Chemically Correct: Bupropion by Andrew Novick

guy just chillinIndicated for the treatment of depression and smoking cessation, bupropion (better known as Wellbutrin and Zyban) is sometimes used “off-label” for ADHD, weight loss, and even sexual dysfunction. Needless to say, this neat little compound has a few interesting properties that make it relevant to those interested in performance and physique enhancement. So without further adieu, here’s the run down….


Bupropion’s chemical structure differs from all other antidepressants on the market. It belongs to the aminoketone class of compounds, sharing the category with the anorectic drug diethylpropion (Tenuate). The main difference between the two aminoketones is that diethylpropion has two ethyl groups connected to its nitrogen, where bupropion has a single butyl group (hence bupropion). Because bupropion and diethylpropion have a phenyl group attatched to the aminoketone part, they look an awful lot like phenylethylamines. Phenylethylamines, of course, are home to some of sciences’s more “fun” compounds: amphetamine, methamphetamine, and MDMA (Ecstacy). Bupropion’s 3D crystal structure even resembles cocaine, methylphendiate (Ritalin), and other drugs with stimulant properties (1). Although preparations of bupropion are racemic, both bupropion’s (+) and (-) enantiomers have demonstrated similar affinity for monoamine re-uptake sites (2).


There’s quite a bit of controversy surrounding bupropion’s mechanism of action. Its primary pharmacological action appears to be monoamine uptake inhibition, and while it produces stimulant effects in rats, the effects are not reliably re-produced in humans at clinical dosages (3). Bupropion’s effects are probably related to several receptor complexes, most notably dopaminergic, noradrenergic, serotonergic and nicotinic:


Bupropion has relatively weak yet selective affinity for the dopamine re-uptake pump (4). It’s much weaker than cocaine as an inhibitor of dopamine re-uptake (5), and even sertraline (which is considered a Selective Serotonin Re-uptake Inhibitor) has a stronger in vitro affinity for the dopamine transporter (4). Yet, despite bupropion’s lack of potency, meaningful dopaminergic activity appears to take place, as bupropion can effectively substitute in rats for a plethora of dopaminergic stimulants from cocaine to methamphetamine (6,7). In vivo, bupropion increases interstitial dopamine concentrations (8), can prevent dopamine depletion from the neurotoxic effects of 6-hydroxydopamine (9,10), and increases dopamine transporter mRNA expression (11).

Bupropion’s “dopamine controversy” comes into focus when we see that when given to humans at actual clinical dosages, bupropion fails to significantly occupy the dopamine transporter compared to placebo (12). Also, unlike other dopaminergic drugs, bupropion doesn’t affect prolactin and growth-hormone levels in humans at clinical dosages (13). Furthermore, if bupropion did have pronounced dopaminergic and stimulant qualities, it might be expected to appeal to stimulant abusers. However, at therapeutic dosages, experienced stimulant users have a hard time distinguishing bupropion from placebo (14). Yet at dosages slightly above the usual therapeutic level, bupropion does produce mild amphetamine and “liking” effects in test subjects (15).

Probably the best conclusion that can be drawn from this conflicting research is that because of bupropion’s weak affinity for the dopamine re-uptake pump, pronounced dopaminergic activity doesn’t kick in until the higher dosages.


Bupropion’s affinity for the noradrenaline re-uptake pump is approximately half that of it’s affinity for the dopamine pump (16). Despite being less potent at inhibiting noradrenaline re-uptake, most of bupropion’s “antidepressant” action is attributed to its noradrenergic mechanisms (17). How can this be? Bupropion’s active metabolite, hydroxybupropion has almost equal affinity for the NA re-uptake pump as bupropion yet its concentrations during clinical treatment reach 6-fold that of the parent drug (17). This increase in concentration would make up for the lack of affinity and thus cause meaningful inhibition of NA re-uptake, even at therapeutic dosages. Hydroxybupropion has been said to be more “antidepressant” and less “stimulant” due its noradrengeric mechanism with lack of dopaminergic action (18). But we’ll talk more about hydroxybupropion and other metabolites later.

Bupropion downregulates beta-adrenergic receptors (a trademark of most antidepressants with NA activity) and decreases NA stimulation of adenylate cyclase (19). It also reduces the firing rate of NA neurons, a phenomenon which can be reversed by the administration of adrenergic antagonists, such as yohimbine (16,20). There is also evidence that bupropion increases the release of NA from the synapse (20). The the addition of yohimbine to bupropion could poteniate its noradrengic effects. Yohimbine would probably be a good augmentation strategy for almost any antidepressant, yet is not widely used due to status as an older drug (a.k.a unmarketable).


Traditionally, bupropion was thought to have no action on serotonin, being that its affinity for the serotonin re-uptake pump is negligible (21). However, a more recent study has demonstrated that bupropion increased the firing rate of serotonergic neurons, possibly by an NA facilitated mechanism (20).

Also of interest might be the synergistic role that serotonin itself can play with other neurotransmitters and how this could apply to bupropion. Fluoxetine (better known as Prozac, a serotonin re-uptake inhibitor) can greatly potentiate bupropion’s extracellular increases of dopamine and serotonin (22). There is some evidence that fluoxetine itself can be used for weight loss (23), and a bupropion-fluoxetine combination would resemble the once popular noradrenergic-serotonergic combination “Phen-fen.”


Bupropion’s efficacy as an anti-smoking aid can be attributed to two reasons: 1) bupropion acts as a nicotine substitute (24,25) and 2) bupropion acts as a nicotinic antagonist (26). Besides sharing similar stimulant properties with nicotine, bupropion has modest selectivity for neuronal nicotinic receptors, particularly blocking activation of alpha(3)beta(2), alpha(4)beta(2) and alpha(7) neuronal acetylcholine nicotinic receptors, thus blunting the effects of nicotine. (26)

Pharmacokinetics (15)

When administered orally, peak concentrations of bupropion occur within 1-3 hours and 84% of it is bound to plasma protein. The half-life of bupropion is anywhere from 10-21 hours. It is metabolized in the liver to form three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. Hydroxybupropion is the most potent of the metabolites and has a half-life of 20-25 hours. As stated earlier, hydroxybupropion concentrations reach several times that of the parent drug. Elimination occurs mainly through the urine.

Safety and Side-Effects

Bupropion is remarkably free of side-effects, the most common being insomnia, nervousness, and tremors (27). An early study done on bupropion revealed a high seizure rate which caused the drug to be withdrawn shortly after it was approved by the FDA. However, this study focused mainly on bulimic patients, and after the development of the sustained release formula of bupropion along with updated dosing recommendations (daily dose should not exceed 400mg and any one dose should not exceed 200mg), the seizure rate with bupropion is no more than that of other antidepressants (28).

Effects on Weight

One of the initial studies done on bupropion demonstrated that 19% of patients receiving 400mg/day of bupropion lost 5lb or more, compared to 6% receiving placebo. (15) Other studies have confirmed bupropion’s robust effects on weight loss, though mainly in obsese people with and without depression (29-31). Bupropion’s weight loss effects are attributed to increased thermogenesis (32). Anorectic effects are not prevalent (15) unless higher dopamine activating dosages are used (33).


The original studied dosages of bupropion in humans for depression were 600-900mg per day (28). However, because an increased risk of seizures has been reported at dosages above 450mg per day, the current clinical doses are 200-450mg per day (15). Manufactured by GlaxoSmithKline, sustained released tablets of bupropion are available in 100mg, 150mg, and 200mg versions (15). The immediate release formula is supplied in 75mg and 100mg tablets (34). The manufacturer warns against taking single doses more than 200mg in order to minimize seizure risk (15). In most of the weight loss studies, dosages between 150mg and 450mg per day produced significant results (29-31).


Obviously, bupropion could have several potential uses for athletes and others interested in performance enhancement. The mood-brightening and anti-smoking effects are things that could always come in handy (especially for those on intense diets and/or using nicotine to aid weight loss). Its mild stimulant effects could be useful for increasing energy and focus, as well as providing an interesting adjunct to a weight loss regimen. As mentioned above, combining it with a serotonergic agent and/or yohimbine might make bupropion’s weight loss effects even more pronounced.


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