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After 4 weeks, cigarette cravings decreased significantly, from a mean score of 4.35 to 2.33 as measured by the Questionnaire for Smoking Urges-Brief (QSU-B).
The study was funded in part by a grant from GlaxoSmithKline.
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Participants also attended 12 office visits across the 2 weeks preceding and 8 weeks following the quit date. At the 8-week visit, 7-day abstinence rates were confirmed with carbon monoxide testing.
The participants who received the bupropion were twice as likely to be abstinent as those receiving placebo. Of those who received no pharmacotherapy or counseling, only 18% achieved abstinence, compared with 20% of those who received counseling and a placebo, 31% of those who received bupropion but no counseling, and 35% of those who received both bupropion and counseling. Contrary to past studies, however, counseling was not associated with a significantly higher abstinence rate in either the active-medication or the placebo group.
“Although counseling appears to increase the odds of successful tobacco cessation when offered as a primary intervention, it does not consistently increase abstinence rates when offered in conjunction with pharmacotherapy,” Ms. McCarthy noted. Also, women were less likely to achieve abstinence in this study, and bupropion did not equalize quit rates across genders.
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The Evidence
Bupropion is an inhibitor of norepinephrine and dopamine reuptake (J. Clin. Psychopharmacol. 23[3]:233-39, 2003). Since drugs that increase dopaminergic activity often cause or exacerbate psychosis, it stands to reason that bupropion may be problematic for at-risk patients.
An early case report by Dr. Robert N. Golden and his colleagues of four patients described the development of acute psychosis in patients treated with bupropion (Am. J. Psychiatry 142[12]:1459-62, 1985). Three of the patients had previously experienced psychotic symptoms. The authors speculate that the mechanism of action responsible for that development might involve perturbations of dopamine systems and suggested that caution be exercised when using this medication with patients vulnerable to psychosis.
In Dr. Golden’s follow-up study, 11 patients were treated for depression with 300-500 mg/day bupropion. Of the four nonresponders, three became psychotic. Those three patients had elevated homovanillic acid levels consistent with those seen in schizophrenia (Arch. Gen. Psychiatry 45[2]:139-43, 1988).
More recent case reports have reported similar findings in nonschizophrenic/schizoaffective disordered patients. For example, in one case report, a 29-year-old man with no previous psychiatric history experienced positive psychotic symptoms after treatment with 300 mg/day bupropion (prescribed for nicotine addiction). Substance abuse was ruled out as causative (Pharmacopsychiatry 35[6]:247-48, 2002).
In another report, a 79-year-old man with no history of psychiatric disorders or substance abuse was treated with 300 mg/day bupropion for depression. Within 1 week, he also began experiencing positive psychotic symptoms. He ultimately did well with 25 mg t.i.d. bupropion, suggesting that such toxicity might be dose related (Am.J. Psychiatry 156[12]:2017-18, 1999).
In an open study, 20 patients diagnosed with schizoaffective disorder, depressed type were randomly assigned to receive treatment with bupropion or bupropion plus haloperidol (Haldol). Most of the patients received 750 mg/day bupropion (a far higher dosage than that currently used). The authors found that of the nine patients treated with bupropion monotherapy, three experienced exacerbation of psychotic symptoms. The authors concluded that treating schizoaffective disordered patients with bupropion alone carries significant risk of exacerbating psychosis (J. Clin. Psychiatry 44[7]:253-55, 1983).
In a more recent open study, eight patients with a mean age of 29 years who had been diagnosed with schizophrenia were examined for the effects of bupropion and supportive group therapy on cigarette consumption. Bupropion was prescribed at a dosage of 300 mg/day. Clinical assessments included the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS).
Between baseline and study completion at week 14, no significant changes were seen in BPRS scores. Bupropion treatment was associated with an 18% drop in the SANS score, but the difference was not significant. But a significant decrease was seen in the SANS alogia factor score (Am. J. Psychiatry 158[4]:635-7, 2001).
Finally, Dr. Tony P. George and his colleagues performed a randomized, double-blind, placebo-controlled study on 32 patients diagnosed with schizophrenia or schizoaffective disorder. Inclusion criteria included stability of psychotic and affective symptomatology. Subjects received either placebo or 300 mg/day bupropion combined with either typical or atypical antipsychotics. Subjects had been treated with an antipsychotic for at least 6 months before study entry. Positive and negative symptoms were rated with the Positive and Negative Syndrome Scale. The authors concluded, in part, that “there were no effects of bupropion versus placebo on positive symptoms of schizophrenia … but there was a reduction in negative symptoms by bupropion during the trial” (Biol. Psychiatry 52[1]:53-61, 2002).
The Conclusion
Available evidence suggests that bupropion does pose a risk in a dose-related manner of creating or exacerbating psychosis in a fashion consistent with inferences from its mechanism of action. At particular risk are those who suffer with a primary psychotic disorder. Evidence also suggests that vulnerable patients may have this risk of exacerbating psychosis reduced if they are first stabilized on antipsychotics. But given the small sample sizes in the studies cited above, the side effects may have been underestimated.

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Dr. Horrigan, of GlaxoSmithKline, reported the results of the company’s multicenter randomized placebo-controlled trial of extended-release bupropion in 162 ADHD patients aged 18-60 years. The active group contained 81 patients and the placebo group contained 81 patients.
All patients began with a 150-mg dose given once daily in the morning. In weeks 2-4, patients received 300 mg each morning. In weeks 5-8, the dosage could be increased to 450 mg/day if there was less than a 30% improvement on the ADHD Rating Scale, or if the Clinical Global Impression-Improvement Scale score was greater than two, and if the patient was tolerating 300 mg/day. Dosages could be reduced to a 300 mg/day minimum if adverse events occurred.
By the end of the study, 70.4% of the patients in the active group were taking 450 mg/day, 28.4% were taking 300 mg/day, and 1.2% (only one patient) was taking 150 mg/day. The mean final dose of bupropion XL was 393 mg/day.
By week 5, 55% of patients taking the study drug had experienced at least a 30% reduction on both the inattentive and hyperactivity-impulsivity domains of the ADHD Rating Scale. The study indicated that patients experienced relief from symptoms compared with placebo. Previous studies have shown that serum levels of bupropion XL increase soon after an 8 a.m. dosing, rising to a peak level of 120 ng/mL from noon to 2 p.m., and slowly falling to around 60 ng/mL by 8 p.m. and 20 ng/mL by 8 a.m. the next day.
The most commonly reported adverse events were headache (17% bupropion vs. 14% placebo) and dry mouth (12% bupropion vs. 5% placebo), compared with 5% placebo. Other adverse events reported were nausea, nasopharyngitis, dizziness, constipation, somnolence, fatigue, irritability, and tinnitus. Most adverse events occurred in the first 2 weeks. Bupropion and placebo had equal effects on blood pressure and heart rate.
BY MICHELE G. SULLIVAN
Mid-Atlantic Bureau
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The patients in Jorenby et al’s study received intensive counselling, which comprised more than three hours of face to face counselling and 80 minutes of telephone support over the 12 months. It is not realistic for the NHS to provide this level of support. The manufacturers are offering a telephone line for patients to ring for support, but this is not likely to be as effective in motivating and supporting patients. The high success rates reported by Jorenby et al are therefore unlikely to be repeated in day to day practice.
Britton and Jarvis could have pointed out that half of patients who successfully stop smoking with the aid of bupropion will start again within 12 months of coming off the drug. They could also have referred in more detail to the side effect profile and the number of patients for whom the drug will be unsuitable. Bupropion may have a 1 in 1000 risk of inducing seizures (product information from GlaxoWellcome, the manufacturer of the drug). This may be an acceptable risk for drugs to treat disease but is less so for lifestyle drugs.
Bupropion may well prove to be a useful adjunct to smoking cessation, but I would have preferred a more balanced appraisal in a BMJ editorial.
Christopher Harrison general practitioner Barlow Medical Centre, Manchester M20 6TR charrison@doctors.org.uk
Competing interests: None declared.
[1] Britton J, Jarvis MJ. Bupropion: a new treatment for smokers BMJ 2000;321:65-6. (8 July.)
[2] Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-91.
Drug is almost identical in structure to diethylpropion, a controlled drug
EDITOR–Britton and Jarvis’s editorial on bupropion does not mention that the drug is an amphetamine derivative.[1] It is almost identical in structure to diethylpropion hydrochloride, which is a controlled (schedule 3) drug because of its supposed potential for misuse. Bupropion has been released in the United Kingdom on the strength of only two American clinical trials financed by the manufacturer. Many patients to whom it will be given will have addictive personalities. Shouldn’t the Medicines Control Agency rethink its decision?
When I asked the agency to explain the discrepancy regarding the classifications of the two drugs I was referred to the Home Office, whose advisers said that because bupropion is not a stimulant it need not be classified like diethylpropion. As the drugs are so similar in structure it would be surprising if one was a stimulant and one not. Certainly, dose related stimulation of the central nervous system occurs with bupropion in animals.[2] Both drugs come in a crushable tablet form, which facilitates parenteral misuse.
Drugs do not have to be stimulants for people to become dependent on them (for example, ethanol and diazepam), and not all stimulants give rise to dependency (only a few people say that caffeine withdrawal is a serious problem). And not all sympathomimetic drugs are stimulants (the appetite suppressant phenylpropanolamine, a sister sympathomimetic to bupropion and diethylpropion, is sold over the counter in the United States).
If bupropion is not a stimulant why does GlaxoWellcome’s product monograph list insomnia as its commonest side effect (occurring in just under half of patients)? And if it has none of the anorexigenic properties of the amphetamines why was the 11th congress on tobacco or health in Chicago on 6-11 August 2000 told that smokers taking bupropion gain less weight than those taking placebo (this information was also contained in the two clinical trials)?
A mass of evidence indicates that diethylpropion is safe and efficacious,[3] yet the Medicines Control Agency has made no objections to the European Commission’s current attempts to delicense it. Bupropion is being foisted on an unsuspecting British public with little evidence that it works much better than placebo.[4] The recommended dose of bupropion is much greater than that of diethylpropion. I suspect that a politically correct antismoking drug, however poorly researched and ineffective, will always be given the benefit of the doubt compared with a politically incorrect slimming drug, however safe and effective.
Herbert G Kinnell medical adviser Berkshire Diet Centre, Reading, Berkshire RG1 1SN
Competing interests: None declared.
[1] Britton J, Jarvis MJ. Bupropion: a new treatment for smokers BMJ 2000;321:65-6. (8 July.)

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We looked at popular culture first by doing Google searches for “Wellbutrin snort” and “snorting Wellbutrin.” Some Web sites describe the effects of snorting bupropion (www.erowid.org/experiences/exp.php?ID=9266) and some give advice on extracting bupropion from Wellbutrin SR tablets for the purpose of insufflation (http://bupropion.home.comcast.net). Wondering what has been published on this topic in the medical literature, we first searched the Cochrane Database of Systematic Reviews (www.cochrane.org/reviews) without result. We then searched Medline, combining “bupropion” and “abuse or misuse.”
The Evidence
Bupropion’s amphetaminelike abuse potential was suggested in preclinical trials in which animals substituted bupropion for amphetamine in a drug-discrimination task, and in another study in which it was self-administered intravenously by monkeys.
We were able to find two case reports (N. Engl. J. Med. 2002;347:951;J. Child Adol. Psychopharm. 2004;14:157-8) that described adolescents who insufflated bupropion in an attempt to obtain an amphetaminelike effect. One 16-year-old boy insufflated 600 mg of sustained-release bupropion and experienced a seizure. A 15-year-old girl snorted an unspecified amount of sustained-release bupropion and reported a marijuanalike buzz that only lasted a few seconds.
In a double-blind crossover study conducted to determine the amphetaminelike abuse potential of bupropion, 13 male subjects (aged 22-31 years) with “substantial” histories of psychostimulant abuse were randomized to receive, at intervals of at least 3 days, bupropion (100 mg, 200 mg, and 400 mg); d-amphetamine (15 mg and 30 mg); and placebo (J. Clin. Psychiatry 1983;44:206-8).
Drugs were administered at 8:00 a.m., with physiologic measures taken a half hour before administration and then hourly post dose. Bupropion had no measurable effect (relative to placebo) on blood pressure, pulse rate, respiratory rate, temperature, pupil size, appetite, caloric intake, or sleep. On self-rating scales, bupropion was perceived as an active drug only as often as placebo. The investigators concluded, “It is unlikely that bupropion will give rise to [amphetaminelike] patterns of abuse among normals or among those predisposed to psychostimulant abuse.” (The study came from the Baylor College of Medicine, the Houston Veterans Administration Medical Center, and the Burroughs Wellcome Research Laboratories.)
A double-blind, placebo-controlled, crossover study conducted at the Medical University of Innsbruck (Austria) examined the abuse liability of bupropion using caffeine as a positive control (Pharmacology 2004;70:206-15).
In all, 60 male smokers, aged 18-65 years, were enrolled; 50 completed the trial. The subjects were given two doses, 6 hours apart, of placebo, caffeine (178 mg), or bupropion slow-release (Zyban, 150 mg). They completed standardized telephone questionnaires at hourly intervals. Of the 50 subjects, 50% were able to report “any effect” to caffeine or bupropion. In those who reported “any effect” to caffeine, bupropion was reported as having essentially no effect. Subjects who reported effects from bupropion reported “much more intense effects” after bupropion than caffeine. The authors concluded that bupropion might be of some abuse liability.
The authors of this study cited another study, not picked up by our search, which was in part sponsored by a pharmaceutical company. That study compared bupropion with dexamphetamine and showed essentially no abuse liability of bupropion (Br. J. Clin. Pharmacol. 1979;7:469-78).
Investigators at the University of Chicago conducted a double-blind, placebo-controlled crossover study examining the effects of d-amphetamine and bupropion on cigarette smoking (Psychopharmacology 2001;157:243-53). In this study, 17 subjects, aged 19-54 years, received d-amphetamine (10 mg and 20 mg); bupropion (150 mg and 300 mg); and placebo. Subjective, physiologic, and behavioral effects were monitored, and amphetamine and bupropion increased self-reports of arousal, mood, and euphoria.
The Conclusion
The two university sponsored studies found an abuse liability of bupropion, and the two studies that were partly sponsored by pharmaceutical companies found no abuse liability. Our experience suggests that ingenious and determined patients have found ways, overlooked by published studies, to bypass bupropion’s first-pass metabolism and achieve highs similar to amphetamine.

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During the 7-week treatment phase, conducted Sept. 1, 1998, to March 31, 2001, subjects on bupropion had non-significant increased quit rates, compared with subjects on placebo (64% vs. 57%, respectively). Bupropion users continued to have the edge over placebo users at 3 months of follow-up (57% vs. 47%), although the difference also failed to reach statistical significance (Arch. Intern. Med. 164[16]:1797-803, 2004).
But at 6 and 12 months of follow-up, self-reported quit rates were nearly identical in both groups (about 40% at 6 months vs. about 32% at 12 months).
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The 300 patients who were randomized to treatment with bupropion SR had a cessation rate of 36% at the end of treatment (week 7), which was significantly higher than the 19% rate in the 300 patients in the placebo group. Patients who were lost to follow-up were assumed to be smokers (JAMA 288[4]:468-74, 2002).
The patients in the bupropion SR group were significantly more likely to be continuously abstinent at weeks 1, 3, 6, and 26 than were those on placebo. The abstinence rate at 26 weeks was 21% with bupropion SR and 14% with placebo. Previous studies of bupropion SR in mostly white, middle-class individuals have found abstinence rates of 27%-35%. After adjustment for age differences, bupropion SR was associated with a 19% increase in the odds of quitting, compared with placebo.
Besides African Americans, “smoking cessation treatments that address the cultural needs and perspectives of Asian, Hispanic, Native American, and Pacific Islander populations are likely to be more effective than treatments that do not address cultural issues,” Dr. Neal L. Benowitz of the University of California, San Francisco, said in an editorial (JAMA 288[4]:49799, 2002).
The patients who received bupropion SR had significantly lower average weight over time than the patients who received placebo, but the patients who were continuously abstinent for 6 weeks had a significantly higher average weight over time than those who were not continuously abstinent for 6 weeks. A relationship between continuous abstinence and weight gain was independent of the use of the drug.
Dr. Ahluwalia and Dr. Benowitz have served as consultants to GlaxoSmithKline, Research Triangle Park, N.C., the manufacturer of bupropion SR.
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While all patients had depressive symptoms–defined as a score of 10-30 on the Beck Depression Inventory–the study focused on 92 patients reporting a past history of major depression. Of these patients, 50 were in the bupropion SR group and 42 were in the placebo group. Of those in the bupropion group, 52% lost at least 5% of their body weight during the 26-week study, compared with 15% of the placebo group. “The changes in weight were significant for the overall population as well.”
But bupropion was effective in reducing depression symptoms only in patients with a history of major depression. Among the 92 patients with major depression, 52% of those taking bupropion SR achieved a depression index score reduction of 50%, compared with 28% of those taking a placebo. In contrast, scores for the overall study population did not change significantly.
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Doug Herman, Vice-President and General Manager of BPC, said that Wellbutrin(R) XL is an effective first-line treatment for depression with a low incidence of side effects of greatest concern to patients.
“The favorable side-effect profile of Wellbutrin(R) XL is due to its unique dual-mode of action on norepinephrine and dopamine,” Mr. Herman said. “As the only first-line anti-depressant that does not affect serotonin, Wellbutrin(R) XL has a low risk of sexual dysfunction, weight gain and somnolence.”
Wellbutrin(R) XL is efficacious in the treatment of depression in adults, and is among the agents recommended for the first-line treatment of major depressive disorder. As a result of the unique dual-mode of action of bupropion (norepinephrine and dopamine), Wellbutrin(R) XL is typically not associated with those adverse effects common to agents that affect serotonin, such as sexual dysfunction, weight gain and somnolence.
Since it was launched in the United States in September 2003 by Biovail’s marketing partner GlaxoSmithKline, Wellbutrin(R) XL has captured 7.4% of the anti-depressant market in the United States. For the month ended February 28, 2006, Wellbutrin(R) XL captured 57.9% of new prescriptions written for the Wellbutrin(R) brand, including generics.
Canadian Depression Market
Wellbutrin(R) XL will participate in the C$770-million depression market in Canada. For the 12-month period ended December 31, 2005, bupropion SR prescriptions grew at more than twice the rate of the overall market.
About Depression
Depression affects an estimated 5%, or 1.45 million Canadians at any given time. A recent study conducted by Health Canada suggests that depression and distress cost Canadians at least $14.4 billion per year in treatment, medication, lost productivity and premature death. Depression is the second-leading cause of long-term disability among workers.
About Wellbutrin(R) XL
Wellbutrin(R) XL is the first and only once-daily norepinephrine dopamine reuptake inhibitor for the treatment of depression in adults. The active ingredient in Wellbutrin(R) XL, bupropion, acts upon norepinephrine and dopamine, two chemicals in the brain believed to help regulate different aspects of mood, cognition, and behavior. Imbalances in these brain chemicals may be associated with depressed mood and other symptoms of depression. Bupropion has no clinically significant impact on serotonin.
Wellbutrin(R), Wellbutrin(R) SR, and Wellbutrin(R) XL are trademarks of The GlaxoSmithKline Group of Companies, and are used by Biovail under license.
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To the extent any statements made in this press release contain information that is not historical, these statements are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and within the meaning of the “safe harbor” provisions of applicable Canadian securities legislation. These forward-looking statements relate to, among other things, our objectives, goals, strategies, intentions, plans estimates and outlook, and can generally be identified by the use of words such as “believe”, “anticipate”, “expect”, “intend”, “plan”, “will”, “may” and other similar expressions. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements.
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