Hyperforin May Help Combat Alzheimer’s Disease

Hyperforin Acquires New Importance

Hyperforin May Help Combat Alzheimer’s Disease
St. John’s wort component reduces formation and
toxicity of amyloid-beta, and it ameliorates depression
By Richard P. Huemer, M.D.

The advantage of a bad memory is that one enjoys
several times the same good things for the first time.

— Friedrich Nietzsche

© iStockphoto.com/Steve Luker
wag’s list of the advantages of Alzheimer’s disease includes always meeting new people, looking forward to TV reruns, and being able to hide your own Easter eggs. We laugh uneasily at such cruel humor, all too aware that any of us could, without apparent cause, fall victim to the dread disease. It’s an illness that robs us of our dignity and our relationships by stealing what the Scottish poet Tryon Edwards called “a man’s real possession”—his memory. We make jokes to mask our fear.

In Alzheimer’s disease, critical neurons (nerve cells) in certain parts of the brain are irreparably damaged or defunct—or, as my teenagers used to say, “permanently out to lunch.” Scientists have spent decades trying to find out why. We now have a pretty good handle on how things go wrong, but no way to stop the process—we can only slow it down or interrupt it briefly. In that vein, a recent paper from a Chilean research team offers evidence that a simple herbal remedy might retard or even reverse a key pathological feature in Alzheimer’s disease.1

When Brains Grow Older

To explain what the researchers discovered, and why they pursued their idea in the first place, we need to understand how Alzheimer’s disease develops. It happens so slowly and insidiously that people are often surprised when it finally becomes apparent to them that they or a loved one have fallen victim to it. By then, it’s too late for anything but delaying actions to forestall the inevitable. Scientists now believe that the beginnings of Alzheimer’s occur not just years, but probably decades before the disease becomes manifest. Thus, no adult is too young to take the threat seriously.

In some aging people, mental abilities decline sufficiently to be deemed mild cognitive impairment (MCI) according to standardized tests of cognitive function. MCI always precedes Alzheimer’s disease (even if it goes unrecognized), but not everyone with MCI progresses to the next stage, when memory, judgment, and concentration have deteriorated to the point of significant functional impairment. That’s called dementia, of which Alzheimer’s is the most common type.

Oh, What a Tangled Plaque We Weave . . .

It has been known for a century, thanks to Alois Alzheimer, that the brains of demented people are palpably diseased. This German medical pioneer helped establish the neuroanatomical and biochemical basis of mental illness back in the days when Freud was teaching that it was all due to how you felt about your mother. What Alzheimer saw under his microscope, as he peered at the brain tissue of a woman dead of dementia, was ugly clumps of matter between her neurons, and strange knots of matter within them. In a paper published in 1907, he told the world about those defining neuroanatomical features of the disease that came to bear his name. We now call the clumps neuritic plaques (or senile plaques) and the knots neurofibrillary tangles.

First come the plaques, which form between the neurons before the latter begin their slow decay to oblivion. The plaques consist mainly of a small protein called amyloid-β (amyloid-beta, abbreviated Aβ), which is derived from a larger molecule called amyloid precursor protein (APP). Aβ causes inflammation in the brain and is toxic to neurons.

The tangles usually appear later; their formation, in fact, is brought about in part (and indirectly) by the plaques. They consist of knots of a protein called tau (rhymes with wow), which is a structural element in neurons. There has been some friendly dispute among brain researchers as to which feature—Aβ or tau—plays the more destructive role in Alzheimer’s disease. At present, Aβ has the edge.

Scientists Get Around to St. John’s Wort . . .

Several strategies seem feasible for ameliorating the degenerative process in Alzheimer’s disease. One strategy is to inhibit the production of Aβ molecules from APP; another is to inhibit the formation of Aβ fibrils and their aggregation into neuritic plaques; yet another is to inhibit the inflammatory responses caused by the plaques.

Many substances have been tried, with some success, in an effort to inhibit the formation of Aβ fibrils. Some are esoteric, but others are more familiar, including the herb Ginkgo biloba, the hormone melatonin, and various antioxidant polyphenols, such as resveratrol from red wine and EGCG from green tea. A remedy that had not been tried until 2006 was the well-known herb St. John’s wort (Hypericum perforatum).

Hyperforin and Drug Interactions

Before 1999, problems associated with the use of St. John’s wort were almost unheard of. Then, suddenly, reports of adverse interactions with an astonishingly wide variety of drugs started showing up in medical journals. What had happened? It turns out that in 1998, the chemical process for producing St. John’s wort extracts had been improved so as to stabilize the hyperforin molecule (which tends to decompose easily) and increase its concentration by 10 to 20 times. This technological advance was motivated by an increasing awareness of the evidence for hyperforin’s important role in the herb’s antidepressant action.

It had previously been thought that the principal active component of St. John’s wort was a compound called hypericin. Now, however, hyperforin had come to the fore in that regard. It’s worth noting, though, that even hyperforin-free extracts of St. John’s wort show antidepressant activity, indicating that hypericin (and other biologically active components of the herb) can yield this benefit on their own. Thus hyperforin, despite its evident value, is not essential for antidepressant action—it’s merely desirable.

In any case, the troubling reports began to appear in 1999, and the problem was soon attributed to the newly increased levels of hyperforin in some of the St. John’s wort extracts then being sold.1 Too much of a good thing, it seemed, was a bad thing. This came as no great surprise, as the same principle applies to virtually everything we ingest—even water. Amounts matter, and it behooves everyone to ensure that they do not take too much of anything.

How much hyperforin one ingests depends, of course, on two things: the amount of the extract ingested and the percentage of hyperforin in the extract. The St. John’s wort products currently on the market have hyperforin concentrations ranging from a low of less than 0.2% to a high of almost 6%—a 30-fold range. Knowing the percentage, it’s easy to calculate the amount of hyperforin in any given amount of the extract.

No problems are associated with low-hyperforin extracts (less than 1%). High-hyperforin extracts (in the range of several percent) can cause problems—but only if too much of the extract is taken, as many people found out when they took the same quantities as they had before of St. John’s wort products now containing 10 to 20 times more hyperforin.

So what’s a safe amount of hyperforin? (Remember, it’s the daily amount that counts, not the percentage in the product.) It’s safe to say that several milligrams or less is a safe daily amount, as there do not appear to be any reports of adverse drug interactions with hyperforin in these amounts. A conservative estimate is that anything less than 2 mg/day is almost certain to be safe. If you are taking any kind of medication, however, it would be prudent to check with your doctor or pharmacist before taking a high-hyperforin extract of St. John’s wort, to be certain that you are not taking too much of it.


  1. Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St. John’s wort drug interactions. Eur J Clin Pharmacol 2006;62:225-33.

St. John and His Wort

Discovering the benefits of St. John’s wort is like peeling back the layers of an onion, but more exciting—sort of like watching Salome’s dance of the seven veils. We invoke Salome in this context because she gave St. John such a hard time. Yes, that St. John—the one for whom the herb is named, better known as John the Baptist. He condemned the marriage of Salome’s mother, Herodias, to her uncle Herod Antipas (who was one of King Herod’s sons). Perhaps John the Baptist should have been more tolerant— Herodias took revenge through Salome, who ordered his head served up on a silver platter. Her stepfather obliged. (We can’t imagine what dinner conversation was like in the Herod and Herodias household.)

Salome with the head of John the Baptist (Titian, c. 1515)
Eventually John became a saint, his feast day being June 24. By chance, that’s Midsummer Day, which is observed in Europe and Latin America (and in Scandinavian communities in the United States) in commemoration of the summer solstice. The day before is Midsummer Eve, also called St. John’s Eve, when, by tradition, St. John’s wort is gathered. The herb-gathering tradition is the older of the two. Apart from this coincidence in dates, there seems to have been no connection between St. John and his wort (the word means “plant,” by the way, and it rhymes with word, not ward).

The herb’s healing powers were known in St. John’s time, of course. It was valued for its ability to heal battlefield wounds, and it has also been used (with unproven efficacy) for lung complaints, tonsillitis, gastritis, colic, worms, menopausal mood swings, muscle pain, gout, and rheumatism, among others. In modern times, it has been approved by the German Commission E (the most authoritative source regarding the medicinal uses of herbal products) for anxiety, depressive moods, skin inflammation, blunt injuries, wounds, and burns.

St. John’s wort is effective against a wide array of bacteria—even resistant ones—including Escherichia coli and Staphylococcus aureus (the dreaded “staph”). As studies continue, its veiled properties will increasingly become revealed to us. What’s behind the seventh veil—something for Alzheimer’s victims, perhaps? Stay tuned.

. . . Whose Principal Active Component Is Hyperforin

To the Chilean researchers, St. John’s wort seemed like a natural, because depression is a common feature of Alzheimer’s disease, and the herb is a natural antidepressant (it’s also an anti-inflammatory). The herbal component thought to be primarily responsible for the antidepressant activity is the chemical compound hyperforin, a substance that also apparently enhances memory in rodents. Why not, therefore, see what hyperforin does in rats with Alzheimer’s disease?1

It would be impractical to buy a bunch of healthy lab rats and then sit around and wait, hoping they would eventually become demented. Instead, the researchers induced Alzheimer’s in the rats by injecting Aβ fibrils directly into the hippocampus in each side of their brain. The hippocampus is a region that plays a major role in memory, learning, and other cognitive functions. Its shape is vaguely reminiscent of a seahorse, hence its Latin name.

Some of the rats received only Aβ, some received Aβ plus hyperforin, and some received Aβ plus a hyperforin derivative (OHP-Gal or OHP-Li, where Gal and Li stand for galantamine and lithium, respectively). A final group received a placebo injection so that any observed effects of the injection procedure itself could be corrected for. In other experiments, the researchers treated tissue-cultured hippocampal neurons with hyperforin at various concentrations.

After the injections, the rats were given a spatial memory task involving a device called the Morris water maze: using external visual cues, they had to learn how to find their way to a slightly submerged, invisible platform in a water tank in which there was no other place to haul out. After 2 weeks of training, they were killed so their brains could be examined.

Hyperforin Provided Neuroprotection and Enhanced Spatial Memory

A number of results emerged from this study. First, in the living animals, hyperforin protected against the neuropathological changes wrought by Aβ. Inflammatory reactive changes were greatly diminished. With Aβ alone, the number of neurons surviving after the injections was about 70% less than in the controls; with Aβ plus hyperforin, by contrast, the number of neurons surviving was much greater: only about 20% less than in the controls. Hyperforin also protected tissue-cultured hippocampal neurons from Aβ toxicity. In both types of experiment, the two hyperforin derivatives were less effective than hyperforin itself.

When it came to finding their way to the platform in the water tank, the rats injected with Aβ plus hyperforin demonstrated significantly better memory performance than the Aβ-only rats, which fared poorly. Thus, hyperforin apparently afforded protection from Aβ neurotoxicity in the ability to acquire spatial memory. It also suppressed inflammation in the rats’ brains, and it greatly decreased the levels of a marker for oxidative damage.

Hyperforin decreased the formation of Aβ deposits in the rats’ brains. Might it actually cause Aβ fibrils to fall apart? Apparently yes—at least in the laboratory. When Aβ fibrils were incubated with increasing concentrations of hyperforin, the fibrils decreased in a time- and concentration-dependent manner. Whether or not that would occur in an actual brain is impossible to say—there are so many variables, so many unknowns.

The Pale Light of Memory

As sophisticated as it is, this research is still preliminary. It’s not at all certain that hyperforin would work this way in human beings. Even if it did, it’s not certain that it could be administered in sufficient amounts, by a safe route, early enough to abort the Alzheimer’s disease process before a critical number of neurons had been lost. But it does cast another hopeful light on a huge and growing problem.

Memory has light, too. The Romanian dramatist Eugène Ionesco saw it as pallid: “The light of memory, or rather the light that memory lends to things, is the palest light of all. I am not quite sure whether I am dreaming or remembering, whether I have lived my life or dreamed it.” The challenge for all of us is to preserve and protect that pale light as we grow older, for it defines who we are. If it turns out that hyperforin can help in this regard, consider it a gift from a beneficent Mother Nature.


  1. Dinamarca MC, Cerpa W, Garrido J, Hancke JL, Inestrosa NC. Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer’s amyloid-β deposits. Molec Psychiatry 2006;11:1032-48.

Dr. Richard P. Huemer received his M.D. from UCLA and did postdoctoral research in cancer immunology at CalTech. He has specialized in orthomolecular medicine for most of his career, has written and lectured extensively on alternative medicine, and has served on the editorial boards of professional journals. His published books include The Roots of Molecular Medicine: A Tribute to Linus Pauling and, with coauthor Jack Challem, The Natural Health Guide to Beating the Supergerms.

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