Ram mushroom (Maitake, Griflola frondosa) is a medicinal mushroom used for thousands of years. This study examines the antidepressant effects of this fungus and the role of AMPA receptors in the provision of this antidepressant effect. Mice were fed for 1 day or 5 days with a ram mushroom or oyster oyster as a control. The antidepressant effect was determined during the tail suspension test, the forced swimming test and the open field test. The involvement of AMPA receptors was determined by the use of a specific AMPA receptor blocker. Eating food containing lamb mushroom significantly reduced the time of immobility (an indicator of stress) from 30.8 to 60.8%. The food containing the lamb mushroom did not cause hyperactivity during the tests. The antidepressant effect when eating food containing a ram mushroom was significantly stronger than when eating food containing oyster mushrooms. A specific blocker of AMPA receptors GYKI 52466 could block the antidepressant effect of eating food containing a lamb mushroom, which shows that the mechanism of action most likely involves these receptors. Thus, the ram mushroom (maitake) has shown its promise as a safe medicinal food supplement for patients with depression.
A lot of contradictory information can be found about the collection of chaga on the Internet and in the literature. This is especially true of disputes on the topic in which region or part of the planet chaga is the best, and when to properly collect it. As far as I know, serious comparisons of the bioactivity of chag from different regions have not been carried out. However, about 10 years ago, a comparative analysis of the mineral composition of samples from different parts of Siberia, the European part of Russia, Finland, Scandinavia, the USA and Canada was made in one of the private laboratories in the USA with the financing of a company for the production of dietary supplements. According to the data obtained, the chaga of the forests of the Canadian Shield of eastern Canada has the richest mineral composition.
As you understand, it is best to collect chaga in clean birch forests – due to the highest concentration of birches in one area, the probability of finding chaga increases. But good mixed forests with a pronounced participation of birch are also suitable. It is obvious that in aged forests the yield of chaga and the average mass of collected sclerotia is higher than in young ones. It has been noticed that in wet birch forests (moss, swampy, etc.), chaga grows more readily than in dry ones. Chaga does not like polluted air, and it is quite difficult to find her in the city. In urban parks, especially large ones, chags sometimes grow, but in the case of a megalopolis, they willingly begin to grow 3-5 kilometers from their borders, or even further. Comfortable eco-friendly collection of chaga, which has not absorbed any anthropogenic pollutants, begins 30-40 km from large cities.
Consider one more point: chaga should not be collected in regions with a high radioactive background. It is known that the degree of accumulation of radionuclides by fungi strongly depends on what and where they grow. Fungi growing on wood always accumulate radioactive elements to a much lesser extent compared to soil ones. However, chaga, unfortunately, is the only known exception. It contains 10-20 times more of the most dangerous anthropogenic radionuclides americium-231 (231Am) and caesium-137 (137Cs) than in the birches on which it grows.
Chaga has a selective affinity for these elements, and the process of their excessive accumulation is called hyperbioaccumulation. In terms of terrain, the strongest accumulators of radionuclides are sphagnum marshes and their surroundings. They collect precipitation and drainage from a large area, and acidic soil contributes to the greatest participation of radionuclides in metabolic processes. Therefore, although usually near-swamp birch forests are rich in chaga (and any mushrooms), it is especially not recommended to collect it in the Chernobyl cloud passage zone in such places: the amount of radioactive caesium and americium in it will be a record.
The season of collecting chaga, no matter what you read about it, does not matter. Just proceed from when you have free time, or when the chaga is seen best. Neither the active sap movement near the birches, nor the phase of the moon, nor other such popular near-esoteric examples when collecting chaga are really important. As numerous studies have shown, the composition of the chaga rather depends (and gradually changes) on its age than on whether it was harvested in spring or autumn. Usually, chaga is most convenient to extract in winter. At this moment, the forest is bare, and large black sclerotia are perfectly visible against the background of white birches and white snow. The only problem you may encounter is that in severe frosts, the chaga freezes, and its inner tissue becomes the same density as birch wood, or even harder. Therefore, if you are an environmentally oriented person and go out to the chaga in the cold not with an axe and a saw, but with a stone or bare hands, serious difficulties may await you. Most likely, it will not be possible to pick up the frozen chaga with your hands (it is useless to beat with your feet too), and you may have to bludgeon it with a stone for half a day … Recommendations not to extract chaga with the help of evil iron with paramagnetic properties actually arose because if you leave a not smooth slice/cut down / log house (as in the case of an axe or saw), and uneven scrapping (you tore off / knocked down the chaga with your hands or feet / stone), then a new sclerotium is likely to form in this place in a few years if the birch remains alive. Smaller in size, but still…
About the height of the collection. It is proved that the higher the chaga is formed, the more bioactive it is. For example, the content of betulin in the pulp of sclerotia increases statistically with each meter of height. On average, our Russian rule – not to collect chaga if it grows at a height below one and a half meters – works perfectly. In the USA and Canada, it is customary to collect chaga, starting from a height of 3 meters. If the forest in which the chaga has grown is moist, then low-growing specimens are prone to water soaking, swelling and a fairly rapid loss of medicinal properties.
You can collect chaga only from live upright trees. It definitely doesn’t make sense from the fallen ones – the chaga is almost always “empty” there. In winter, if a birch tree has recently died on the root and remained standing, it is not always easy to distinguish such a tree from a living one. In this case, it is necessary to look for fruit bodies – the main sign that the whole tree or its part, where sclerotium grows, is dead. Such sclerotium, as I wrote earlier, loses its medicinal properties very quickly.
From the point of view of the Russian pharmacopoeia, the following requirements are imposed on the qualitatively harvested raw materials of chaga. “The raw materials are dark brown odorless pieces, slightly bitter in taste, no more than 7 mm in size. The quality of raw materials is assessed according to the following indicators: the content of a chromogenic complex (chagic acid, melanin or polyphenol–oxycarboxylic complex) – not less than 10%; humidity – not more than 14%; total ash – not more than 14%; particles that do not pass through a sieve with holes with a diameter of 7 mm – not more than 4%; particles passing through a sieve with holes of 0.2 mm in size – no more than 18%. The shelf life is up to 2 years.”
An extremely productive way to collect chaga is to visit forests where logging is going on. Birch is mostly considered a garbage tree there and is sawn for firewood. Having agreed with the loggers, you can ask them to cut down and save chaga for you in unlimited quantities. For a bottle or its monetary equivalent per day, you will receive chaga for a couple of years of reception. At the same time, the main task will be to explain how chaga differs from similar caps and souvels. Birch cap is a natural outgrowth on a trunk or a large branch, with many woody nodules on the outside, having the appearance of dark thorns and bumps. Usually the size of the mouthpiece is small, 20-30 cm in diameter. Often you can see buds and small twigs growing directly from it. The wood of the cap is 50-70 percent stronger than that of the tree on which it was formed. The formation of the suvel is associated with the disease of the tree, most often outwardly it is a twisted and, as it were, woven into a lump of growth. Suvel reaches an impressive size, usually it is twice as thick as birch or even larger. In addition to the size and “soreness” of the origin, the main difference between the suvel and the cap is that the suvel is formed not from dormant buds, like the cap, but due to the intertwining of annual rings rapidly growing in all directions. Neither cap nor suvel have anything to do with chaga, so before your first trip for chaga, study their images on the Internet.
Quite often, chaga is confused with ordinary tinder (Fomes fomentarius), her old “partner” in manufacture of tinder. This happens simply out of ignorance. The classic gray hoof-shaped common tinder is considered a chaga only by those who have never seen a real chaga before. Because of the name, sometimes chaga is confused with birch sponge (Piptoporus betulinus) it happens becausedue to the fact that both tinder boxes are often called “birch mushroom” on the Internet. Birch sponge is a soft annual tinder with a beige or brownish skin, a flat white tubular layer that darkens when pressed, and a bitter white pulp (at least in young mushrooms). Keep in mind that recipes for birch sponge are rarely suitable for chaga, as are chaga recipes for birch sponge.
For the normal collection of chaga, it makes sense to take with you a light sliding ladder up to 10-15 m high, an axe and a saw. A downed or sawn chaga is usually put in a backpack. If the backpack is small, then to save space, you can immediately clean the chaga from the outer black crust with an axe or a large heavy knife like a machete. And in general, it is more convenient to do it in the forest than to plant dirt at home, and then do cleaning. The chaga can be chopped immediately, so it will become even more compact. Wet specimens, sclerotia damaged by mold or insect larvae should not be collected. Such signs indicate that something went wrong with the mushroom, most likely it is dead and its medicinal properties have been lost.
In good places in summer, 50-100 kg of chaga is collected in 3-5 hours, in winter – in 5-6 hours (the colder it is, the longer, because the more difficult it is to knock down or chop / saw). Unlike most edible mushrooms, which suffer greatly from long transportation from the collection point to the house and react sensitively to the density and ventilation of the container, chaga quite calmly tolerates the longest “excursions”. You can carry it in a damp sealed container for half a day, and it will still arrive normally, neither self-heating, nor moldy, nor beginning to swarm with larvae of mushroom flies and mosquitoes. Nevertheless, having brought chaga from the forest, it is advisable to immediately start processing it in order to preserve all the useful properties as much as possible.
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For many centuries chaga and its infusions are used by the Russian population as a means to improve the quality of hair, nails and skin and as a medicine for them. Relatively recently, these qualities of chaga were appreciated by the world cosmetology industry. Now chaga is included in creams, gels, lotions, shampoos, soaps, scrubs and masks. Extracts of chaga containing a high amount of melanin are added to shampoos, conditioners and cosmetic milk (cream). Such cosmetics help strengthen hair follicles, restore the structure of damaged hair, eliminate inflammation, fragility and split ends, stimulate skin renewal and healthy hair growth.
With rare exceptions, chaga is not the only active component of a cosmetic product, usually manufacturers add other natural ingredients to it, including bioactive extracts of fungi and plants. For example, in the manufacture of chaga soap, some manufacturers add extracts of a series or reishi. At the beginning of 2021, our mushroom pharmacy will offer an innovative therapeutic and cosmetological line based on chaga.
In the meantime, let’s look at what substances of chaga are useful for our integuments and how they work.
Betulin – the famous triterpenoid – is contained in birch bark and migrates from there to chaga. Chaga partially leaves it as it is, and partially translates it into more bioavailable forms for us. No wonder cosmetics manufacturers (especially American ones) have long started adding birch bark extract to various skin care products. The main task of betulin is to protect the skin. Remember: a dead birch tree is lying in the forest, all rotted inside, and the birch bark on it is like fresh. This betulin prevents fungi and bacteria from developing. In the case of the skin, betulin and its derivatives (betulinic acid and lupeol) fight local infections and irritations, enhance the immune response, have an anti-inflammatory effect and simultaneously stimulate the growth of healthy skin cells. Betulin helps with wounds, injuries, burns, frostbite, juvenile acne, inflammation and peeling of the skin, insect bites.
Like betulin, lanostane triterpenoids are beginning to be used in therapeutic and cosmetic preparations. Interesting research was conducted by a Japanese working group from Tokushima University (Tokushima, Japan). They analyzed a homemade traditional chaga shampoo, which is used in Mongolia to maintain hair health. As a result, it was found that the active components of the shampoo affecting the hair follicles were five lanostane-type triterpenes, including lanosterol, inotodiol, lanost-8,24-diene-3b,21-diolitramethenolic acid (all these substances are only in chaga). Experimenting with chaga extract, the Japanese have shown that its proliferative effect is more powerful than that of minoxidil, which is popular today, a well-proven and very popular hair extension agent. Therefore, if you are struggling with alopecia or just want your hair to be luxurious and radiant, use shampoos based on chaga.
In chaga there is ergosterol, a precursor of vitamin D2. Ultraviolet light converts ergosterol into viosterol, which is then converted into vitamin D2. It has been experimentally shown that if we dry large pieces of fresh chaga in the sun, the residual vital processes in the fungus are enough to accumulate vitamin D2 in the tissues. Vitamin D3 is synthesized in our skin under the influence of direct ultraviolet light, it is absorbed within 24-36 hours after formation. Vitamins of group D are necessary for the creation of new skin cells and for the normal growth of bones, teeth and hair.
These are polysaccharides responsible for skin regeneration and have a restorative effect on the skin and hair.
The antioxidant activity of beta-glucans is another of their remarkable medicinal properties. If a tumor develops in the body, as a result of stress, this leads to the appearance of a large number of free radicals. Under the influence of beta-glucans and other biologically active substances of chaga, the immune system comes out of a state of shock and begins to work actively. Therefore, one of the first actions that can be noticed at the beginning of taking chaga or other drugs with beta-glucans is to reduce the level of oxidative damage and stress caused by free radicals. And that, as they say, is not all. Even oxidative damage caused by external factors (for example, burns or exposure to chemically aggressive substances) can be effectively treated with both local and systemic administration of beta-glucans. Studies of their antioxidant properties have shown that they are able to organize even the protection of cells from radiation. Due to the high commercial interest in the ability of fungal beta-glucans to actively influence the regeneration and healing of the skin, numerous laboratory studies are currently being conducted in this direction. For example, a few years ago, the following data were obtained in one of the US laboratories: the effect of a cosmetic preparation containing beta-1,3-glucan on signs of skin aging was evaluated in 150 women aged 35 to 60 years; skin hydration after eight weeks of cream application (twice a day) improved by 27%; noticeable reduction of wrinkles at the end of the study reached 47%, firmness and elasticity increased by 60%, and skin color improved by 26%.
In addition, data have been obtained indicating that beta-glucans protect the skin from burns with preliminary local and internal use. They play a significant role in this effect, about the same as melanin. That is why chaga has a special affinity for fighting melanomas (skin cancer) and other skin diseases, including psoriasis.
According to the research of I. B. Mosse (Belarus) and L. P. Zhavoronkov (Russia), melanin is a unique basis for the prevention of genetic and ontogenetic consequences of radiation exposure. The special value of the research is that the experiments were conducted in vivo. Melanin reduces the accumulation of radionuclides in the body by actively binding uranium and transuranic elements; it is one of the most powerful known antioxidants, giving these properties to chaga. With regular use of chaga, the level of damage to skin cells by penetrating radiation and radioactive precipitation decreases, and radioactive isotopes are transferred to a safe form. These data were obtained during the study of the consequences of the accident at the Fukushima nuclear power plant (Japan).
Chaga contains more melanin than any other mushroom. This is the best natural source of pigment of all possible, and in the form that is closest to the human body. Often with age, due to stress, genetic failures, lack of minerals and for other reasons, the balance of melanin synthesis in the skin can be disrupted, which leads to the appearance of white or dark spots, including, possibly, vitiligo (now this disease is associated with the combined effects of stress and an unknown virus). Due to the presence of melanins, cosmetic preparations of chaga effectively protect us from many troubles, such as skin cancer (melanoma), exposure to ultraviolet radiation, penetrating radiation, high temperatures and chemical stresses, and even the threat of biochemical invasion, since they increase immunological protection against all kinds of pathogenic microorganisms. Melanin promotes beauty, healthy shine and improves the appearance of hair, nails, skin and eyes, helps to restore and maintain a younger appearance. As you understand, the inclusion of chaga in a permanent diet will make up for a possible lack of melanin or reduce the load on the body engaged in the extraction of substances necessary for its synthesis. This will positively affect hearing, the pineal gland and adrenal glands, the immune system, and the quality of the skin.
As a result, we can say the following. Due to the high concentration of melanin and the content of antioxidants and beta-glucans, chaga is effective in eliminating signs of skin aging (wrinkles and weakening of tone), photo damage, dark circles and puffiness around the eyes, scars, skin fatigue, acme, enlarged pores, poor blood microcirculation, symptoms of cellulite and stretch marks. It is also useful for skin damaged by chemical peeling, laser resurfacing and other cosmetic procedures. To get an external effect, it is not necessary to use cosmetics, sometimes it is enough to regularly consume drinks prepared on the basis of chaga (especially good in this regard is chaga of long-term boiling), and jelly with chaga based on gelatin (an excellent light breakfast or dessert that has immunomodulatory properties and really cares about your beauty).
Laboratory studies conducted on rodents have shown that edible morel polysaccharides have antitumor (ethanol extract), immunomodulatory, antiviral and restorative activities. The methanol extract of fruit bodies has antioxidant properties.
In Chinese medicine, it is used for indigestion, copious sputum and shortness of breath. In Russia, it is used in folk medicine for the treatment of pulmonary and gastrointestinal diseases, for joint diseases, rheumatism, tincture from morel caps was rubbed into sore spots. A decoction of morels is used to stimulate appetite, enhance the activity of the gastrointestinal tract, as well as as a tonic, regulating the flow of vital energy and a complex health remedy. To prepare a decoction in 250 ml of water, boil 1 tablespoon of fresh or dry morels for 30 minutes, insist for 4 hours and filter. Take 50 ml 4 times a day 10-15 minutes before meals.
Oral use in the proportion of 1 mg per 1 kg of weight led to a decrease in the volume of the tumor by 74.1% and a decrease in weight by 79.1% over 30 days of the course. A 50% ethanol extract of the mycelial culture of M. esculenta showed activity against Dalton’s lymphoma.
Methanol extract of mycelium showed high antioxidant activity. When compared with common antioxidants — ascorbic acid, α-tocopherol and BHA (butylhydroxyanisole) — it was 36.9%, 80.5% and 98.1%, respectively.A 50% ethanol extract of M. esculenta mycelium grown in a semi-submerged culture has shown efficacy against acute inflammation caused by the use of carrageenan and chronic inflammation induced by formalin. A single oral application of the extract at the rate of 500 mg per 1 kg of weight led to a reduction in the zone of acute inflammation by 66.6% and chronic by 64.2%. Such activity is comparable to the action of the best modern anti-inflammatory drugs, for example, diclofenac.
In order for a mushroom dish to turn out delicious, it is important not only to have high-quality mushroom raw materials, but also to know which products mushrooms are combined with. It must be remembered that the taste of fresh mushroom dishes is determined primarily by the natural mushroom smell. Therefore, it is undesirable to add such strong spices as black pepper, basil, coriander, cloves and cinnamon to mushroom soups, sauces and roasts. On the contrary, such seasonings and spicy vegetables as garlic and onion, bay leaf, dill and parsley are perfectly combined with mushrooms.
Since mushrooms contain almost no sugar and acid, it is always a good idea to acidify them a little during cooking with sour cream, tomato paste or fresh tomatoes, as well as dry white wine.
Mushroom sauces are usually served with meat and fish dishes. According to the rules, they are cooked only on mushroom broth. The best for this purpose is a concentrated decoction of dried porcini mushrooms. Another mandatory component of mushroom sauce is passerovka (fried flour).
The best side dish for the mushrooms themselves, of course, is potatoes, but rice, buckwheat and pasta are also well suited.
Having gathered to cook mushrooms, it is necessary to imagine very well that their fruit bodies are heavy, low—nutritious food, which, with a competent approach, can be made light and nutritious. In this regard, mushrooms resemble oil, which contains a huge amount of energy, but, unfortunately, is completely not absorbed by the body.
A young mushroom, 2-3 days after it appeared from the soil or poked through a crack in the wood, already contains all the organic substances and trace elements “released” to it by nature, and even an almost unchanged number of cells. What we call the further growth of the fungus is actually not growth, but the stretching of cells under the action of water injected under pressure into the fruit body by a mycelium pump. Thus, even the youngest mushroom is almost completely “equipped” with everything necessary for frying, drying, and pickling-pickling, and is especially good because there is nothing superfluous in it, no water (both literally and figuratively). That is why young mushrooms with not yet opened caps are appreciated by mushroom pickers (albeit often subconsciously, but true) most of all. Old and flabby mushrooms are not only unaesthetic, but can also pose a threat to human health, which we will discuss below.
The least requirements are imposed on mushrooms intended for pickling and drying. When marinating, the mushrooms’ own taste is lost very much, it is replaced by the taste of the marinade and is determined by the amount of vinegar, sugar and the types of spices used. Of course, young elastic buttermilk or crunchy cheese “by the tooth” will be perceived better than the old, slimy and flabby, but they will taste almost the same, and in a salad of pickled mushrooms you will not catch the difference at all.
When drying, even very old, already “wet” (if only not wormy) mushrooms can be “pulled out” by prolonged soft treatment in the dryer (if only they don’t burn), and they will behave quite decently in the soup. Of course, again, they will yield to young “breadcrumbs” both in taste and aroma, but after adding sour cream, this difference is also almost leveled. Nevertheless, one rule should be firmly remembered: mushrooms collected for preparations should be approached more legibly than mushrooms collected for today’s or tomorrow’s soup or frying. This will necessarily lead to an increase in the shelf life of the finished product with the correct processing technique.
In late autumn, just before the frosts, there are not many mushrooms in our Tver region.
The white, aspen trees broke off, even the later mushroom – the pine ginger has already departed.
A couple of frozen chanterelles and thin slimy hygrophores do not please the lover of the third hunt.
All that remains for him is to wander sadly through the white–moss forests and breathe the cool pre-winter air, but this does not apply to advanced mushroom pickers.
Pine whiteflies are a favorite place for the growth of an interesting and little–known edible mushroom – the tortoiseshell hedgehog.
It is large, fleshy, even, perhaps, too dense, similar to a large podgruzok with a dark hat with a pattern of scales whipped up and with amazingly delicate spikes under the hat.
Hedgehogs are real stoics among mushrooms. Old, almost lignified, they stand quietly in the forest until spring. But we are interested in young, soft, light mushrooms.
In the families that the hedgehog prefers to grow, there are usually from 2 to 3 pieces. It is better to leave the “oldies” in the forest. It is not difficult to cut a whole basket of weighty hats and bring it home.
The best thing there is to cut them into strips and dry them in a cool dryer and then, in winter, enjoy eating a hedgehog in cabbage soup, borscht and second courses. The hedgehog has a slightly sweet, warm and incomparable mushroom aroma.
In addition, it is a mushroom with medicinal properties.
It is able to lower cholesterol and is a powerful immunomodulator.
The scaly hedgehog has never been used in folk medicine, but scientists in the laboratory were able to extract substances from it that can have a broad-spectrum antimicrobial effect, neutralizing even Staphylococcus aureus and salmonella.
And also studies have proved that preparations from kolchak motley can be beneficial for oncological diseases.
When I brought a basket of black chanterelles to the dacha a couple of weeks ago, the neighbor looked at me in bewilderment: “Chanterelles? Black? I’ve never seen them here.” And he lives there, like us, soon 35 years.
And it’s no wonder to miss these mushrooms — black chanterelles in our northern latitudes prefer to grow in damp mixed forests with birch litter, against which they are almost invisible – even large families and witch circles.
Let the yellow chanterelles cheerfully call for mushroom pickers, let the other neighbors in the mixed forest show snow—white hats from under dark leaves. Black chanterelles like to hide. The only exception is if they run out to a completely swampy edge on the green moss, they are more noticeable there.
But black chanterelles are an interesting and delicious mushroom. In dried form, they acquire a strong, thick and even heavy aroma of mushrooms mixed with dried fruits.
In France, they are called “death pipes” and are used along with truffles and morels in haute cuisine. And we made Korean carrots, risotto, cutlets with them, and even a unique harsh male mushroom jam for steak with lingonberry juice, juniper, rosemary and sea salt.
The recipe, however, was stolen by the Musrooms restaurant, and you can try it there too. For the crazy thousands.
Friends, when we came up with the “Fly Agaric microdosing” TM, we did not know how popular this product would be: we even found ourselves in a situation of shortage of raw materials. But there is a silver lining – now we have a huge amount of feedback that we receive by phone and email. We will share some of the accumulated, and then here on the website fungiline.com , those who want to, will be able to leave their reviews. So, despite our fears and tricks with the test capsule, only 2 people out of more than 10,000 customers returned the drug to us. Thus, we can say that for the vast majority of people it is safe and does not cause any negative consequences.
Now about the pros. The most frequent thanks that we hear from MM customers are the “equalization” of mood, the absence of depression and panic attacks, normalization of sleep and a serious reduction or rejection of bad habits (alcohol and smoking). This, by the way, is the expected effect, since fly agaric as an entheogen “does not like competitors.” We hear such reviews about 80% of the time.
The second most frequent group of thanks is the action of MM as a tonic and activator of vital processes. People have more time, become more active, more collected and more positive. It is better to work in multitasking conditions, stress tolerance increases in a big city. There are about 15% of such reviews.
More rare, but very pleasant reviews are the normalization of the work of internal organs. By the way, sometimes normalization is preceded by a period of exacerbation of pain, fly agaric “shows” sore points before healing occurs. Now “in the collection” of cures and persistent remissions are chronic gastritis, pancreatitis, colitis, tonsillitis and otitis media. This can also include the care of long-standing muscle and joint pain, and recovery after competitions in athletes.
Separately, it is necessary to mention the work of Fly Agaric microdosing with the skin. Atopic dermatitis, eczema are significantly relieved or go away not only from the use of fly agaric cream externally, but also from fly agaric microdosing in the form of systemic therapy.