Introduction
Science is a process for developing and refining our understanding of nature over time. The work of a community of scientists, often with vigorous competition and conflict between individuals, gradually improves the accuracy of our understanding. Perfect comprehension of something as complex as the health of living organisms seems unachievable, but little by little we get better at knowing how nature works and how we can influence natural phenomena. This progress often involves realizing that some aspects of our current understanding are actually wrong, and that our strategies for manipulating nature based on this flawed knowledge may turn out not to be effective.
In medicine, this process creates a kind of life cycle for medical interventions. The popular conception of this life cycle is the story of effective treatments. An insight or accident leads to a hypothesis, which is tested at various levels from in vitro to animal model to clinical use, and ultimately we validate the hypothesis and conquer the original problem.
Unfortunately, this is the exception rather than the rule. Far more often, the life cycle of medical therapies involves an insight or accident leading to a hypothesis which early, flawed evidence appears to support but which ultimately turns out to be wrong. This is a well-established phenomenon of the clinical trial literature, often called the Decline Effect or the Proteus Effect.1-2
Treatments based on such hypotheses are eventually abandoned in most cases, though some prove quite tenacious. Anecdote and personal experience frequently lend ineffective interventions a prolonged post-mortem existence, therapeutic zombies that stagger on long after the scientific evidence should have put them to rest. A great example of the life-cycle of an ineffective treatment is the use of L-lysine for the prevention and management of feline herpesvirus (FHV-1).
Herpesvirus & Lysine: The Scientific Evidence
Early in vitro work on human herpesvirus (HHV-1) suggesting lysine might inhibit replication and could potentially have clinical utility first appeared in the mid 1960s.3 This was followed by the first clinical studies of lysine for HHV-1 about ten years later.4 By the 1980s, the literature on lysine and HHV was glowing, and it seemed a safe and effective therapy had been found.5
Veterinary medicine caught the coattails of this process in the 1990s, with the first published in vitro study of lysine for FHV-1 appearing in 1995.6 Clinical studies followed in the early 2000s, and lysine quickly became a widely available supplement used for FHV-1 management.7
However, the scientific process rolled on, and despite the enthusiasm of clinicians and researchers, cracks in the lysine narrative soon appeared. Limitations and potential sources of bias in the early literature were addressed in subsequent studies, and the apparent benefits melted away. The most recent reviews in human medicine have concluded that there is no reliable evidence to support the use of lysine for herpesvirus management, and it is not included in current treatment guidelines.8-10 Lysine supplements are still available and marketed for this use, of course, because patients and some clinicians cling to their belief in the efficacy of this treatment despite the evidence, based predominantly on anecdotal experience. That patients do this is understandable, but it is always disappointing to see clinicians choose anecdote over science when they have the training to know better.
The story has played out in a similar way in veterinary medicine, with the usual time lag. The initial theoretical rationale for use of lysine, for example, has not held up to subsequent study. According to the theory, lysine should antagonize arginine and reduce the level of this amino acid. This, in turn, should inhibit FHV-1 replication and reduce clinical symptoms and viral shedding. However, research in cats has failed to validate any of the steps in this chain of reasoning. Oral lysine does not appear to antagonize or reduce intracellular levels of arginine, and it does not seem to inhibit FHV-1 replication under normal physiologic conditions.7
A similar fate has befallen the initial claims for clinical effects of lysine Early studies, with small numbers of patients and methodological limitations, produced some positive results which could not be reproduced in larger, better-controlled research.7
The most recent comprehensive reviews of the evidence for lysine in FHV-1 patients are not encouraging.7,11 The more optimistic of the two states that “there is considerable variability” it the research results and that while “data from these studies suggest that lysine is safe when orally administered to cats and, provided that it is administered as a bolus, may reduce viral shedding in latently infected cats…the stress of bolus administration in shelter situations may well negate its effects and data do not support dietary supplementation.”11
A comprehensive systematic review of the subject by Bol and Bannik (2015) is considerably more blunt, systematically rejecting every aspect of the rationale for lysine use:
There is no evidence for lysine-arginine antagonism in the cat.
Lysine supplementation does not have an inhibitory effect on FHV-1 replication in the cat.
The claim that lysine supplementation is effective for the prevention or treatment of herpetic lesions in humans cannot be supported by scientific evidence.
Lysine supplementation is not effective to prevent cats from becoming infected with
FHV-1, it does not decrease the chance of developing clinical signs related to active FHV-1 infection, and it does not have a positive effect on the clinical course of its disease manifestations.
Based on the complete lack of scientific evidence for the efficacy of lysine supplementation, we recommend an immediate stop of lysine supplementation for cats.
The accumulation of evidence against the use of lysine for FHV-1 cases has had an impact. Some shelter medicine specialists, for example, now recommend against this practice.12-13 However, there has also been resistance to abandoning this treatment despite the evidence. Unfortunately, such resistance has not been based so much on any substantive dispute about the science but instead on the seductive power of anecdotal evidence.
When the review by Bol and Bannik (2015) was reported in Veterinary Practice News, for example, objections from some respected veterinarians explicitly cited anecdotal experience as a reason for continuing the use of lysine:14
Anecdotal evidence should not be discarded…I have clients who tell me that every time they take the cat off lysine the problem returns…Maybe it’s just as well to leave those cats on lysine if the clients genuinely feel that it’s making a difference.
[Lysine] is used frequently by many of my clients at the recommendation of Dr. Google…Some cats have a very convincing response in spite of what the science says…Its use should be based on response, whether scientific or not.
Science is, by nature, a competitive community process. Disagreement between individuals is healthy and an integral part of this process, spurring replication of research that helps compensate for the inevitable blind spots and biases we all suffer from. However, the explicit preference for anecdote over controlled research evidence is counterproductive and lends itself to the retention of treatments that do not truly help our patients and which deserve to be abandoned.
There is some limited evidence suggesting lysine could actually exacerbate FHV-1 symptoms, which would certainly make abandoning it the right choice.7 Even if it is completely harmless, however, wasting resources on treatment that has been through the scientific vetting process over 50 years and has still failed to show convincing evidence of benefits is not justified.
As I argued last month, evidence-based medicine is a necessary pillar of effective and ethical clinical practice. This means we must be willing to acknowledge our limitations and set aside anecdotal evidence, even our own, when appropriate research evidence indicates we are mistaken.
References
- Lehrer J. The truth wears off: Is there something wrong with the scientific method. The New Yorker. 2010. pp. 52-7.
- Alahdab F. Farah W. Almasri J. et al. Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study. Mayo Clin Proc. 2017. Epub before print. Available at: http://www.mayoclinicproceedings.org/article/S0025-6196(17)30836-4/pdf Accessed February 21, 2018.
- Tankersley Jr RW. Amino acid requirements of herpes simplex virus in human cells. J Bacteriol. 1964;87:609–13.
- Griffith RS, Norins AL, Kagan C. A multicentered study of lysine therapy in Herpes simplex infection. Dermatologica. 1978;156(5):257–67.
- Griffith RS. Walsh DE. Myrmen KH. Et al. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica.1987;175(4):183-90.
- Collins BK. Nasisse MP. Moore CP. In vitro efficacy of L-lysine against feline herpesvirus type-1. Proc 26th Ann Meeting Amer Col Vet Opthalmologists. Newport, RI. 1995;141.
- Bol S. Bunnik EM. Lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats: a systematic review. BMC Vet Res. 2015:11:284.
- Chi CC. Wang SH. Delamere FM. et al. Interventions for prevention of herpes simplex labialis (cold sores on the lips). Cochrane Database of Systematic Reviews.2015;8. Art. No.: CD010095.
- Mailoo VJ. Rampes. S. Lysine for herpes simplex prophylaxis. Integrative Medicine. 2017;16(3):42-46.
- WHO Guidelines for the Treatment of Genital Herpes Simplex Virus. Geneva: World Health Organization; 2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK396232/
- Thomasy SM, Maggs DJ. A review of antiviral drugs and other compounds with activity against feline herpesvirus-1. Vet Opthalmology. 2016;19(Suppl 1):119-130.
- UC Davis Koret Shelter Medicine Program. Feline upper respiratory infection aka URI. 2015. Available at: https://www.sheltermedicine.com/library/resources/?utf8=%E2%9C%93&search%5Bslug%5D=feline-upper-respiratory-infection-aka-uri Accessed February 21, 2018.
- Slater M. Interpreting research (and making it work for you): Is lysine a good investment for shelters wanting to prevent URI in cats? Available at: https://www.aspcapro.org/blog/2017/05/03/interpreting-research-and-making-it-work-you-lysine-good-investment-shelters-wanting Access February 21, 2018.
- Niedziela K. Researchers question lysine use in FHV cases. Vet Pract News. 2016;28(1):36-7.
Word about this doesn’t seem to have trickled down to very many vets in practice (as with glucosamine). I was giving l-lysine to my cat faithfully for a couple years after he developed an eye ulcer, but since I read a previous article you wrote about it, I gave it up. Thanks for being so diligent in analyzing the facts for us readers about so many supplements!
What about lactoferrin? Lysine and lactoferrin have often been given togethor for feline herpes. A search of your site seems to indicate you have never looked into lactoferrin, a quick google shows there have been some studies, maybe you might look at that.
A quick search of PubMed and CAB Abstracts shows a handful of in vitro and rodent studies, mostly more than 10 years old. I have found no clinical studies in cats (or in dogs or humans, for that matter), so I don’t see any evidence to support clinical use for this purpose. Are you aware of any clinical trials?
Seems most studies of lactoferrin against FHV have been in vitro, but a small clinical study evaluating the effectiveness of the lysine+lactoferrin combination is the first google result for “lactoferrin lysine study”. I don’t think this study is particularly useful for various reasons, but it exists.
Evaluation of lysine and lysine-lactoferrin association in cats infected by feline herpesviras-1
https://www.researchgate.net/publication/287592386_Evaluation_of_lysine_and_lysine-lactoferrin_association_in_cats_infected_by_feline_herpesviras-1
Thanks for finding that one!
Unfortunately, you’re right that it doesn’t provide any support for the proposed efficacy of lactoferrin. Cats getting lactoferrin with lysine recovered by 2 weeks at rates of 60-80%. 60% of cats getting lysine alone recovered by 2 weeks. and 100% of cats getting neither but an antibiotic instead also recovered by 2 weeks. There was no placebo group or no-treatment group (though arguably an antibiotic should be viewed as a placebo when used for a viral infection), so we have no way of knowing what the rate of recovery in this group would be without treatment. However, historically a majority of cats recover from clinical signs within 2 weeks regardless of treatment. So the most reasonable interpretation is that none of the therapies shortened the clinical course.
https://avmajournals.avma.org/doi/abs/10.2460/AJVR.2002.63.99
Conjunctivitis was diminished in treated cats
That study included only 8 cats, and it was critically evaluated in a systematic review of the literature, which concluded that neither that study alone nor the balance of the evidence supported the efficacy of lysine:
“The first study investigating the effect of lysine supplementation
on the clinical course of cats suffering
from FHV-1 infection was published in 2002 by Stiles
et al. [13]. This blinded, randomized and placebocontrolled
study with a total study population of only
8 cats, specifically studied the effect of lysine supplementation
on experimentally induced conjunctivitis. For a
period of 3 weeks, the cats received 1000 mg lysine daily
or a placebo (lactose), beginning 6 h prior to inoculation
with the virus. Although higher in the lysine group,
plasma lysine increased significantly during the study
period, in both the lysine and the placebo group. Contrary
to the authors’ hypothesis, compared to baseline values,
plasma arginine levels were significantly increased as well,
both in cats receiving supplemental lysine and in cats
receiving the placebo. Arginine levels were never significantly
different between the two groups. Irrespective of
the similar and increased plasma arginine levels, the
authors reported a statistically significant lower mean
clinical score for conjunctivitis for the lysine group when
compared to the placebo group. However, this was only
observed for the period of day 5–15, not for the entire
study period of 21 days. In the third week of the study,
there was no difference between the two groups of cats,
and time to resolution also was the same. Finally, viral
shedding was not different in the lysine group when
compared to the controls.”
My vet recently recommended lysine for my cat having a chronic watery eye. He came from a shelter I work at and we used lysine all the time for years until last year when a few others and I came across research that revealed lysine had no effect on herpes virus. How do I bring this up with my current vet? He holds the DVM and I respect his training but shouldn’t he be up to date on this already?
Lysine is pretty widely used despite the poor evidence. Some vets are convinced it works based on anecdotes or personal experience, others feel obliged to offer something besides “wait for it to go away” even when there isn’t much evidence that something will actually help. It never hurts to tell your vet that you feel the evidence doesn’t support the treatment so you would rather not use it, but I wouldn’t judge him too harshly since, unfortunately, most vets rely pretty heavily on anecdotal evidence since we so seldom have the high-quality research data we should have.