use in epilepsy and other conditions that lower the seizure threshold, including anorexia nervosa, bulimia nervosa and withdrawal from benzodiazepines or alcohol. It also advises avoiding monoamine oxidase inhibitors. The label urges caution in liver damage, severe kidney disease, severe hypertension, and in children, adolescents and young adults.

  Dry mouth, nausea, constipation, insomnia, anxiety, tremor and excessive sweating stand out most against placebo. Bupropion has the highest rate of insomnia among second-generation antidepressants except desvenlafaxine, and it carries about 20% more headache risk. In one study, 10% of patients saw systolic blood pressure rise by an average of 6 mm Hg. Rare cases of liver toxicity have led to death or transplantation. The label warns that it can trigger an angle-closure glaucoma attack, though it may lower the risk of open-angle glaucoma. Stevens-Johnson syndrome has rarely been reported. Mothers who took it in the first trimester of pregnancy showed a 23% increase in the odds of congenital heart defects in their children.

  The boxed warning on every antidepressant rests on 295 trials of 11 antidepressants combined by the FDA. For people under 25 it found a two-fold rise in suicidal thought and behavior among children and adolescents and a 1.5-fold rise at ages 18-24. Bupropion alone did not differ statistically from placebo. A large analysis of the FDA's adverse event database, however, found suicidality to be frequently reported. Used for smoking cessation, bupropion brings a 25% rise in psychiatric side effects, including about 40% more anxiety and about 80% more insomnia. In 2009 the FDA issued a health advisory based on 75 reports of suicidal adverse events over ten years, and follow-up trials led to its removal in 2016.

  Psychosis can rarely occur, mostly at doses above those recommended, and usually clears with a lower dose, stopping the drug or adding an antipsychotic. Case reports hint at a discontinuation syndrome after abrupt withdrawal, and compulsive behavior has rarely been linked to the drug.

  Adjusted for the number of prescriptions, US poison center data place bupropion and venlafaxine highest in mortality and illness among newer antidepressants. In significant overdoses, about a third of cases involve seizures, along with hallucinations, loss of consciousness and abnormal heart rhythms. Most people recover, but deaths have occurred from repeated uncontrolled seizures and heart attack.

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• 7. Drug Interactions

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  Carbamazepine reduces exposure to bupropion by 90% and raises exposure to its metabolite hydroxybupropion by 94%. The cause is an enzyme called CYP2B6, which converts bupropion into hydroxybupropion. Drugs that block that enzyme, including paroxetine, sertraline, diazepam, clopidogrel and orphenadrine, raise bupropion and lower the metabolite. Ticlopidine and clopidogrel do this considerably. Drugs that speed the enzyme up, such as rifampicin, ritonavir, St John's wort and phenobarbital, do the opposite. Efavirenz and lopinavir with ritonavir have also been shown to lower levels of bupropion or its metabolites.

  Bupropion works the other way on a second enzyme, CYP2D6. It and its metabolites block it, mostly through hydroxybupropion, and may reduce how much of the enzyme the liver makes. At 300 mg a day, the ratio of dextromethorphan to its metabolite rose about 35-fold. Desipramine exposure increased five-fold, and atomoxetine levels rose 5.1-fold. Metoprolol, imipramine, nortriptyline, venlafaxine and nebivolol have also been affected. A notable exception is that fluoxetine and paroxetine concentrations do not seem to change.

  With MDMA, exposure to both drugs rises about 30%, with improved mood but weaker heart rate effects from the MDMA. Bupropion prevents methamphetamine from releasing norepinephrine and dopamine and reduces its effects in humans.

  Theophylline, antipsychotics, tricyclic antidepressants and systemic corticosteroids also lower the seizure threshold, so combining them with bupropion needs care. The prescribing information advises minimizing alcohol, because in rare cases bupropion reduces alcohol tolerance. Pairing it with a monoamine oxidase inhibitor may cause a hypertensive crisis.

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• 8. Quality, Law, and Misuse

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  In October 2007, ConsumerLab.com and The People's Pharmacy released comparative tests of bupropion brands. The People's Pharmacy had received multiple reports of more side effects and weaker results from generic versions. The tests found that one generic of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, did not perform like the brand-name pill in the lab. The FDA first concluded the two were equivalent and blamed natural mood variation. On the 3rd of October 2012 it reversed itself, announcing that Budeprion XL 300 mg failed to demonstrate therapeutic equivalence. It asked four manufacturers for data by March 2013 and has since found some formulations not bioequivalent.

  Also in 2012, the US Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine. Part of the case concerned promoting Wellbutrin for weight loss and sexual dysfunction, uses the FDA had not approved.

  In 2017, the European Medicines Agency recommended suspending several nationally approved medicines because Micro Therapeutic Research Labs in India had misrepresented bioequivalence study data. The list included several 300 mg modified-release bupropion tablets. In November 2022, during an industry-wide review of nitrosamine impurities, GlaxoSmithKline paused batch release and distribution of bupropion 150 mg tablets. After the agency raised the acceptable daily intake in July 2023, the company said distribution would resume across the EU and Europe by the end of 2023.

  Recreational use is uncommon. Case reports describe a high like cocaine or amphetamine but weaker, while the bulk of evidence shows oral bupropion feels very different from addictive stimulants. Injection or insufflation has been reported in the United States and Canada, notably in prisons. It has also turned up as a novel designer drug or adulterant in the United States and Europe. Some people taking bupropion have produced false-positive urine tests for amphetamine.

  Russia bans bupropion as a narcotic because it derives from methcathinone. In Australia, France and the UK, smoking cessation is the only licensed use, and no generics are marketed.

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