Epithalamin/Epithalon – Alzheimer’s Drug Discovery Foundation

Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug
Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-indevelopment, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic
interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain
health, as well as for age-related health concerns that can affect brain health (e.g.,
cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports
include evaluation of safety data, from clinical trials if available, and from preclinical models.
Epithalamin/Epithalon
Evidence Summary
No human studies regarding effects on cognition or neuroprotection; however, some clinical evidence
suggests it may decrease human mortality. Limited evidence suggests epithalamin is likely safe for longterm use.
Neuroprotective Benefit: Have not been tested in humans for prevention of cognitive decline,
but preclinical studies suggest they may have anti-oxidant activity in the brain and increase
melatonin levels.
Aging and related health concerns: Several Russian clinical trials suggest epithalamin may
decrease mortality in older adults with cardiovascular disease, but these results have not been
independently confirmed. Both epithalamin and epithalon may increase lifespan in flies, mice
and rats.
Safety: Two 3-year epithalamin treatment trials (one with a 12-year follow-up) reported no
severe adverse events in older adults and preclinical studies support a favorable safety profile,
but a well-conducted Phase1 safety study and independent validation is needed to confirm
safety.
2
What is it? Epithalamin (sometimes spelled “epithalamine”) is a crude polypeptide extract of bovine
pineal glands while epithalon (also spelled “epitalon”) is a tetrapeptide isolate (Ala-Glu-Asp-Gly) from
epithalamin that can also be made synthetically.
Because epithalamin contains a mixture of polypeptides it is difficult to determine which effects are due
solely to epithalon. This also means that the contents likely vary between preparations of epithalamin
extracts. Similarly, impurities in the synthetic preparation of epithalon may explain some observed
discrepancies between in vitro and in vivo results (discussed below).
It is critical to note that every preclinical and clinical study discussed here has been conducted by Dr.
Khavinson’s group in Russia with no independent confirmation of their results. It should also be noted
that at least half of the approximately 110 published articles on epithalamin and epithalon are in Russian
and are not available in English translations, and thus were not included in this analysis
Neuroprotective Benefit: Have not been tested in humans for prevention of cognitive decline, but
preclinical studies suggest they may have anti-oxidant activity in the brain and increase melatonin levels.
Types of evidence:
• 1 clinical trial
• Several preclinical studies
There is no evidence from preclinical animal or clinical human studies to suggest that either epithalamin
or epithalon is neuroprotective. Neither substance has ever been tested in humans or animals for
dementia prevention or treatment. However, several proposed mechanisms of action have bearing on
brain health.
Epithalamin stimulates melatonin production in elderly adults with pineal gland dysfunction (Korkushko
et al, 2004) as well as old rats (Anisimov et al, 1992). There is conflicting preclinical evidence as to
whether the synthetic epithalon has similar actions. Epithalon failed to stimulate melatonin production
in rats (Djeridane et al, 2003) but was reported to increase melatonin levels in older primates
(Khavinson et al, 2001: abstract only, paper not available). The reasons for this discrepancy are not
clear, but may be due to contaminants in the synthetic tetra-peptide preparation or differences in the
test animals.
3
Epithalon may have several mechanisms of action distinct from possibly stimulating melatonin
production. Lower levels of DNA damage were observed in senescence-accelerated mice (SAMP-1)
treated with epithalon, an effect not observed with melatonin treatment (Rosenfeld et al, 2002). This
may be attributable to eptihalon’s antioxidant capacity. Several studies suggest that it may cross the
blood-brain barrier, where it may stimulate cortical neurons (Sibarov et al, 2007) and increase levels of
phosphor-CREB (Khavinson et al, 2012), a DNA-binding protein important in learning and memory.
However, none of the available reports directly measured epithalon levels in the brain after
administration.
Both epithalamin and epithalon show antioxidant activity and may improve organismal (flies and rats)
antioxidant defense systems (Anisimov et al, 1997; Khavinson et al, 2000a; Kozina et al, 2007).
APOE4 interactions: There is no evidence to suggest that either epithalamin or epithalon affects APOE4
carriers differently than non-carriers.
Aging, mortality and related health concerns: Several Russian clinical trials suggest epithalamin t may
decrease mortality in older adults with cardiovascular disease, but these results have not been
independently confirmed. Both epithalamin and epithalon may increase lifespan in flies, mice and rats.
Types of evidence:
• Two clinical trials (one of which the paper is not available)
• Several preclinical in vitro and in vivo studies
One clinical trial treated 266 elderly adults with epithalamin (unknown dose/scheduling) for 2-3 years
and observed them for the subsequent 4-5 years. The abstract states that treatment “normalize[d] the
basic functions of the human organism, i.e. to improve[d] the indices of cardiovascular, endocrine,
immune and nervous systems, homeostasis and metabolism.” Unfortunately, the paper describing this
trial is not available in English (Khavinson et al, 2003a).
A second placebo-controlled trial treated 70 older adults (~65 years old) with “accelerated aging” due to
cardiovascular disease with epithalamin every 6 months for 3 years and followed them for another 9
years (Korkushko et al, 2006). Treatment consisted of 5 intramuscular injections of 10 mg epithalamin
or saline with 3-day intervals. Over 12 years, the treatment group experienced a 28% decreased
mortality rate and 2-fold lower rate of cardiovascular disease-specific mortality. A 3-year (15-year total)
4
follow-up study reported that epithalamin treatment “prevented age-associated impairment of physical
endurance, normalized circadian rhythm of melatonin production and carbohydrate and lipid
metabolism” (Korkushko et al, 2011). These results have not been validated by an independent trial.
Epithalamin and epithalon reportedly increase lifespan in flies, mice and rats (Anisimov et al, 1992;
Anisimov et al, 1997; Anisimov et al, 1998; Khavinson et al, 2000b; Anisimov et al, 2003; Vinogradova et
al, 2007; Vinogradova et al, 2008). However, none of these results has been replicated by a lab
independent of Dr. Khavinson’s group.
Several relevant potential mechanisms of action for epithalon have been described in in vitro human cell
culture experiments. Epithalon treatment of human fetal fibroblasts increased telomere length
(Khavinson et al, 2003b), while treatment of cultured leukocytes resulted in chromatin remodeling
events, suggesting possible epigenetic actions (Khavinson et al, 2003c; Lezhava et al, 2006). Treatment
of fetal fibroblasts resulted in cell proliferation beyond their Hayflick limit, suggesting epithalon may also
have anti-senescence activity (Khavinson et al, 2004). But there are no publications independently
replicating these results outside of Dr. Khavinson’s group.
Lastly, epithalon may have utility in cancer prevention. Several preclinical studies in rats and cancerprone mice suggest epithalon treatment decreased tumor formation rates (Anisimov et al, 2002; Kossoy
et al, 2006; Vinogradova et al, 2007; Vinogradova et al, 2008).
Safety: Two 3-year epithalamin treatment trials (one with a 12-year follow-up) reported no severe
adverse events in older adult, and preclinical studies support a favorable safety profile, but a wellconducted Phase1 safety study and independent validation is needed to confirm safety.
Without data from a well-conducted phase I safety trial or extensive epidemiological data, it is quite
difficult to determine the safety of epithalamin or epithalon treatment. Since epithalamin is a crude
polypeptide extract from a bovine gland, its overall safety is still questionable and is likely to be highly
dependent on the manufacturing process. Similarly, since epithalon is either isolated or made
synthetically, any impurities could pose a safety risk.
Dosing and Sources: Clinical studies on epithalon have not been conducted. However, epithalamin is
approved in Russia for treatment of menopause-related symptoms, anovulatory infertility and hormonedependent tumors (Anisimov et al, 1998). It is not approved for any medical uses outside of Russia.
Reviewed clinical trials used different dosing, delivery and scheduling. Most rounds of treatment were
5
followed by a 4-6 month pause in treatment before resuming. Common doses and schedules were
intranasal delivery (10-30 mg/day for 20-30 days) and intramuscular injection (5-10 mg/day for 10-20
days). Some animal experiments used subcutaneous injections but there was no available human data
on this route of delivery.
Future research: The results discussed here would benefit greatly from independent replication and
validation.
PubMed Search terms:
Epithalamin or epithalamine or epitalon or epithalon + following terms with and without filters for
“clinical trial”, “meta-analysis”, and “review”
• Alzheimer’s disease
• Neurodegeneration
• Dementia
• Cancer
• Cardiovascular
• Cognition
• Cognitive decline
• Aging
• Longevity
• Lifespan
• Telomere
• Telomerase
• Diabetes
• Lipids
• Cholesterol
• Hypertension
• Blood Pressue
• Toxicology
• Safety
6
Disclaimer: Cognitive Vitality Reports® do not provide, and should not be used for, medical
advice, diagnosis, or treatment. You should consult with your healthcare providers when
making decisions regarding your health. Your use of these reports constitutes your agreement
to the Terms & Conditions.