Indicated 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)
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.
References:1.Froimowitz M, George C. Conformational analysis and a crystal structure of bupropion, an antidepressant with dopamine reuptake blocking activity. J Chem Inf Comput Sci. 1998 May-Jun;38(3):506-10. 2. Musso DL, Mehta NB, Soroko FE, Ferris RM, Hollingsworth EB, Kenney BT. Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion.
Chirality. 1993;5(7):495-500. 3. Terry P, Katz JL. Dopaminergic mediation of the discriminative
stimulus effects of bupropion in rats. Psychopharmacology (Berl) 1997 Nov; 134(2):201-12 4. Richelson, E., 1994. Pharmacology of antidepressants – characteristics of the ideal drug. Mayo Clin. Proc. 69, pp. 1069–1081 5. Izenwasser S, Terry P, Heller B, Witkin JM, Katz JL (1994) Differential relationships among dopamine transporter affinities and stimulant potencies of various uptake inhibitors. Eur J Pharmacol 263:277-283 6. Broadbent J, Michael EK, Riddle EE, Apple JB. Involvement of opamine uptake in the discriminative stimulus effects of cocaine. Behav Pharmacol. 1991 Jun;2(3):187-191 7. Munzar P, Goldberg SR. Dopaminergic involvement in the discriminative-stimuluseffects of methamphetamine in rats. Psychopharmacology (Berl.) 2000 Feb;148(2):209-16 8. Nomikos , G.G., Damsma, G., Wenkstern, D. and Fibiger, H.C., 1992. Effects of chronic bupropion on interstitial concentrations of dopamine in rat nucleus accumbens and striatum. Neuropsychopharmacology 7, pp. 7–14 9.Canning H, Goff D, Leach MJ, Miller AA, Tateson JE, Wheatley PL (1979) The involvement of dopamine in the central actions of bupropion, a new antidepressant. Br J Pharmacol 66:104P 10. Cooper , B.R., Hester, T.J. and Maxwell, R.A., 1990. Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo. J. Pharmacol. Exp. Ther. 215, pp. 127–134 11. Petrie EC, Veith RC, Szot P. Bupropion and desipramine increase dopamine transporter mRNA expression in the ventral tegmental area/substantia nigra of rat brain. Prog Neuropsychopharmacol Biol Pscychiatry. 1998 Jul;22(5):845-56 12. Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S. Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl.). 2002 Aug;163(1):102-5. 13. Whiteman PD, Peck AW, Fowle ASE, Smith P (1982) Bupropion failsto affect plasma prolactin and growth-hormone in normal subjects. Br J Clin Pharmacol 13:743-745 14. Miller L, Griffith J (1983) A comparison of bupropion, dextroamphetamine, and placebo in mixed-substance abusers. Psychopharmacology 80:199-205. 15. GlaxoSmithKline. Prescribing Information: Wellbutrin SR. October 2002. 16. Ferris, R.M. and Cooper, B.R., 1993. Mechanism of antidepressant activity of bupropion. J. Clin. Psychiatry Monograph. 11, pp. 2-14 17. Ascher , J.A., Cole, J.O., Colin, J.-N., Feighner, J.P., Ferris, R.M., Fibiger, H.C., Golden, R.N., Martin, P., Potter, W.Z., Richelson, E. and Sulser, F., 1995. Bupropion: A review of its mechanism of antidepressant activity. J. Clin. Psychiatry 56, pp. 395–401 18. Martin P, Massol J, Colin JN, Lacomblez L, Puech AJ. Antidepressant profile of burpopion and three metabolites in mice. Pharmacopsychiatry 1990 Jul; 23(4):187-94 19. Gandolfini O, Barbaccia ML, Chuang DM, Costa F. Daily bupropion injections for 3 weeks attenuate the NE stimulation of adenylate cyclase and the number of beta-adrenergic recognition sites in the rat frontal cortex. Neuropharmacology. 1983 Jul;22(7):927-9 20. Dong J, Blier P. Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment. Psychopharmacology (Berl). 2001 Apr; 155(1)52-7. 21. Horst WD, Preskorn SH. Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J. Affective Disorders. 1998 Dec; 51(3)237-54. 22. Li SX, Perry KW, Wong DT. Influence of fluoxetine on the ability of bupropion to modulate extracellular dopamine and norepinephrine concentrations in three mesocorticolimbic areas of rats. Neuropharmacology. 2002 Feb; 42(2):181-90 23. Yen TT, Fuller RW. Preclinical pharmacology of fluoxetine, a serotonergic drug for weight loss. Am J Clin Nutr 1992;55:177S-180S. 24. Young R, Glennon RA. Nicotine and bupropion share a similar discriminatie stimulus effect. Eur J Pharmacol. 2002 May 17;443(1-3):113-8. 25. Wiley JL, Lavecchia KL, Martin BR, Damaj MI. Nicotine-like discriminative stimulus effects of bupropion in rats. Exp Clin Psychopharmacol. 2002 May;10(2):129-35. 26. Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 2000 Oct;295(1)321-7. 27. Preskorn, SH. The Relative Adverse Effect Profile of Non-SSRI Antidepressants: Relationship to In Vitro Pharmacology. Journal of Psychiatric Practice. July 2000. 218-223. 28. Preskorn, SH. Bupropion: What Mechanism of Action? Journal of Practical Psychiatry and Behavioral Health. January 2000. 272-276. 29. Jain AK, Kaplan RA, Gadde KM, Wadden TA, Allison DB, Brewer ER, Leadbetter RA, Richard N, Haight B, Jamerson BD, Buaron KS, MetzA. Bupropion SR vs. placebo forweight loss in obsese patients with despressive symptoms. Obes Res. 2002 Oct;10(10):1049-56. 30. Anderson JW, Greenway FL, Fujioka K, GaddeKM, McKenney J, O’Neil PM. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res. 2002 Jul;10(7):633-41. 31. Croft H, Houser TL, Jamerson BD, Leadbetter R, Bolden-Watson C, Donahue R, Metz A. Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks. Clin Ther. 2002 Apr;24(4):662-72. 32. Liu Y, Connoley I, Harrison J, Heal D, Stock M. Comparison of the thermogenic and hypophagic effects of sibutramin’s metabolite 2 and other monoamine reuptake inhibitors. Eur J Pharmacol. 2002 Sep 27;452(1):49. 33. Zarrindast MR, Hosseini-Nia T. Anorectic and beahavioural effects of bupropion. Gen Pharmacol. 1988;19(2):201-4. 34. GlaxoSmithKline. Prescribing Information: Wellbutrin tablets. October 2002.