Category: Holistic Healing

I listened to the lecture of professor Dr. Bill J. Gurley titled “Clinically relevant herb-drug interactions: past, present, and future” at the National Center for Complementary and Integrative Health, National Institutes of Health of the U.S.A. I was impressed with the presentation from one pharmacy professor who is highly specialized in the pharmacokinetics and pharmacodynamics (metabolism of medications and supplements) of conventional medicines and supplemental herbal products. After the lecture, I started wondering what we really know about herbal remedies or their combination with conventional prescription medications as a part of complementary treatment. How many people are aware and knowledgeable about that? Indeed, we learned about herbal medicine a lot, but how about its combination with conventional therapeutics in the form of complementary therapy?

Did we learn something from the case of ephedra (Ephedra sinica)?

Clearly was stated in the lecture that, for example, ephedra (Ephedra sinica) was used in Traditional Chinese Medicine for over 5000 years for the treatment of asthma and nasal congestion for only 7 – 10 days, and that’s it, either a patient is healed or not, but not chronic use of ephedra was considering and proper treatment by ephedra in Traditional Chinese Medicine. However, in the U.S.A., from 1994 until 2004, ephedra was used chronically as a potent stimulant, not as a remedy for bronchial asthma, nasal congestion, cold, flu, fever, cough, and wheezing. In response to substantially collected evidence of adverse effects and deaths related to ephedra, the U.S. Food and Drug Administration (FDA) banned the sale of supplements containing ephedrine alkaloids in 2004. Ephedrine is a potent sympathomimetic that stimulates alpha, beta one, and beta two adrenergic receptors. It excites and stimulates the sympathetic nervous system, causes tremendous vasoconstriction and cardiac stimulation, and produces effects similar to epinephrine (adrenalin). Ephedra extracts that do not contain ephedrine have not been banned by the FDA and are sold legally today. Yet, Chinese and others who know how to use ephedra effectively cure some acute diseases in short-term treatment, NOT chronically.

Do we really use herbal remedies correctly in our Western culture and conventional treatment with prescription medications and then call that complementary treatment?

Do we consider numerous factors regarding combining conventional medicines and herbal remedies in complementary therapy, such as patient characteristics, gender, age, ethnicity, co-morbidity, frailty, rare genotypes, and others? Also, the fact that the majority of currently available dietary and supplemental herbal remedies are products containing multiple herbal components, that their formulation utilizes highly concentrated herbal (botanical) extracts, which is not a proper way of preparing herbal remedies in alternative medicine, that many commercially available supplemental herbal products have the presence of numerous phytochemicals that have not been tested for pharmacological activities. These facts do not “sound” like traditional herbal therapy and their proper use as supplemental therapy in complementary and conventional medicine by using prescribed medications.

What is the level of the current clinical evidence?

The next surprise, when I was searching for the scientific literature data, results of clinical studies regarding using herbal remedies as a supplement therapy to conventional therapeutics, calling that complementary treatment, mostly they are isolated case studies or case series, case reports, and results of in vitro analysis performed on cell cultures expressing human genes (for example). Mostly, clinical evidence has been on the level of preliminary case studies, case reports, an adverse event unlikely from a pharmacological viewpoint, and case reports providing some evidence for interaction; however, other cases not entirely excluded, case series, some pharmacokinetic trials in patients or healthy people, there are numerous contradictory data, or adverse events are highlighted by case reports but not confirmed by clinical trials or mega clinical trials. Most authors were allowed to generalize. Generally, generalization is acceptable only if you perform experimental clinical research design. No doubt, scientifically, case studies are a useful “tool” to set up a future hypothesis in clinical research and to conduct further research in that particular field.

Complementary medicine is teamwork between conventional (Western medicine) specialists and alternative herbal medicine specialists

Well, where we are regarding understanding herbal medicine, do we really appreciate them, maybe we misuse them, how properly they should be used, and how can they be applied as an additional therapy with conventional medications in the form of complementary medicine? Also, there is one more question, if we do not know how to use them properly, why we do not leave it to the patient to make a decision either to use herbal medicine (correctly) or conventional drugs to treat their diseases or provide prescription authorities with additional education regarding a complementary approach for therapy. Certainly, complementary medicine is teamwork. Indeed, the “street” is in two directions, a two-way street, not one. It looks like some bigger picture is behind all these facts.

Current clinical evidence of interactions between herbal (botanical) and conventional medications

Herbal medicines have been well known worldwide, in European countries, America, Russia, China, India, and Arabic countries for centuries. Currently, Western herbal medications can be classified into botanical-derived conventional medicines and dietary supplements. However, over the past two decades, intensive interest in herbal medicine has overgrown in all countries. In addition, due to cultural diversities in the EU and Russia, traditional herbal remedies of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular (Sammons H.M. et al., 2016).

The typical scenario today is a combination of herbal medicines used in conjunction with conventional drugs in the form of complementary treatment. Unfortunately, this condition may give rise to the potential for harmful herb-drug interactions.

Some clinically critical herb-drug interactions have been reported in the literature. Still, many are from case studies, case reports, and limited clinical observations or literature searches and reviews of published case reports. Common herbal medicines that exhibited some interactions with conventional medications (prescription medications) include St John’s wort (Hypericum perforatum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John’s wort could significantly reduce the area under the plasma concentration-time curve, and blood concentrations of conventional medications prescribed by medical specialists such as cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon, and theophylline. The standard drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus, and irinotecan.

Herbal medicines may interact with medications in the intestine, liver, kidneys, and action targets. Most of them are actually substrates for specific metabolizing enzymes such as cytochrome P450s and P-glycoprotein. Well, the underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and pharmacodynamic events are implicated in many of these interactions but not fully understood and investigated. In particular, enzyme induction and inhibition may be essential in some herb-drug interactions. Because herb-drug interactions can significantly affect circulating levels of conventional medications and alter the clinical outcome, identifying herb-drug interactions has important implications (Chen X.W. et al., 2012).

Clinical consequences of herbal/botanical medicine-drug interactions depend on various factors, such as the co-administered drugs, the patient characteristics, general patient conditions, the origin of the herbal medicines, the composition of their constituents, and the applied dosage regimens. Therefore, to optimize the proper use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and delineate the underlying mechanisms (Shi S. et al., 2012, Singh D., 2012).

Various clinical and other medical literature reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. For example, The World Health Organisation indicated that approximately 80% of the Asian and African populations rely on traditional herbal medicine as the primary method for treating various diseases (Neergheen-Bhujun V.S., 2013).

The use of botanical/herbal dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, their concentration in the final product, mechanisms of action, efficacy, and safety. An essential but under-investigated safety concern is the potential for popular botanical/herbal dietary supplements to interfere with the absorption, transport, and metabolism of conventional medications prescribed by prescription authorities. Therefore, clinical trials of drug-botanical interactions should be the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical in vitro studies.

For example, phase one clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 (Sprouse A.A., 2016). The complementary use of medications and herbal/botanical products is becoming increasingly prevalent over the last decade as a highly concentrated supplemental product (Cho H.J. et al., 2015). Herb-induced enzyme inhibition and induction may result in enhanced and decreased tissue, plasma, bile, and urine drug concentrations, leading to a change in a conventional medication’s pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects (Li B. et al., 2016). Cytochrome P450 enzymes metabolize many FDA-approved pharmaceuticals (conventional medications) and herbal supplements. This metabolism of medicines and supplements can be augmented by concomitant use. For example, the xenobiotic receptors androstane receptor (CAR) and the pregnane X receptor (PXR) could respond to xenobiotics by increasing the expression of many genes involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s enzymes. Induction of the expression or inhibition of the action of CYP450s enzymes can result in drug-drug interactions and toxicity (Brewer C.T.et al., 2017).

Herbal medications, herbal dietary supplements, and other nutritional supplements are highly prevalent among older people

Herbal medications and other dietary supplements (herbal, vitamin-minerals, and probiotics) are prevalent in older people. Physicians, particularly primary care physicians, are often unaware that their patients use herbal remedies and other nutritional supplements concomitantly with conventional medicines. Herbal remedies and other dietary supplements contribute to high rates of polypharmacy, particularly among older people with multimorbidity. Herbal medicines and other nutritional supplements can interact with conventional drugs and be associated with various adverse side effects. Physicians should be patient-centered and non-judgmental when initiating discussions about herbal medicines and other dietary supplements. Maintaining and developing patient empowerment and self-management skills (Pitkälä K.H. et al., 2016) is vital. In addition to conventional medicine prescribed by a physician(s), many patients regularly use alternative therapies as a self-directed complementary treatment. Communication between patients and providers about complementary therapy use is not consistent. There is an extreme demand for interventions in health care that provide timely, integrative communication support. Delivering herb-drug-disease alerts through multiple channels could help meet critical patient information needs (Christensen C.M. et al., 2017). It is essential to state that conventional medicine specialists should consult alternative medicine specialists if the patient is determined to undergo complementary treatment.

Clinical professionals and specialists, as well as alternative medicine specialists, should enhance risk management on herbal-medication interactions such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant herbal/medication interaction by computerized reminder system, selecting the alternatives, adjusting the dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation (Zhang X.L. 2017).

Severe herb-drug interactions were noted for St. John’s wort (Hypericum perforatum) and mistletoe (Viscum album). The most severe interactions resulted in transplant rejection, delayed emergence from anesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis, and death. Moderately severe interactions were noted for ginkgo (Ginkgo biloba), ginseng (Panax ginseng), kava kava (Piper methysticum), saw palmetto (Serenoa repens), and green tea (Camellia sinensis). Antiplatelet agents and anticoagulants were the most commonly interacting drugs (Posadzki P. et al., 2013).

Although (unfortunately) several studies on pharmacokinetic and pharmacodynamic herb-drug interactions have been conducted in healthy volunteers, there is tremendous uncertainty on the validity of these studies. Unfortunately, a qualitative review and a meta-analysis were performed to establish the clinical evidence of these interaction studies. According to the literature data, out of 4026 screened abstracts, 32 studies were included in the qualitative analysis. The meta-analysis was performed on only eleven additional studies (Awortwe C. et al., 2019).

Many patients treated with cardiovascular medication like to drink green tea because of their cultural tradition or because of its beneficial effects on general wellness and health. However, green tea may affect the pharmacokinetics and pharmacodynamics of many cardiovascular medications and compounds. Some recent data showed that green tea and some cardiovascular medications interact, and drug interactions were reported for rosuvastatin, sildenafil, and tacrolimus. Putative mechanisms involve inhibitory effects of green tea “catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol, and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, data on green tea interaction with cardiovascular substances with a narrow therapeutic index, such as warfarin and tacrolimus, are derived from single case reports. Conversely, green tea interactions with simvastatin, rosuvastatin, nadolol, and sildenafil were documented through pharmacokinetic studies” (Werba J.P. et al., 2018).

There has been substantial interest lately in using herbs to treat hypertension and cardiovascular disease.

“Herbs and other botanicals contain numerous phytochemicals that effectively treat cardiovascular diseases and hypertension. Accumulating scientific evidence provides a reason for the use of herbs by health practitioners for treating their patients. The rationale for this expanding use of herbs is patients’ belief in a “holistic medicine” and that herbs are natural, safe, and effective. However, there are reasons for concern with the use of herbs because they are not regulated or supervised carefully, and their use could lead to severe complications or interactions with their combination with traditional medicines. Also, their use is associated with significant out-of-pocket expenses because their use is not compensated by health insurance providers” (Chrysant SG et al., 2017).

Malongane F. and colleagues stated in 2017 in their article: “Tea is one of the world’s most widely consumed non-alcoholic beverages next to the water. It is classified as Camellia sinensis and non-Camellia sinensis (herbal teas). The common bioactive compounds found mainly in green teas are flavan-3-ols (catechins) (also called flavanols), proanthocyanidins (tannins), and flavonols. Black tea contains theaflavins and thearubigins, white tea contains l-theanine and gamma-aminobutyric acid (GABA), while herbal teas contain diverse polyphenols. Phytochemicals in tea exhibit antimicrobial, anti-diabetic, and anti-cancer activities that are perceived to help manage chronic diseases linked to lifestyle. Many of these phytochemicals are reported to be biologically active when combined. Knowledge of the synergistic interactions of tea with other teas or herbs in terms of biological activities will benefit therapeutic enhancement. There is evidence that various types of teas act synergistically in exhibiting health benefits to humans, improving consumer acceptance and economic value. Similar observations were made when combined with teas, herbs, or medicinal drugs.” (Malongane F et al., 2017).

St. John’s wort is a common medicinal herb for treating mild to moderate depression.

Hyperforin, one of the main components of St. John wort, plays an essential role in the induction of cytochrome P450 enzymes and P-glycoprotein transporter and consequentially affects the pharmacokinetics of various drugs. Several clinical studies demonstrate the interaction of St. John wort with the metabolism of conventional medications, which may cause life-threatening events such as probably serotonin syndrome if combined with SSRI antidepressant therapy (Soleymani S et al., 2017).

In one article published in 2017, Asher G.N. and colleagues stated: “Nearly 25% of U.S. adults report concurrently taking prescription medications with dietary supplements. Some supplements, such as St. John’s wort and goldenseal, are known to cause clinically significant drug interactions and should be avoided by most patients receiving any pharmacologic therapy. However, many other supplements are predicted to cause interactions based only on in vitro studies that have not been confirmed or have been refuted in human clinical trials. Some supplements may cause interactions with a few medications but are likely safe with other medications (e.g., curcumin, echinacea, garlic, Asian ginseng, green tea extract, and kava kava). Some supplements have a low likelihood of drug interactions and, with certain caveats, can safely be taken with most medications (e.g., black cohosh, cranberry, ginkgo, milk thistle, American ginseng, saw palmetto, valerian). Clinicians should consult reliable dietary supplement resources, or clinical pharmacists or pharmacologists, to help assess the safety of specific herbal supplement-drug combinations. Because most patients do not disclose supplement use to clinicians, the most crucial strategy for detecting herb-drug interactions is to develop a trusting relationship that encourages patients to discuss their dietary supplement use” (Asher GN et al., 2017). Izzo A.A. and colleagues published data in 2016. They stated: “Systematic reviews/meta-analyses suggest preliminary or satisfactory clinical evidence for agnus castus (Vitex agnus castus) for premenstrual complaints, flaxseed (Linum usitatissimum) for hypertension, feverfew (Tanacetum partenium) for migraine prevention, ginger (Zingiber officinalis) for pregnancy-induced nausea, ginseng (Panax ginseng) for improving fasting glucose levels as well as phytoestrogens and St John’s wort (Hypericum perforatum) for the relief of some symptoms in menopause. However, firm conclusions about efficacy cannot be generally drawn.”

On the other hand, inconclusive evidence of effectiveness or contradictory results has been reported for Aloe vera in the treatment of psoriasis, cranberry (Vaccinium macrocarpon) in cystitis prevention, ginkgo (Ginkgo biloba) for tinnitus and intermittent claudication, echinacea (Echinacea spp.) for the prevention of common cold and pomegranate (Punica granatum) for the prevention/treatment of cardiovascular diseases. A critical evaluation of the clinical data regarding the adverse effects has shown that herbal remedies are generally better tolerated than synthetic medications. Nevertheless, potentially dangerous adverse effects, including herb-drug interactions, have been described. This suggests the need to be vigilant when using herbal remedies, particularly in specific conditions, such as during pregnancy and in the pediatric population” (Izzo AA et al., 2016).

Ginkgo biloba leaf extracts are popular herbal remedies for the treatment of Alzheimer’s dementia, tinnitus, vertigo (Meniere’s disease), and peripheral arterial disease

Unger M., in an article published in 2013, stated: “As ginkgo biloba leaf are taken regularly by older people, who are likely to also use multiple other drugs for the treatment of, e.g., hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest.” (Unger M., 2013).

The statement that many people have the mistaken notion that natural, all herbs and foods are safe; is not so. Why?

The market contains highly concentrated dietary, supplemental products from botanical/herbal sources, aromatherapy, vitamin-minerals, additional products, and probiotics. Indeed, these herbal remedies are far different than the ones supposed to be administered; they are diverse, concentrated, and combined with conventional medicines and compete for metabolism with our xenobiotic metabolizing enzymes from a family of cytochrome CYP450 s and others. The patient should decide in consultation with a traditional/conventional medicine specialist (Western medicine) or alternative medicine specialist what treatment would be the best option for a patient. The complementary aspect should be conducted carefully with synchronized conventional and alternative medicine administration. A pharmacist should be a great source of knowledge with their knowledge of pharmacokinetics, pharmacodynamics, and pharmacognosy. Unfortunately, many people use Internet resources for consultation and so-called self-healing instead of using the practices of conventional medicine specialists and alternative medicine specialists.

Also, as you can see from this short review, there are no reliable scientific data on herbal/medicine interaction and side effects; all data are from isolated case reports with suspicion of conflict of interests. However, during the last twenty years, the practice of herbalism and the production of highly concentrated herbal remedies as supplemental products has become mainstream worldwide. Again, this is due to recognizing the value of conventional medical practice globally. Herbal remedies traditionally are mixtures of more than one active ingredient or single herbal sources such as a tincture or tea, but they are not highly concentrated. In addition, they should be administered for a certain period, NOT chronically, as explained in the case of ephedra.

Undoubtedly, the possibility of herb-drug interactions is theoretically higher than drug-drug interactions because synthetic drugs usually contain a single chemical entity, even though it is not scientifically confirmed. As Hussain M.S. explained in the article published in 2011: “Case reports and clinical studies have highlighted the existence of some clinically significant interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in significantly reduced drug pre-systemic metabolism. An additional mechanism is the inhibition of P-glycoprotein. This transporter carries the drug from the enterocyte back to the gut lumen, further increasing the fraction of the drug absorbed. Some herbal products (e.g., St. John’s wort) have been shown to lower the plasma concentration (and the pharmacological effect) of some conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives, and digoxin” (Hussain MS., 2011).

Respectfully,

Holistic Healthful

References:

Sammons HM, Gubarev MI, Krepkova LV, Bortnikova VV, Corrick F, Job KM, Sherwin CM, Enioutina EY. Herbal medicines: challenges in the modern world. Part 2. European Union and Russia. Expert Rev Clin Pharmacol. 2016 Aug;9(8):1117-27.

Chen XW1, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H, Zhou SF. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab. 2012 Jun 1;13(5):640-51.

Shi S1, Klotz U. Drug interactions with herbal medicines. Clin Pharmacokinet. 2012 Feb 1;51(2):77-104.

Singh D1, Gupta R, Saraf SA. Herbs-are they safe enough? An overview. Crit Rev Food Sci Nutr. 2012;52(10):876-98.

Neergheen-Bhujun V.S. Underestimating the toxicological challenges associated with the use of herbal medicinal products in developing countries. Biomed Res Int. 2013;2013:804086.

Sprouse A.A, van Breemen R.B. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements. Drug Metab Dispos. 2016 Feb;44(2):162-71.

Cho H.J, Yoon I.S. Pharmacokinetic interactions of herbs with cytochrome p450 and p-glycoprotein. Evid Based Complement Alternat Med. 2015;2015:736431.

Li B, Zhao B, Liu Y, Tang M, Lüe B, Luo Z, Zhai H. Herb-drug enzyme-mediated interactions and the associated experimental methods: a review. J Tradit Chin Med. 2016 Jun;36(3):392-408.

Pitkälä KH, Suominen MH, Bell JS, Strandberg TE. Herbal medications and other dietary supplements. A clinical review for physicians caring for older people. Ann Med. 2016 Dec;48(8):586-602.

Brewer CT, Chen T. Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450. Int J Mol Sci. 2017 Nov 8;18(11).

Christensen CM, Morris RS, Kapsandoy SC, Archer M, Kuang J, Shane-McWhorter L, Bray BE, Zeng-Treitler Q. Patient needs and preferences for herb-drug-disease interaction alerts: a structured interview study. BMC Complement Altern Med. 2017 May 19;17(1):272.

Zhang XL, Chen M, Zhu LL, Zhou Q. Therapeutic Risk and Benefits of Concomitantly Using Herbal Medicines and Conventional Medicines: From the Perspectives of Evidence Based on Randomized Controlled Trials and Clinical Risk Management. Evid Based Complement Alternat Med. 2017;2017:9296404.

Posadzki P1, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol. 2013 Mar;75(3):603-18.

Awortwe C, Bruckmueller H, Cascorbi I. Interaction of herbal products with prescribed medications: A systematic review and meta-analysis. Pharmacol Res. 2019 Mar;141:397-408.

Werba JP, Misaka S, Giroli MG, Shimomura K, Amato M, Simonelli N, Vigo L, Tremoli E. Update of green tea interactions with cardiovascular drugs and putative mechanisms. J Food Drug Anal. 2018 Apr;26(2S):S72-S77.

Chrysant SG, Chrysant GS. Herbs Used for the Treatment of Hypertension and their Mechanism of Action. Curr Hypertens Rep. 2017 Sep 18;19(9):77.

Malongane F, McGaw LJ, Mudau FN. The synergistic potential of various teas, herbs and therapeutic drugs in health improvement: a review. J Sci Food Agric. 2017 Nov;97(14):4679-4689.

Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M. Clinical risks of St John’s Wort (Hypericum perforatum) co-administration. Expert Opin Drug Metab Toxicol. 2017 Oct;13(10):1047-1062.

Asher GN, Corbett AH, Hawke RL. Common Herbal Dietary Supplement-Drug Interactions. Am Fam Physician. 2017 Jul 15;96(2):101-107.

Izzo AA, Hoon-Kim S, Radhakrishnan R, Williamson EM. A Critical Approach to Evaluating Clinical Efficacy, Adverse Events and Drug Interactions of Herbal Remedies. Phytother Res. 2016 May;30(5):691-700.

Unger M. Pharmacokinetic drug interactions involving Ginkgo biloba. Drug Metab Rev. 2013 Aug;45(3):353-85.

Hussain MS. Patient counseling about herbal-drug interactions. Afr J Tradit Complement Altern Med. 2011;8(5 Suppl):152-63.

Undoubtedly, dietary and supplemental interventions in treating major depressive disorder (MDD) are a part of integrative psychiatry, and I would add holistically shaped psychiatric practices. You probably changed many antidepressants from different groups without any subjective or clinical improvement, even though you tried some alternative methods such as repetitive transcranial magnetic stimulation, ketamine infusions, and others. Still, you are stuck in MDD, and you are tired of depression and feeling hopeless. However, there is hope, and worth trying some alternative and holistic treatments. One of them is edible, medicinal mushrooms.

Generally, dietary interventions and changes for people suffering from the major depressive disorder are an ongoing field of research

Edible medicinal mushrooms contain 5-hydroxy-L-tryptophan (5-HTP), a direct precursor of serotonin, one of the neurotransmitters targeted in the pharmacotherapy of MDD (Agata Fijałkowska et al., 2022). Agata Fijałkowska and colleagues exhibited the results of studies on dietary supplementation with three species; Lion’s mane (Hericium erinaceus), Caterpillar mushroom (Cordyceps militaris), and Lingzhi/Reishi (Ganoderma lucidum) (Agata Fijałkowska et al., 2022). Their review article is impressive, with 121 peer-reviewed articles in reference.

Serotonin does not cross the blood-brain barrier; however, L-tryptophan is an exogenous amino acid that acts as a precursor for serotonin synthesis in a metabolic pathway involving tryptophan hydroxylase (TPH) as well as aromatic amino acid decarboxylase (DDC). 5-Hydroxy-l-tryptophan (5-HTP), a product of TPH and an immediate precursor of serotonin, is processed by DDC. Indeed, the total pool of serotonin in the brain is determined by the amount of substrates and the activity of TPH, which is the rate-limiting step for serotonin synthesis. The primary source of serotonin in the brain is the neurons of nine raphe nuclei located in the medial brainstem. The axons of these neurons project to most of the brain, with rostral raphe nuclei mainly sending their serotonergic projections to the forebrain and caudal group to the lower brainstem and spinal cord (Agata Fijałkowska et al., 2022).

Several edible mushroom species have been identified with a relatively high content of 5-HTP. The highest content was detected in all species of Pleurotus (oyster mushrooms), which is popular in vegetarian cuisine (Agata Fijałkowska et al., 2022).

Using Lion’s mane mushrooms (Hericium erinaceus) to treat depression

Chong and colleagues 2019 published an article about using Lion’s mane mushrooms (Hericium erinaceus) to treat depression. Bioactive compounds extracted from the mycelia and fruiting bodies of H. erinaceus have been found to promote the expression of neurotrophic factors that are associated with cell proliferation, such as nerve growth factors. Although the antidepressant effects of H. erinaceus have not been validated and compared to the conventional antidepressants, based on the neurotrophic and neurogenic pathophysiology of depression, H. erinaceus may be a potential alternative medicine for the treatment of depression (Pit Shan Chong et al., 2021).

Griflola frondosa (Fr) S.F. Gray (GF) (Meripilaceae) is a medical fungus commonly known as Maitake or Hui-shu-hua. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA receptor) signaling regulated by GF might be essential for its robust antidepressant effects (Hongkun Bao et al., 2017).

Medicinal mushrooms, their bioactive compounds, their use, and completed clinical trials

Giuseppe Venturella and colleagues published a review article in 2021 about medicinal mushrooms, their bioactive compounds, their use, and completed clinical trials. The article is abundant with information and data from over 100 references related to medicinal mushrooms. The authors stated that medicinal mushrooms had been used to promote and maintain good health and treat diseases since ancient times in Asian regions. At the same time, in the West, this approach is considerably more recent. Medicinal mushrooms are reported to have numerous pharmacological actions such as antimicrobial, anti-inflammatory, immunomodulatory, antidiabetic, cytotoxic, antioxidant, hepatoprotective, anticancer, antioxidant, antiallergic, antihyperlipidemic, and prebiotic properties, among others. These activities are attributable to many bioactive metabolites in the mycelium but, above all, in the fruiting body, whose biological effect varies according to the chemical nature and distribution varies according to the fungal species. A lot of research has been done. It is increasingly being undertaken to identify and characterize mycochemicals and define their actions and mechanisms due to the growing interest in using natural products, including as adjuvants in traditional therapies (Giuseppe Venturella et al., 2021).

Regarding bioactive compounds, the most important are polysaccharides, structural components of the fungal cell wall. The polysaccharides have a solid ability to carry biological information. They have antitumor, immunomodulatory, antioxidant, anti-inflammatory, antimicrobial, and antidiabetic activity. In reality, the type and modulation of these biological activities are influenced by the specific structural features of the molecule, such as the weighted degree of branching, backbone linkage, side-chain units, and the type of constituent monosaccharides. The best-known and most abundant are α- and β-glucans. Heteroglycans, peptidoglycans, and polysaccharide-protein complexes also contribute to biological activity. They are primarily responsible for immunomodulatory effects because they bind to specific cell membrane receptors and stimulate particular immune responses. Medicinal mushrooms are usually used in cancer treatments as biological response modifiers (BRMs), helpful in treating cancer, reducing the side effects of therapies, and improving the quality of the patient’s life (Giuseppe Venturella et al., 2021).

Another class of compounds that are very important for their bioactivity are the terpenes, characterized by units of five-carbon isoprene atoms and whose addition of functional groups produces the terpenoids. They modulate the immune system by stimulating the expression of genes coding for proteins involved in the immune response. They also have anti-inflammatory, antioxidant, and antitumor properties. High terpenoid contents are found in mushrooms belonging to the genus Ganoderma P. Karst. Mushrooms are rich in proteins, which have cytotoxic and anticancer properties. In addition, some of them are known for their characteristics and marked immunomodulatory effects. These proteins are indicated as fungal immunomodulatory proteins (FIPs), whose mechanisms of action can be diverse. Proteins also include lectins, which bind reversibly to mono- and oligosaccharides with high specificity, recognizing and interacting with various carbohydrates and proteoglycans on the cell surface. They are involved in many biological activities, such as innate immunity and cell-to-cell interaction, and their immunomodulatory mechanism varies depending on the origin of the compound. They also have immunomodulatory, antitumor, and antiproliferative properties (Giuseppe Venturella et al., 2021).

Other fungal metabolites with bioactivity are phenolic compounds, antioxidants with different mechanisms of action (oxygen scavenging, metal inactivation, free radical inhibition, peroxidase decomposition), laccases (copper-containing oxidases), and fatty acids (Giuseppe Venturella et al., 2021).

Medicinal mushrooms (MM) science made great progress in the last 30 years

Professor Solomon P. Wasser published an excellent review article in 2014, Biomedical Journal; Medicinal Mushroom Science: Current Perspectives, Advances, Evidences, and Challenges. Professor Wasser stated: “Medicinal mushrooms (MM) science made great progress in the last 30 years. A really successful new branch of science (Medicinal Mushroom Science) has been recognized.” (Solomon P. Wasser, 2014). “New classes of MM drugs and different types of MM products have been developed. A unique journal in the field, the International Journal of Medicinal Mushrooms (Begell House, USA), was organized. Approximately 400 clinical trial studies using MMs have been published on different illnesses. More than 50,000 scientific papers have been published, and approximately 15,000 patents dedicated to studying different aspects of MMs have been received.” (Solomon P. Wasser, 2014). However, professor Wasser also stated: “On the other hand, there are many unsolved, serious problems in the future of MM development, which in turn can also affect the continuation of MM science in the 21st century.”

How to approach medicinal mushrooms to make it a successful journey of healing?

Start with your integrative psychiatrist with a friendly and constructive discussion regarding using them. Next, you and your integrative psychiatrist are confident that you are a good candidate; it is absolutely “a must.” Finally, go over your prescriptions and supplements that you regularly use with your pharmacist and integrative psychiatrist. Drug-supplement interactions are possible; however not always predictable in high percentages. Perhaps you are wondering why integrative/holistic psychiatrist? Integrative healthcare brings conventional and alternative approaches to a much broader spectrum; it emphasizes a holistic, patient-centered, and individualized/personalized approach to healthcare and wellness.

This approach is different. It not only treats your acute or chronic disease but also brings balance and healing to your body, mind, and soul. It includes a broad spectrum to treat the whole person and not only focus on one organ or organ system or simply your diagnosis. It is not just to treat your symptoms. This approach can be very demanding because it involves mental health, emotional, spiritual, social, and community aspects. It is complex and requires a well-coordinated team of conventional and alternative healing providers. Nevertheless, these approaches to the treatment brought good results in treatments of many conditions and diseases, such as depression, major depressive disorder, treatment-resistant depression, and other mental health disorders.

Finding a good provider for medicinal mushrooms will take time. It considers the panel of products and services, customer service, and real testimonials. So take your time and fill out the survey (if it is available) truthfully and with as many details as possible. It will help your vendor determine what would benefit you as an initial treatment.

Undoubtedly, healing has to start with you; a good plan, treatment, and following protocol promptly will lead to healing.

“What mental health needs are more sunlight, more candor, and more unashamed conversation.” – Glenn Close

Respectfully,

Holistic Healthful

References:

Agata Fijałkowska, Karol Jędrejko, Katarzyna Sułkowska-Ziaja, Marek Ziaja, Katarzyna Kała, Bożena Muszyńska. Edible Mushrooms as a Potential Component of Dietary Interventions for Major Depressive Disorder. Foods. 2022 May 20;11(10):1489.

Pit Shan Chong, Man-Lung Fung, Kah Hui Wong, Lee Wei Lim. Therapeutic Potential of Hericium erinaceus for Depressive Disorder. Int J Mol Sci. 2019 Dec 25;21(1):163.

Hongkun Bao, Pengzhan Ran, Lijuan Sun, Weihong Hu, Hongliang Li, Chunjie Xiao, Keming Zhu, and Jing Dua. Griflola frondosa (GF) produces significant antidepressant effects involving AMPA receptor activation in mice. Pharm Biol. 2017; 55(1): 299–305.

Giuseppe Venturella, Valeria Ferraro, Fortunato Cirlincione, Maria Letizia Gargano. Medicinal Mushrooms: Bioactive Compounds, Use, and Clinical Trials. Int J Mol Sci. 2021 Jan 10;22(2):634.

Solomon P. Wasser. Medicinal Mushroom Science: Current Perspectives, Advances, Evidences, and Challenges. Biomed J 2014;37:345 356.

L-theanine from green tea readily crosses the blood-brain barrier, where it exerts a variety of neurophysiological and pharmacological effects helping depression, as a sleeping aid, and many more

L-theanine (N-ethyl-L-glutamine) is an amino acid found in green tea (Camellia sinensis). Some authors even mentioned black tea. L-theanine has been reported as a relaxing agent. Animal studies suggest that L-theanine increases brain serotonin, dopamine, and GABA levels. It has micromolar affinities for AMPA, Kainate, and NMDA receptors. In addition, neuroprotective effects in animal models have been shown, possibly through its antagonistic effects on group 1 metabotropic glutamate receptors. Finally, behavioral studies in animals suggest improvement in learning and memory. Overall, L-theanine exhibits neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans (Pradeep J Nathan, 2006).

Importantly, L-theanine crosses the blood-brain barrier, where it exerts various neurophysiological and pharmacological effects. Its most well-documented effect has been its apparent anxiolytic and calming effect due to its up-regulation of inhibitory neurotransmitters and possible modulation of serotonin and dopamine in selected brain areas. It has also recently been shown to increase levels of the brain-derived neurotrophic factor. In addition, many studies demonstrate neuroprotective effects following cerebral infarct and injury. However, the exact molecular mechanisms remain fully elucidated. Theanine also elicits improvements in cognitive function, including learning and memory, in human and animal studies.

Furthermore, theanine administration elicits selective changes in alpha brain wave activity with concomitant increases in particular attention during the execution of mental tasks. Emerging studies also demonstrate a promising role for theanine in augmentation therapy for schizophrenia. At the same time, animal models of depression report positive improvements following theanine administration. Finally, several studies are beginning to examine a putative role in attention deficit hyperactivity disorder. Theoretical extrapolations for theanine’s therapeutic role in other psychiatric disorders such as anxiety disorders, panic disorder, obsessive-compulsive disorder, and bipolar disorder are beneficial, too (Anne L Lardner, 2014).

L-theanine is associated with numerous mental health benefits, including improvements in mood, cognition and a reduction of stress and anxiety-like symptoms (Jackson L Williams et al., 2020).

Hidese and colleagues, in their study, suggest that (8-week) L-theanine administration is safe. Furthermore, it has multiple positive effects on depressive symptoms, anxiety, sleep disturbance (insomnia), and cognitive impairments in patients with major depressive disorder (MDD) (Shinsuke Hidese et al., 2017).

Depression is a psychological disorder that affects 20 – 30% of the world’s population. Traditional Chinese medicine is gaining increasing attention due to its unique therapeutic effect in depression treatment. The article (Yan-Shuo Wang et al., 2019) “summarizes the work done on the natural products from TCM that have been reported to conceive antidepressant effects in the past two decades, which can be classified according to various mechanisms including increasing synaptic concentrations of monoamines, alleviating the hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, lightening the impairment of neuroplasticity, fighting towards immune and inflammatory dysregulation.” According to this particular article (Yan-Shuo Wang et al., 2019), “the antidepressant active ingredients identified can be generally divided into saponins, flavonoids, alkaloids, polysaccharides, and others. Albiflorin, Baicalein, Berberine chloride, beta-Asarone, cannabidiol, Curcumin, Daidzein, Echinocystic acid (EA), Emodin, Ferulic acid, Gastrodin, Genistein, Ginsenoside Rb1, Ginsenoside Rg1, Ginsenoside Rg3, Hederagenin, Hesperidin, Honokiol, Hyperoside, Icariin, Isoliquiritin, Kaempferol, Liquiritin, L-theanine, Magnolol, Paeoniflorin, Piperine, Proanthocyanidin, Puerarin, Quercetin, Resveratrol (trans), Rosmarinic acid, Saikosaponin A, Senegenin, Tetrahydroxystilbene glucoside, and Vanillic acid are specified in this review. In addition, Chinese compound prescriptions and extracts that exert antidepressant effects are also introduced, which may serve as a source of inspiration for further development. In the present study, the antidepressant effect of certain TCMs is affirmative and encouraging. However, much work needs to be done to evaluate the exact therapeutic effects and mechanisms of those active ingredients, specifically, to establish a unified standard for diagnosing and evaluating curative effects (Yan-Shuo Wang et al., 2019).”

Sleep deprivation and insomnia are associated with an elevated risk of numerous diseases. It leads to inferior quality of life and negative socioeconomic consequences. Sleep inducers such as drugs and herbal remedies may lead to dependence and other side effects. L-theanine has anxiolytic effects via the induction of alpha brain waves without side effects associated with conventional sleep inducers (sleeping aids). Anxiolysis is required for the initiation of high-quality sleep. As per Theertham P. Rao et al., 2015, “L-theanine does not induce daytime drowsiness; it may be useful at any time of the day. Sleep deprivation-associated morbidity is an increasing public health concern posing a substantial socioeconomic burden. Chronic sleep disorders may seriously affect the quality of life. They may be etiological factors in many chronic diseases such as depression, obesity, diabetes, and cardiovascular diseases. Most sleep inducers are sedatives and are often associated with addiction and other side effects. L-Theanine promotes relaxation without drowsiness. Unlike conventional sleep inducers, L-theanine is not a sedative but promotes good sleep quality through anxiolysis.” This review suggests that L-theanine is a safe, natural sleep aid (Theertham P. Rao et al., 2015).

Respectfully,

Holistic Healthful

References

Pradeep J Nathan, Kristy Lu, M Gray, C Oliver, The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30.

Anne L Lardner. Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders. Nutr Neurosci. 2014 Jul;17(4):145-55.

Jackson L Williams, Julian M Everett, Nathan M D’Cunha, Domenico Sergi, Ekavi N Georgousopoulou, Richard J Keegan, Andrew J McKune, Duane D Mellor, Nicola Anstice, Nenad Naumovski. The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review. Plant Foods Hum Nutr. 2020 Mar;75(1):12-23.

Shinsuke Hidese, Miho Ota, Chisato Wakabayashi, Takamasa Noda, Hayato Ozawa, Tsutomu Okubo, Hiroshi Kunugi. Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatr. 2017 Apr;29(2):72-79.

Yan-Shuo Wang, Chun-Yan Shen, Jian-Guo Jiang. Antidepressant active ingredients from herbs and nutraceuticals used in TCM: pharmacological mechanisms and prospects for drug discovery. Pharmacol Res. 2019 Dec;150:104520.

Theertham P Rao, Motoko Ozeki, Lekh R Juneja. In Search of a Safe Natural Sleep Aid. J Am Coll Nutr. 2015;34(5):436-47.

Are you still confused about the actual meaning of conventional, complementary, alternative, holistic, integrative, and functional healing (medicine)? Where is the soul in all of these treatments?

Indeed, finding a healthier you and your family, your loved one will make you happy. Did you ask yourself recently how well are you, but really? Being healthy at every age is our goal. It should also be our primary goal. However, almost every day, we are met with some terms we do not understand (at least not entirely), such as complementary, conventional, alternative, and holistic healing (medicine). Even recently, we are finding words such as integrative and functional healing (medicine), which sound more complex.

It is imperative to know all those terms because the part of the decision on your treatment is up to you, not just your healthcare provider. Generally, you have probably realized some substantial differences between your healthcare providers, from one to the second; some are maximalists, some are minimalists, some are more technology-oriented (forcing medications), some are naturalists, some are doubters, and some are firm believers.

Moreover, when they are all combined, they represent the six medical mindsets in our healthcare. All of these professionals can struggle from one “disease,” and that is because of a lack of decision-making skills. The art of medical decision-making is a set of complex skills. It leads to one phenomenon, and that is medical specialists can disagree. Each professional has a different mindset.

Complementary treatments include combining conventional therapies with some additional natural products, including body and mind practices.

Suppose your healthcare provider recommends to you a combination of some conventional therapies with some supplemental (dietary) botanical products that mean they are conducting complementary treatment. In that case, complementary treatments include combining conventional treatments with some additional natural products, including body and mind practices. The panel of natural products can be extensive as it contains vitamins and minerals, botanical extracts, medicinal herbs, probiotics, special diets, and homeopathy. Mind and body practices are broad-spectrum activities and treatments such as meditation, progressive relaxation, deep breathing, yoga, Tai Chi, Qi Gong, massage, and others. Complementary treatment for your condition or disease would be a fusion of conventional (Western medicine practice, including pharmacy) and alternative healing therapies. Many healthcare providers use this treatment. For example, in Europe, with your antibiotic treatment, you will get advice to use probiotics immediately, or even some psychiatrists suggest that antidepressant therapy could be more effective if you, for example, practice meditation or any type of body and mind practice such as Tai Chi, Qi Gong, or yoga. Then your treatment is so-called complementary, and your healthcare provider is conducting complementary therapy or treatment for your condition or disease.

Alternative therapy does not use conventional (Western medicine) treatment.

In other words, that means during your treatment, you use only alternative therapies such as herbal-botanical (supplemental) remedies, aromatherapy, remedies of traditional Chinese medicine, Ayurveda therapy, homeopathy, and special diets. However, alternative therapies use many mind and body practices during the healing process, such as yoga, meditation, Tai Chi, Qi Gong, massage, deep breathing treatments, progressive relaxation, guided imagery, and some chiropractic and osteopathic manipulations, acupuncture, hypnotherapy, Feldenkrais method, Alexander technique, Pilates, Rolfing Structural Integration, and Trager psychophysical integration and others.

Integrative healthcare brings conventional and alternative approaches to a much broader spectrum – it emphasizes a holistic, patient-centered, and individualized approach to healthcare and wellness

This approach is different. It does not only treat your acute or chronic disease, but it tries to bring balance and healing to your body, mind, and soul/spirit. It includes a broad spectrum to treat the whole person and not only focus on one organ or organ system. This approach can be very demanding because it involves mental health, emotional, spiritual, social, and community aspects. It is complex and requires a well-coordinated team of conventional and alternative healing providers. Nevertheless, these approaches in the treatment brought good results in treatments of many conditions and diseases, such as pain management and symptoms management in the cancer patients and cancer survivors. I would add depression, major depressive disorder, and treatment-resistant depression.

What is functional medicine? How can this approach help us?

You may also hear about the term functional medicine. Still, you are unsure what that means precisely, besides complementary, conventional, alternative, holistic and integrative terms. The term “functional medicine” sometimes refers to a concept similar to integrative healthcare. Still, it may also apply to an approach that more closely resembles naturopathy. Naturopathic practitioners use many different treatment approaches such as stress reduction, herbalism, dietary supplements, homeopathy, psychotherapy and counseling, and dietary and lifestyle changes. Some practitioners of functional medicine use other methods as well. Functional medicine specialists often refer patients to conventional healthcare providers and specialties of conventional Western medicine treatment. It is essential to state that functional medicine focuses on the body’s optimal functioning, organ systems, and organs, involving holistic or alternative medicine systems.

And… finally, holistic healing (medicine)! Why is this healing unique?

Holistic healing (medicine) seriously considers the whole person, not just the body or mind. It is healing that brings appropriately functioning body, mind, spirit/soul to the person in the quest for optimal, balanced wellness and health. Directly, it is bringing balance between body, mind, and soul to function appropriately and synchronized. Holistic practitioners can use the treatment of conventional medicine combined with an alternative emphasizing spiritual, mental, and social factors as contributing factors for treating conditions or diseases. Why is holistic healing (medicine) different from all other forms? Holistic treatment involves fixing the cause of the state, not only alleviating the symptoms; a patient is a person and not a disease; all people have inner healing power. Holistic healing (medicine) is teamwork, including a holistic practitioner and a patient. It considers explorations of all aspects of a patient’s life, mental status, spiritual, social, and other factors.

We hope that we have helped you better understand some of the terms, what they mean to us, and how to find a healthier you in the 21^st century.

Respectfully,

Holistic Healthful