How many times have you asked yourself, "Where did I put the keys?" or grapple for words during a "senior moment?" While aging is associated with the impairment of multiple metabolic pathways that can erode brain function, we don't have to resign ourselves to dwindling memory, foggy thinking, or poor attention span as we grow older. Thankfully, there is something we can do about it.
The drug hydergine acts on numerous fronts to slow down or even reverse age-related alterations in brain physiology and improve cognitive function. It's one of the safest, most effective, and intensively researched smart drugs available today. Over the past few decades, this potent cerebral enhancer has been shown in innumerable animal and clinical studies to boost memory and retrieval, alertness, intellectual capacity and even mood, while fending off the many deleterious processes that can lead to brain aging and mental decline.
Hydergine (also known as ergoloid mesylates or co-dergocrine mesylate) is the brand name for a mixture of three alkaloids derived from ergot, a fungus that grows on rye. The drug was developed in the 1940's by Albert Hofmann (known famously as the inventor of LSD) when working as a chemist for Sandoz (now Novartis and coincidentally, a former employer of the author of this article) and is still one of that pharmaceutical giant's most important drugs. Since the early 1970's, hydergine has been used clinically to treat senile dementia (including Alzheimer's), cerebral vascular disorders and the typical progressive deterioration of mental capacity known as age-related cognitive decline. Its efficacy has been well documented. The drug was approved by the FDA in 1981 for the treatment of dementia, defined as a loss of mental ability severe enough to interfere with daily life and characterized by symptoms such as decreased mental alertness, confusion, poor short-term memory, depression, emotional instability and problems related to motor skills. But perhaps the drug has an equally important role when used “off-label” as a smart drug, or cerebral enhancer, in healthy people who wish to protect against brain aging, sharpen their wit and mental agility, improve their memory and focus, and even gain a competitive edge in their career or pursuits. It's interesting to note that Hoffman, who lived to be 102, regularly consumed hydergine as a brain tonic, which may in part be responsible for his longevity and brain power.
Research supporting the cognitive effects of hydergine in animals and humans
In animal models, patients with cognitive decline, and aging but otherwise healthy people, hydergine has been shown to improve measures of cerebral function such as learning, memory, attention, as well as mood. Animal studies typically use a maze, or similar apparatus, as a "paradigm" for assessing cognitive behavior. One such study showed that hydergine increased the "intelligence" of rats trained in a maze to receive a liquid reward, as evidenced by increased accuracy in their attempts to obtain the treat. (1) In a similar maze experiment, hydergine improved memory and retrieval processing in mice, with the typical "inverted U" dose-response curve characteristic of memory enhancers. (2) (We’ll see more on the inverted U curve later.)
In clinical studies, hydergine was well tolerated in virtually every study, and often demonstrated statistically significant effects on cognitive measures in healthy subjects exhibiting "normal" aging and in patients with more accelerated cognitive decline. Here are some highlights of the studies, (note; the latter four were placebo-controlled and the first three were double-blind; they are listed in order of clinical severity, from the most to the least mental impairment):
A trial on 36 patients with severe dementia found that daily intravenous (IV) hydergine (3 mg) for two weeks significantly improved cognitive dysfunction, mood and social withdrawal. (3)
As in the above study, improvements in mental deficits were demonstrated in 97 elderly patients with age-related mental decline who were administered 4.5 mg hydergine tablets for 6 months; the researchers observed a progressive increase in efficacy throughout the course of the trial, indicating that treatment in patients with mental decline should be long-term. (4)
In a trial on 41 outpatients between the ages of 55 to 80 who were otherwise healthy, but experiencing mild memory impairment (a common complaint for the general aging population), a 6 mg daily oral dose of hydergine for 12 weeks considerably improved memory function. (5)
A fascinating and revealing study of the effects of hydergine on a subset of the healthy but aging population was performed on over 100 disease-free retirees for five years. This was an unusual study on two counts: it evaluated the effects of a drug on healthy, rather than impaired subjects, and it was long-term. The study authors observed that retirees receiving 4.5 mg hydergine per day for the length of the study exhibited not only better mental performance than those on placebo, but also enhanced physical health, as evidenced by factors such as lowered lipid fractions and fewer diagnoses of major disease. The authors went on to say that although they felt that each individual improvement in and of itself was not dramatic, overall, the combined positive effects pointed to the "prophylactic effect of ergoloid mesylates [hydergine] on the pathological concomitants of aging." (6) In other words, hydergine protects against multiple aspects of age-related physical and mental decline – an impressive conclusion.
Hydergine acts by diverse mechanisms to enhance brain function
We’ve just seen the proven cognitive-boosting effects of hydergine in animals and humans. Now, let’s take a look at the aging brain, and discuss how hydergine counteracts eroding mental performance.
The brain is especially vulnerable to the effects of aging on numerous fronts: decreased blood and oxygen flow, diminished mitochondrial energy production, hindered neurotransmission, loss of structural integrity, oxidative damage and decreased neuronal activity. Each of these factors alone impairs mental function; in combination, as is often (if not always) the case, the effects can be disastrous. The good news is that hydergine has been shown to influence many aspects of brain metabolism and ameliorate all of the effects of aging we just mentioned. Early research showed that hydergine acted primarily by increasing blood supply and oxygen to the brain, but a plethora of brain-boosting mechanisms have since been discovered:
Hydergine enhances neuronal metabolism: In middle-aged rats, hydergine stimulates local cerebral glucose utilization in parts of the brain associated with learning and memory, (7) and the same effect has been found in patients with dementia. (8) Glucose is the main substrate for brain metabolism, (8) and measurements of increased cerebral glucose utilization in response to hydergine indicate enhanced neuronal activity. Hydergine was also shown to stimulate neuronal functioning in short-lived (i.e., rapidly aging) mice. (9) In addition, hydergine preserves neuronal ATP stores. (10) ATP (adenosine tri-phosphate) is the cellular energy currency crucial to metabolism. (We’ll see below how hydergine reverses age-related changes in mitochondria, the ATP-generating cellular powerhouses.)
Hydergine modulates neurotransmission in several ways: First, hydergine decreases levels of the monoamine oxidase (MAO) enzymes in the brain. (11-12) MAO enzymes degrade used neurotransmitters and are essential to normal brain metabolism, but an age-related increase in MAO activity can deplete the catecholamine neurotransmitters (dopamine, noradrenaline, and adrenaline), (11-12) impairing mental function. Hydergine counteracts this effect. Second, hydergine regulates the release of the neurotransmitter acetylcholine from the hippocampus, (13) the part of the brain that helps transfer information from short-term to long-term memory. The drug also increases the number of cholinergic (acetylcholine) receptors in the aging hippocampus; (14-15) a decline in the number of cholinergic receptors can lead to a decrease in learning ability and memory function, (14-15) and hydergine can at least partially reverse these effects. Another characteristic of brain aging is a deficiency in enzymes necessary for the synthesis of acetylcholine. In aged rats and mice, treatment with hydergine restored the activity of one of these enzymes, choline acetyltransferase. (16) Third, hydergine prevents disturbances in monoamine (dopamine, noradrenaline and serotonin) neurotransmission in different areas of the brain: it can either compensate for a neurotransmitter deficit or counteract its over-activity, (17-18) restoring balance in the interaction of the monoamines. (10)
Hydergine protects the brain against hypoxia: Hydergine can prevent mental impairment and physical damage to the brain caused by insufficient oxygen reaching the brain (hypoxia). In a placebo-controlled trial, 15 healthy volunteers inhaled a gas combination simulating high altitude conditions (6000 m altitude), which induced hypoxia and resulted in decreased vigilance, intellectual function and performance in a reaction time task. But after oral administration of 5 mg hydergine, volunteers again subjected to the same conditions exhibited significant protection against hypoxia-induced brain dysfunction. (19) Because of its neuroprotective effects, hydergine is used in emergencies to treat strokes or accidents that interrupt oxygen supply to the brain.
Hydergine slows down age-related structural changes in the brain: Aging is associated with the loss of structural integrity of parts of the brain, which can negatively affect cognition. Two of these components are mossy fibers, (nerve fibers that surround nerve cells of the cerebellar cortex) and granule cells (a type of neuron). (20) In rats, medication with hydergine increased the density of mossy fibers and the number of granule cells in the hippocampus. (20) The aging brain has also been shown to undergo a loss of synapses, (21-22, 10) the gaps between neurons where nerve impulses are transmitted. But hydergine reverses this loss: four weeks of hydergine treatment significantly increased the number of synapses in the brains of old rats, compared to untreated rats. (22)
Hydergine fights lipofuscin: Lipofuscin is the yellow-brownish colored pigments--oxidation products--that accumulate in cells (including neurons) over time. In old rats, six months of hydergine treatment caused a significant dose-related decrease in lipofuscin accumulation in various types of nerve cells. (23)
Hydergine enhances antioxidant status: Free radical damage is involved in many, if not all, age-related disease processes, including dementia and cognitive decline. (12) One generator of free radicals in the brain is the increased activity of MAO (12) that accompanies aging. As discussed earlier, hydergine suppresses MAO over-activity, which, besides preserving neurotransmitters, leads to a reduction in oxidative stress. (12) Hydergine further counters free radicals by increasing the endogenous antioxidants superoxide dismutase (SOD) and catalase (CAT) in the brain. (12)
Hydergine reverses age-related mitochondrial alterations: Mitochondria are tiny but extremely important organelles (cellular subunits), the machinery necessary for the production of energy (ATP). Aging is associated with yet another example of deterioration--the loss in number and metabolic efficiency of these crucial organelles. (10) Nerve cells, especially at their synaptic ends, need a high and steady energy supply, generated by their mitochondria, to carry out their job of cell-to-cell information processing in an efficient manner. Any impairment in mitochondrial activity can lead to a "power failure" situation in which insufficient energy is available to run the brain's circuits, with adverse effects on mental functioning. In a noteworthy study, a group of researchers examined the structural features of mitochondria specifically located at nerve cell terminals at the synaptic gap, in young, adult, and old rats. They found age-related differences in the mitochondria of older versus younger rats. The old rats exhibited fewer but larger (i.e., elongated) mitochondria compared with younger rats, in which smaller and more numerous mitochondria were equated with greater ATP-generating capacity. So, in the old rats, the few enlarged organelles were an indication that the cellular machinery struggled to keep up with energy-dependent synaptic activity, especially in high-demand circumstances. But four weeks of hydergine treatment (at an ultra-high dose) partially reversed these alterations in old rats, as shown by an increase in number and a reduction in size of the mitochondria, indicating improved metabolic efficiency more comparable to the younger animals.(10)
This list of varied mechanisms underlies the efficacy of hydergine in ameliorating and potentially reversing, age-related brain deterioration and improving cognitive function. Plus, this list is not exhaustive. Undoubtedly, on-going research will uncover additional beneficial effects of this powerful cerebral enhancer.
Some researchers cast doubt?
Even with the wealth of compelling findings obtained in dozens of animal and human trials, some researchers questioned hydergine's efficacy in treating advanced cognitive decline, (i.e., dementia, including Alzheimer's). In response to this uncertainty, meta-analyses were performed to statistically evaluate the data obtained in multiple human trials. Two of these overviews, (one evaluating 21 trials and another analyzing 47 trials) concluded that "hydergine shows significant treatment effects" especially when initiated early and at higher doses than the FDA-approved 3 mg dose. (24-25) One reason why some trials reported only modest improvements in hydergine-treated patients is simply that the dose used was too low and therefore, ineffective. In Europe, the drug is prescribed at doses of at least 9 mg per day, but in the US, the recommended starting point is 3 mg. Since the drug exhibits low, if any, toxicity, and higher quantities have been linked with greater efficacy, it seems counterproductive (and unscientific) to use the lower dose.
The four clinical studies we reviewed earlier, in which significant improvements were obtained, used oral doses of 4.5 mg to 6 mg and an IV dose of 3 mg (note that a 3 mg IV dose has far greater potency than a 3 mg oral dose; directly injecting a drug into the bloodstream markedly increases its bioavailability). Also, unfavorable results in some trials may be due to the fact that treatment was initiated too late in the progression of cognitive decline. This indicates that medication with hydergine should be started as early as possible in those experiencing the first signs of mental deterioration, since treatment may prevent the cascade of brain alterations that can lead to more advanced cognitive decline and Alzheimer's.
Maintaining a healthy brain as we grow older, rather than rescuing cognition later, is a key component of an effective longevity strategy.
More on dosing −how to use hydergine
It’s difficult to recommend a universal starting dose for everyone, since response depends on each person’s unique physiology, sensitivity to medications and cognitive status. If used alone, you may consider starting with half of a 4.5 mg tablet for a few days, note your response, then increase to a full tablet, again rate your response and increase as necessary. Also, keep in mind that hydergine exhibits an inverted-U dose-response curve, which means that the dose should be increased slowly to reach an ideal response, after which any further increase in dose may lead to a fall-off in effect. Hydergine may also be combined with other smart drugs, such as deprenyl or piracetam, where it acts synergistically (i.e., at higher potency, while enhancing the effects of these other agents), so dosages may need to be adjusted down. As with other smart drugs, the best advice is to start low, increase gradually, evaluate the effect, and fine-tune as necessary.
Whether used alone, or in combination, hydergine should be a central element of any comprehensive antiaging program to preserve brain health, boost cognitive function and defend against the potentially devastating effects of age-related mental decline.
1. Jaton AL, Vigouret JM. Effects of Hydergine and its components on Lashley maze acquisition in rats. J Pharmacol. 1985;16 Suppl 3:51-6.
2. Flood JF, Smith GE, Cherkin A. Hydergine enhances memory in mice. J Pharmacol. 1985;16 Suppl 3:39-49.
3. Arrigo A, Casale R, Giorgi I, Guarnaschelli C, Zelaschi F. Effects of intravenous high dose co-dergocrine mesylate ('Hydergine') in elderly patients with severe multi-infarct dementia: a double-blind, placebo-controlled trial. Curr Med Res Opin. 1989;11(8):491-500.
4. Rouy JM, Douillon AM, Compan B, Wolmark Y. Ergoloid mesylates ('Hydergine') in the treatment of mental deterioration in the elderly: a 6-month double-blind, placebo-controlled trial. Curr Med Res Opin. 1989;11(6):380-9.
5. Thienhaus OJ, Wheeler BG, Simon S, Zemlan FP, Hartford JT. A controlled double-blind study of high-dose dihydroergotoxine mesylate (Hydergine) in mild dementia. J Am Geriatr Soc. 1987 Mar;35(3):219-23.
6. Huber F, Köberle S, Prestele H, Spiegel R. Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: 5-year results. Curr Med Res Opin. 1986;10(4):256-79.
7. Walovitch RC, Ingram DK, Spangler EL, London ED. Co-dergocrine, cerebral glucose utilization and maze performance in middle-aged rats. Pharmacol Biochem Behav. 1987 Jan;26(1):95-101.
8. Nagasawa H(1), Kogure K, Kawashima K, Ido T, Itoh M, Hatazawa J. Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography. Tohoku J Exp Med. 1990 Nov;162(3):225-33.
9. Serino A, Kan K, Graves K, Kule C, Anthony A. Age, strain, and semi-chronic hydergine treatment effects on motor activity and neuronal nucleic acid-protein metabolism in male mice. Life Sci. 2000 Aug 11;67(12):1489-505.
10. Bertoni-Freddari C, Fattoretti P, Casoli T, Spagna C, Meier-Ruge W. Morphological alterations of synaptic mitochondria during aging. The effect of Hydergine treatment. Ann N Y Acad Sci. 1994 Jun 30;717:137-49.
11. Büyüköztürk A, Kanit L, Ersöz B, Menteş G, Hariri NI. The effects of hydergine on the MAO activity of the aged and adult rat brain. Eur Neuropsychopharmacol. 1995 Dec;5(4):527-9.
12. Sözmen EY, Kanit L, Kutay FZ, Hariri NI. Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain. Eur Neuropsychopharmacol. 1998 Feb;8(1):13-6.
13. Imperato A, Obinu MC, Dazzi L, et al. Co-dergocrine (Hydergine) regulates striatal and hippocampal acetylcholine release through D2 receptors. Neuroreport. 1994 Feb 24;5(6):674-6.
14. Amenta F, Cavallotti C, Franch F, Ricci A. Muscarinic cholinergic receptors in the hippocampus of the aged rat: effects of long-term hydergine administration. Arch Int Pharmacodyn Ther. 1989 Jan-Feb;297:225-34.
15. Le Poncin-Lafitte M, Rapin JR, Duterte D, Galiez V, Lamproglou I. Learning and cholinergic neurotransmission in old animals: the effect of Hydergine. J Pharmacol. 1985;16 Suppl 3:57-63.
16. Dravid AR, Hiestand P. Deficits in cholinergic enzyme activities in septo-temporal regions of the senescent rat hippocampus, and in the forebrain of aged mice: effect of chronic Hydergine treatment. J Pharmacol. 1985;16 Suppl 3:25-32.
17. Wadworth AN, Chrisp P. Co-dergocrine mesylate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in age-related cognitive decline. Drugs Aging. 1992 May-Jun;2(3):153-73.
18. Markstein R. Hydergine: interaction with the neurotransmitter systems in the central nervous system. J Pharmacol. 1985;16 Suppl 3:1-17.
19. Saletu B, Grünberger J, Anderer R. On brain protection of co-dergocrine mesylate (Hydergine) against hypoxic hypoxidosis of different severity: double-blind placebo-controlled quantitative EEG and psychometric studies. Int J Clin Pharmacol Ther Toxicol. 1990 Dec;28(12):510-24.
20. Amenta F, Jaton AL, Ricci A. Effect of long term hydergine treatment on the age-dependent loss of mossy fibers and of granule cells in the rat hippocampus. Arch Gerontol Geriatr. 1990 May-Jun;10(3):287-96.
21. Masliah E(1), Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer's disease. J Alzheimers Dis. 2006;9(3 Suppl):91-9.
22. Bertoni-Freddari C, Giuli C, Pieri C, et al. J Gerontol. The effect of chronic hydergine treatment on the plasticity of synaptic junctions in the dentate gyrus of aged rats. 1987 Sep;42(5):482-6.
23. Amenta D, Ferrante F, Franch F, Amenta F. Effects of long-term Hydergine administration on lipofuscin accumulation in senescent rat brain. Gerontology. 1988;34(5-6):250-6.
24. Olin J, Schneider L, Novit A, Luczak S. Hydergine for dementia. Cochrane Database Syst Rev. 2001;(2):CD000359.
25. Schneider LS, Olin JT. Overview of clinical trials of hydergine in dementia. Arch Neurol. 1994 Aug;51(8):787-98.