Shannon Williams is a Research Associate at Valisure

Does your bupropion medication reek of rotten eggs or vinegar?

Do you dread swallowing malodorous pills? Unfortunately, many medicines naturally produce odors that make treatment unpalatable. For example, there are some formulations of metformin tablets that do not sufficiently mask the naturally fishy scent of metformin molecules.1 The human nose contains receptors that are sensitive to molecules with nitrogen atoms attached to hydrogen atoms. Compounds like those, called amines, commonly emanate from rotting meats and decaying fish.2 Metformin contains several of these groups, and thus, smells like fish. Sometimes it’s less clear what causes a bottle of medication to smell.

Valisure began to investigate this issue focusing on the antidepressant bupropion, the generic form of Wellbutrin.  All stinky bupropion tablets Valisure received are formulated using cysteine as an inactive ingredient. Cysteine is an odorless amino acid common in proteins in all organisms. It’s a free-radical scavenging antioxidant3,4 and can be used in medication as a stabilizer.5 Free-radicals are charged atoms that can react with molecules. The interaction of free-radicals and medicine can potentially cause the active ingredient to degrade. Cysteine reacts with the free-radicals before they can react with the bupropion, increasing the medication’s shelf-life. Degradation of cysteine can produce hydrogen sulfide, ammonia, and acetaldehyde;6 all compounds which have foul aromas, two due to the presence of amine groups or sulfur. Hydrogen sulfide is particularly toxic at higher concentrations, but easily detected by the human nose at 0.01-1.5 parts per million (ppm),7 which is well below toxic levels. If opening your bupropion bottle makes you want to hold your nose, cysteine may be degrading, and there is a possibility that the medication could be compromised. The influence of degradation also explains why some refills of the same medication are fine while others are gag-worthy. At this time, questions about cysteine’s longevity, and its impact on the longevity of the bupropion molecules it is meant to preserve, require more research.

An alternate explanation for the unpleasant odor is that the cysteine derivatizes into N-acetylcysteine (NAC), a variant of cysteine that has many possible health benefits, but a naturally sulfurous smell. The NAC molecule contains both a sulfur-containing thiol group and a carboxyl group. A thiol group is composed of a sulfur atom attached to a hydrogen atom and is responsible for the smells of rotting eggs and skunk spray.8 Carboxyl groups are made of an oxygen double bonded to a carbon that is also bound to an oxygen and a hydrogen. Carboxyl groups give vinegar and body odor their sourness.9 Studies have suggested that the supplementation of antidepressant medications like escitalopram and imipramine with NAC makes treatment subtly more effective. However, NAC did not improve treatment with bupropion.10 Other studies suggest that NAC helps restore brain functions that are damaged by chronic depression11 or might make treatment-resistant depression more responsive.12,13

Valisure is continuing to investigate the causes of these odors in bupropion.

Meanwhile, there are several alternate bupropion medication manufacturers that do not use cysteine. You can ask your pharmacist for a list of the inactive ingredients in your medication the next time you refill your prescription. Our pharmacists are happy to help you find an alternate formulation and answer any questions you might have. Also, this website allows you to look up your current prescription’s inactive ingredients when you input its national drug code (NDC) in the search bar. The NDC consists of 11 digits and can be found on the medication label. You may need to ask your pharmacist for this information. In sum: trying to figure this out on your own really stinks but Valisure is here to help.

For more information on thiols, amines, and smell science:

General Smell Science

Sulfur and similar elements

Biochemistry of Smell and Molecule Structure

Thiols and Skunk Spray

Amines and Amides



  1. Pelletier AL, Butler AM, Gillies RA, May JR. Metformin stinks, literally. Ann Intern Med. 2010;152(4):267-268.
  2. John W. Hill TWM, Rill A. Reuter, Rill Ann Reuter, Marilyn D. Duerst. Nitrogen-Containing Compounds- Amines and Amides. In. Hill’s Chemistry for Changing Times. 15 ed. LibreText Pearson; 2020.
  3. Sekhar RV, Patel SG, Guthikonda AP, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011;94(3):847-853.
  4. Bourdon E, Loreau N, Lagrost L, Blache D. Differential effects of cysteine and methionine residues in the antioxidant activity of human serum albumin. Free Radic Res. 2005;39(1):15-20.
  5. Wells ML, Williams SO, Sanftleben RA, Balik SB, Evans BA. Investigation into the dissolution rate increase on storage of Wellbutrin SR 100 mg tablets. AAPS PharmSciTech. 2010;11(1):113-119.
  6. Shu CK, Hagedorn ML, Mookherjee BD, Ho CT. pH Effect on the volatile components in the thermal degradation of cysteine. Journal of Agricultural and Food Chemistry. 1985;33(3):442-446.
  7. Administration OSaH. Hydrogen Sulfide. In.
  8. Emsley J. Science: The seven deadly smells of a skunk. New Scientist. 1990(1728).
  9. John W. Hill TWM, Rill A. Reuter, Rill Ann Reuter, Marilyn D. Duerst. Carboxylic Acids and Esters. In. Hill’s Chemistry for Changing Times. 15 ed2020.
  10. Costa-Campos L, Herrmann AP, Pilz LK, Michels M, Noetzold G, Elisabetsky E. Interactive effects of N-acetylcysteine and antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:125-130.
  11. Chakraborty S, Tripathi SJ, Srikumar BN, Raju TR, Shankaranarayana Rao BS. N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes. Neurochem Int. 2020;132:104605.
  12. Berk M, Dean OM, Cotton SM, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2014;75(6):628-636.
  13. Yang C, Bosker FJ, Li J, Schoevers RA. N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial. BMC Psychiatry. 2018;18(1):279.

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