In the realm of medicine, an adverse effect refers to an unwanted and detrimental outcome resulting from medication, surgery, diet, or other interventions. The ketogenic diet has witnessed a substantial surge in popularity in recent years, with a plethora of scientifically supported benefits. However, it is crucial to acknowledge that, like any dietary regimen, the ketogenic diet is not universally suitable, and what may be beneficial for one individual may not be appropriate for another. Therefore, it becomes imperative to recognize and contemplate both the more prevalent adverse effects and the rarer, yet potentially serious, consequences associated with the ketogenic diet.

Adverse Effects of the Ketogenic Diet Terms and Abbreviations:

LDL – Low-Density Lipoprotein
HDL – High-Density Lipoprotein
KD – Ketogenic Diet
MAD – Modified Atkins Diet
MCT – Medium-Chain Triglycerides
MCTD – Medium-Chain Triglyceride Diet

Gastrointestinal Considerations

Gastrointestinal side effects are common, with as many as half to all patients reporting some degree of nausea, constipation, bloating, or vomiting at some point on ketogenic diet therapy.  However, these symptoms generally resolved after the first few days or weeks of treatment with the ketogenic diet  [1 , 2 , 3].  As indicated in these studies, it was rare that the patients were unable to continue with the ketogenic diet treatment due to intractable nausea, constipation, or vomiting.   However, patients involved in these studies did not continue with ketogenic diet treatment for longer than a 9- month period.  

Lipid Considerations

Lipids may increase on ketogenic diets and should be monitored.  A study by Sirven et al. [1] found a significant increase in total fasting cholesterol at 3 and at 6 months on diet, with an increase of the mean cholesterol from 208 mg/dL (range, 120–304) to 291 mg/dL (220–395).   Triglycerides also increased at 3 months from mean 190 mg/dL (41–542) to 203 mg/dL (68–417), and then plateaued [4 ].  The extension of this study continued to show a significant increase in total cholesterol and in the cholesterol/HDL ratio at the time of diet discontinuation after up to 35 months on diet [5].   If extreme lipid changes occur, it may warrant discontinuation of dietary therapy [6].  However, it should be noted that elevated lipids are not present in all patients or in all studies, and triglycerides and LDL may not change [7].

Lipids increase on the MAD as well [8], though end lipid levels in some studies remained within average cardiovascular risk ranges [9] . One study of the MAD actually found a decrease in triglycerides with ketogenic diet treatment over 12 months [10].

It is worth noting that lipids may increase during the initial phase of the diet, then return to baseline: one study of 37 adults on the MAD for at least 3 months found that while total cholesterol and LDL had increased at 3 months, there was no difference from baseline after 1 year (p = 0.2 and p = 0.5, respectively) [11]. 

Further, in the event of hypercholesterolemia, it may still be manageable without stopping dietary therapy.  One patient whose LDL doubled after 3 months continued the MAD, and with carnitine supplementation (and the substitution of saturated fats for polyunsaturated fats) saw his cholesterol and LDL return to normal [12].  Carnitine supplementation successfully decreased elevated triglycerides in three other patients as well [5]. 

Thus, carnitine supplementation may improve this particular adverse effect of the KD. 

Hormonal Considerations

Menstrual irregularities and cessation of menstruation are common in the starvation state.  Given that the ketogenic diet is designed to mimic starvation, it is not surprising that it can also cause menstrual irregularity.  Barborka et al reported in the 1930’s that 21% women had a cessation of their menses during ketogenic diet treatment; however, in the seven that stopped the diet, normal menstruation resumed [13].  In Sirven’s 1999 study, all nine women (100%) developed menstrual irregularities (irregular cycles or cessation of menses), which resolved on diet discontinuation [1].  Menstrual irregularities were also frequent in Mady et al.’s 2003 study of the ketogenic diet (45% of women) [14].   

However, menstrual irregularities seem to be much less common on a MAD, and no menstrual irregularities were found in any of the 19 women in one study [15],  none reported in nine women in a second study [10], and they only were present in 1 out of 17 women in a third stud [12].   Lambrechts found none in two women on the classic KD and two women on the MCTD [16].

Adverse effects of the Ketogenic Diet in Children

While these aforementioned adverse effects of the ketogenic diet are the most common in adults, other less common adverse effects of the ketogenic diet are known to exist in children, warranting further considerations for long-term adherence to a ketogenic diet for children and adults, alike.   In a 2011 study comparing the short-term (8 months) versus long-term ( >24 months), Kang HC et al. found that there was no significant difference in the including relapse tendency, correlated EEG findings, and developmental outcome data between the two groups studied for intractable infantile spasms. 

The study found that of the short-term 8-month group, 37.5% experienced nausea/vomiting, diarrhea/constipation, 50% experienced hypertriglyceridemia, 31% experienced hypercholesterolemia,  31% experienced hepatitis, 0% experienced osteopenia.   However, in the long-term 2-year group, 41% experienced nausea/vomiting, diarrhea/constipation, 33% experienced hypertriglyceridemia,  29%  experienced hypercholesterolemia,  25% experienced hepatitis, and 20% experienced osteopenia. 

Thus, serious complications such as osteopenia, hepatitis, ureteral stones, and growth failure significantly occurred only in the long-term trial group compared to the short-term group (p >0.05).  In effect, the utility of the ketogenic diet for 8 months may be well justified,  however, prolonged KD treatment may result in similar outcomes and seizure recurrence rate, but with more serious complications.  More research into the long-term effects of the ketogenic diet in children is necessary. 

Concluding Thoughts

While the Ketogenic Diet research has shown numerous positive effects of the ketogenic diet,  the potential adverse of effects also deserve attention and consideration from those who have opted for the popular diet both for the purposes of weight loss and metabolic improvements, as well as for treatment of neurological disorders. 

While all diets should be done under the supervision of a medical practitioner, the ketogenic diet may require more observation than other diets to ensure that these more serious adverse effects of the ketogenic diet are accounted for. 

Adverse Effects of the Ketogenic Diet References

Gastrointestinal References

1.  Sirven, J., Whedon, B., Caplan, D., Liporace, J., Glosser, D., O’Dwyer, J., & Sperling, M. R. (1999). The Ketogenic Diet for Intractable Epilepsy in Adults: Preliminary Results. Epilepsia, 40(12), 1721–1726. doi:10.1111/j.1528-1157.1999.tb01589.x

2.Coppola, G., D’Aniello, A., Messana, T., Di Pasquale, F., della Corte, R., Pascotto, A., & Verrotti, A. (2011). Low glycemic index diet in children and young adults with refractory epilepsy: First Italian experience. Seizure, 20(7), 526–528. doi:10.1016/j.seizure.2011.03.008

3. Klein, P., Janousek, J., Barber, A., & Weissberger, R. (2010). Ketogenic diet treatment in adults with refractory epilepsy. Epilepsy & Behavior, 19(4), 575–579. doi:10.1016/j.yebeh.2010.09.016

Lipid References

4. Sirven, J., Whedon, B., Caplan, D., Liporace, J., Glosser, D., O’Dwyer, J., & Sperling, M. R. (1999). The Ketogenic Diet for Intractable Epilepsy in Adults: Preliminary Results. Epilepsia, 40(12), 1721–1726. doi:10.1111/j.1528-1157.1999.tb01589.x

5.  Nei, M., Ngo, L., Sirven, J. I., & Sperling, M. R. (2014). Ketogenic diet in adolescents and adults with epilepsy. Seizure, 23(6), 439–442. doi:10.1016/j.seizure.2014.02.015

6.  Mosek, A., Natour, H., Neufeld, M. Y., Shiff, Y., & Vaisman, N. (2009). Ketogenic diet treatment in adults with refractory epilepsy: A prospective pilot study. Seizure, 18(1), 30–33. doi:10.1016/j.seizure.2008.06.001

7.  Klein, P., Janousek, J., Barber, A., & Weissberger, R. (2010). Ketogenic diet treatment in adults with refractory epilepsy. Epilepsy & Behavior, 19(4), 575–579. doi:10.1016/j.yebeh.2010.09.016

8.Carrette, E., Vonck, K., de Herdt, V., Dewaele, I., Raedt, R., Goossens, L., … Boon, P. (2008). A pilot trial with a modified Atkins’ diet in adult patients with refractory epilepsy. Clinical Neurology and Neurosurgery, 110(8), 797–803. doi:10.1016/j.clineuro.2008.05.003

9. Kossoff, E. H., Rowley, H., Sinha, S. R., & Vining, E. P. G. (2008). A Prospective Study of the Modified Atkins Diet for Intractable Epilepsy in Adults. Epilepsia, 49(2), 316–319. doi:10.1111/j.1528-1167.2007.01256.x

10. Smith, M., Politzer, N., MacGarvie, D., McAndrews, M., and del Campo, M. (2011). Efficacy and tolerability of the MAD in adults with pharmacoresistant epilepsy: a prospective observational study. Epilepsia 52, 775–780. doi:10.1111/j.1528-1167.2010.02941.x

11.Cervenka, M. C., Patton, K., Eloyan, A., Henry, B., & Kossoff, E. H. (2014). The impact of the modified Atkins diet on lipid profiles in adults with epilepsy. Nutritional Neuroscience, 19(3), 131–137. doi:10.1179/1476830514y.0000000162

12. Cervenka, M., Terao, N., Bosarge, J., Henry, B., Klees, A., Morrison, P., and Kossoff, E. (2012). Email management of the MAD for adults with epilepsy is feasible and effective. Epilepsia 53, 728–732. doi/full/10.1111/j.1528-1167.2012.03406.x

Hormone References

13. Barborka, C.J. (1930). Epilepsy in adults: results of treatment by ketogenic diet in one hundred cases. Arch Neurol Psych 23, 904–914. doi:10.1192/bjp.76.315.856-a

14. Mady, M.A., Kossoff, E.H., McGregor, A.L., Wheless, J.W., Pyzik, P.L., and Freeman, J.M. (2003). The ketogenic diet: adolescents can do it, too. Epilepsia 44, 847–851. doi: 10.1046/j.1528-1157.2003.57002.x

15.Kossoff, E. H., Krauss, G. L., McGrogan, J. R., & Freeman, J. M. (2003). Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology, 61(12), 1789–1791. doi:10.1212/01.wnl.0000098889.35155.72

16. Lambrechts, D. A. J. E., Wielders, L. H. P., Aldenkamp, A. P., Kessels, F. G. H., de Kinderen, R. J. A., & Majoie, M. J. M. (2012). The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: Efficacy and tolerability in clinical practice. Epilepsy & Behavior, 23(3), 310–314. doi:10.1016/j.yebeh.2012.01.002

Lesser-known adverse effects of the Ketogenic Diet References

17. Kang, H.-C., Lee, Y. J., Lee, J. S., Lee, E. J., Eom, S., You, S. J., & Kim, H. D. (2011). Comparison of short- versus long-term ketogenic diet for intractable infantile spasms. Epilepsia, 52(4), 781–787. doi:10.1111/j.1528-1167.2010.02940.x