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Hydergine - Update - Still Highly Recommended
By Ward Dean, MD
Many life extension physicians and enthusiasts first learned
of the concept of "smart drugs" from reading the
blockbuster best-seller, Life Extension, A Practical Scientific
Approach, by Durk Pearson and Sandy Shaw.
Pearson and Shaw extolled the virtues of a drug called Hydergine-
a Sandoz trademark (ergoloid mesylates), a combination of
three ergot alkaloids.
They reported that Sandoz Pharmaceuticals claimed Hydergine
was the "most intensively studies drug in the world"
and at the time they wrote their book it was "the fifth
best selling drug in the world."
Hydergine was originally developed as an anti-hypertensive
medication, but it was soon found that it really wasn't very
effective in reducing elevated blood pressure.
However, a number of people who used it did report improvements
in memory, mood and overall sense of well being. At first,
it was believed that these effects were due to increased cerebral
blood flow. Later, however, it was determined that Hydergine
actually acted to improve brain cell metabolism in a number
of ways.
Hydergine increases stores of the universal energy molecule,
adenosine triphosphate (ATP), stabilises the intracellular
messenger molecule cyclic adenosine monophosphate (cAMP) content
of nerve cells, improves utilization of glucose in the brain,
and enhances cerebral microcirculation.
The FDA approves Hydergine for persons "over sixty who
manifest signs and symptoms of an idiopathic decline in mental
capacity" (i.e. cognitive and interpersonal skills, mood,
self-care, apparent motivation-Physician's Desk Reference
1995).
The PDR description went on to report that "the efficacy
of Hydergine was evaluated using a special rating scale...
on which modest but statistically significant changes were
observed at the end of twelve weeks include; mental alertness,
confusion, recent emory, orientation, emotional lability,
appetite, dizziness, fatigue, bothersome (ness) and an overall
impression of clinical status."
It should be noted that the modest but significant changes
referred to above were all in the positive direction. It should
also be noted that these improvements all took place using
the measly 3mg dose that is approved and most commonly used
in the USA.
Despite the vast amount of research that has been conducted
with Hydergine, and its enviable record of near-absolute safety,
little research has been conducted with this substance in
recent years.
In fact, one of the most recent studies with Hydergine was
published seven years ago in the New England Journal of Medicine,
in which the authors arrived at the conclusion that it "was
ineffective as a treatment for Alzheimer's disease."
Their assessment was based on their findings that three-mg/
day of Hydergine for six months was ineffective in improving
symptoms of eighty patients with Alzheimer's disease. What
I think the authors really proved, however, was that three-mg
per day is an inadequate dose for Alzheimer's disease (surprise,
surprise!).
Previous studies indicated that higher doses were usually
required to benefit patients with Alzheimer's disease.
For example, a team of physicians at Stanford University (Yesavage,
et al., 1979) administered 6mg of Hydergine each day to 14
hospitalised patients (aged 62-84) with senile deterioration.
All of these patients had been treated for at least 4 months
with 3mg Hydergine per day, without noticeable improvement.
However, after 12 weeks of treatment at the higher dose, seven
of eleven surviving patients (three of the patients died due
to unrelated causes) had shown improvement. One patient, who
had been hospitalised for two years, improved so dramatically
he was discharged from hospital!
In another study in Japan, Yoshikawa and colleagues (1983)
conducted a large double blind study of Hydergine in 550 patients.
They found that "almost half of the patients in the 6mg
group- 48.9%, showed a moderate to marked improvement, compared
with only 17.9% in the 3mg group.
Furthermore, they noted that "the superiority of a higher
Hydergine dose was particularly pronounced in patients with
heavy-headedness, sleep disturbances of various kinds, problems
of concentration, loss of vigor, memory disturbances and giddiness."
They concluded that "the favourable effects of Hydergine
on psychiatric, subjective and neurologic symptoms in patients
with cerebrovascular disease are considerably increased when
a higher dose is used, that "a daily dose of 3mg may
therefore be insufficient," and that "clinically
relevant improvement may be obtained in more cases if the
dose is increased to 6mg per day."
No adverse effects of the 6mg dose were reported in either
study. It is possible that even higher doses may be required
for those who are severely demented.
Hydergine - Long term high dose Italian studies
A long term, multi-center randomized placebo-controlled double
blind study is currently being carried out in Italy (Cucinotta,
et al, 1996). The study initially involved 215 patients from
14 geriatric and neurologic centers, and included a 1-month
pre-treatment phase with placebo, followed by 1 year of double
blind treatment.
The dosage was 5mg twice a day for the first 2 weeks, 10mg
twice a day for the next 2 weeks and then 20mg twice a day
for the following 11 months. That's a whopping dose of 40mg
per day!
Results from the first year of this study indicated that the
patients on Hydergine either improved or at least deteriorated
at a slower rate than before, while those on placebo continued
to deteriorate an additional 8% over baseline.
Although the Hydergine group showed overall benefit in nearly
every parameter tested, one test in particular that evaluated
quality of life showed highly significant improvement in the
Hydergine treated group.
The massive doses used also confirm the safety and tolerance
of Hydergine, as there was no difference in the dropout rate
between the two groups.
Frankly, I'm surprised at the lack of side effects- I would
have expected to see a great deal of agitation and hyperexcitability
in the high dose Hydergine group. However, perhaps it confirms,
as the studies cited above imply, that the more demented one
is, the more Hydergine is required to effect a positive change.
Furthermore, there was no change in blood pressure, heart
rate, or other routine laboratory tests in the Hydergine group.
This is in stark contrast to the common occurrence of liver
toxicity with tacrine (Cognex®), a drug commonly used
for Alzheimer's disease in the US.
The study is now well into its second year, and is now an
open phase study (physicians and patients are aware of who
is taking the active drug). We look forward to further results
from this study.
Restoring functionality and energy production in old mitochondria
One of the heretofore believed-to-be-inevitable consequences
of aging, is a decrease in the number of synapses- i.e., connections
between brain cells. This decrease of brain cell to brain
cell connection has been hypothesised to be due to impairment
in the energy supply at synaptic regions.
Because of Hydergine's known ability to improve nerve cell
metabolism, a group of Italian scientists studied the ultrastructural
features of synaptic mitochondria of the brain cells of rats
of different ages, to determine if long-term Hydergine treatment
could prevent or delay the loss of synaptic connections (Bertoni-Freddari,
et al, 1994).
The mitochondria, remember, are the "intracellular powerhouses"
where the universal energy molecule- adenosine triphosphate
(ATP) is produced. Using a computer assisted image analyzer,
the researchers measured three mitochondrial parameters, (1)
volume density, Vv, the fraction of the cell volume occupied
by the mitochondria, (2) numerical density, Nv, the number
of mitochondria per cubic micrometer and (3) average size,
Sk, mitochondrial skeletal length.
They found that the number of mitochondria is greatest at
about 12 months of age in rats (the equivalent of a human
25-year-old), and then progressively decreases.|
The size of the mitochondria, however, increased progressively
after 12 months, in an apparent effort to compensate for the
reduction in the number and efficiency of energy producing
mitochondria. Because of this reciprocal relationship between
mitochondrial size and number, there was little change in
the overall total volume of mitochondria per cell.
Thus in young adult animals, the energy required at synaptic
regions is provided by a large number of small, highly efficient
mitochondria, whereas in old animals, energy is produced by
a smaller number of larger, less efficient mitochondria.
Unfortunately, despite their larger size, because of decreased
functionality of a number of mitochondrial enzymes, the few
enlarged mitochondria tend to be less able to accomplish their
tasks, especially when there is a high demand for energy.
After treatment with Hydergine, it can be seen that the total
mitochondrial volume of old rats was nearly the same as the
young adults, and the number and mitochondrial size was altered
in a more youthful direction.
Hydergine - Conclusions
The above combined clinical and laboratory data support the
recommendation of many anti-aging physicians that Hydergine
should continue to be incorporated in an anti-aging/ smart
drug regimen.
Although the FDA approved recommended dosage in the US remains
3mg per day- and many people do well on 2-3mg per day, I believe
that most life extensionists would benefit by somewhat higher
doses (I personally take 5mg per day).
Hydergine - References
1. Bertoni-Freddari, C., Fattoretti, P., Casoli, T., Spagna,
C., and Meier-Ruge, W. "Morphological alterations of
synaptic mitochondria during aging- The effect of Hydergine
treatment in Pharmacology of Aging Processes- Methods of Assessment
and Potential Interventions, Annals of the New York Academy
of Sciences, Volume 717, by Imre Zs.- Nagy and Kenichi Kitani,
eds.), NYAS, New York 1994.
2. Cucinotta, D., De Leo, D., Frattola, L., Trabucchi, M.,and
Parnetti, L., Dihydroergokryptine vs. placebo in dementia
of Alzheimer type; Interim results of a randomized multicentre
study after a 1 year follow up. Archives of Gerontology and
Geriatrics, 22; 169-180 (1996).
3. Physician's desk reference, Medical Economics, Chicago,
1995.
4. Scheibel, ME and Scheibel AB, Structual changes in the
aging brain, in; Aging, Vol. 1, Clinical, Morphologic and
Neurochemical Aspects in the Aging Central Nervous System,
by Brody, H., Harman, D., and Ordy JM (eds.), Raven Press,
New York 1975.
5. Thompson TL, Filley II, Mitchell WD, Culig KM, Lo Verde
M and Byyny R; Lack of efficacy of Hydergine in patient's
with Alzheimer's disease. New England Journal of Medicine
323; 445-448, 1990.
6. Yesavage JA, Hollister LE and Burian E. Dihydrorgotoxine
(Hydergine); 6mg versus 3mg dosage in the treatment of senile
dementia. Preliminary report, Journal of the American Geriatrics
Society, 27; 80-2, 1979.
7. Yosikawa M, Hirai S, Aizawa A, Kuroiwa Y, Goto F, Sofue
I, Toyokura Y, Tamamura H and Iwasaki Y, A dose dependant
study with dihydroergotoxine mesylate (Hydergine) in cerebrovascular
disturbances. Journal of the American Geriatrics Society 31;
1-7, 1983.
DISCLAIMER: ALL INFORMATION IS EDUCATIONAL AND PROVIDED UNDER
ETERNITY MEDICINE TERMS AND CONDITIONS. IT DOES NOT, AND SHOULD
NOT, REPLACE THE ADVICE OF YOUR PHYSICIAN.
Last Updated: Wednesday, March 21, 2001
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