Comprehensive Meldonium Review 2022 – Dosage, Side Effects, Meldonium in Sports, Covid-19, and Other Uses, Experiences & FAQs

Meldonium is produced under the brand name Mildronate®. Meldonium definition suggests that it is a metabolic corrector. It provides multifactorial protection of organs and tissues through normalization of cellular energy metabolism.

As such, it is usually used to treat angina, myocardial failure, and reduce alcohol withdrawal symptoms. Off-label use of Meldonium includes increasing exercise tolerance in sports, learning, memory, and even sexual function.

Meldonium is available in three forms:

  1. Mildronate 5 ml injections,
  2. Mildronate 250 mg capsules, 
  3. Mildronate 500 mg capsules.

MELDONIUM REVIEW: LIST OF CONTENT

meldonium review

MELDONIUM USES

Meldonium is widely used in the complex treatment of the following diseases. [5] [6] [10] [11] [12] [13] [14] [16] [20] [21] [22]

Mildronate injections:

  • Coronary heart disease (angina, myocardial infarction); 
  • Chronic heart failure and dishormonal cardiomyopathy; 
  • Acute and chronic cerebrovascular disorders (stroke, cerebrovascular insufficiency);
  • Intraocular hemorrhage of different etiology, thrombosis of the central vein of the retina and its branches, retinopathies of different etiology (diabetes, hypertonic);
  • Withdrawal syndrome in chronic alcoholism.
  • Reduced performance and mental and physical overload (including in athletes).

Mildronate 500 mg capsules: 

  • Coronary heart disease (angina, myocardial infarction); 
  • Chronic heart failure and dishormonal cardiomyopathy; 
  • Acute and chronic cerebrovascular disorders (stroke, cerebrovascular insufficiency);
  • Withdrawal syndrome in chronic alcoholism.
  • Reduced performance and mental and physical overload (including in athletes).

Mildronate 250 mg capsules: 

  • Reduced performance, 
  • Mental and physical overload.

BRIEF HISTORY OF MILDRONATE CREATION

Mildronate was created in the 1970s at one of the USSR research institutes by Latvian professor Ivars Kalvins. He was studying body chemicals to aid patients with cardiovascular diseases. The task was to facilitate myocardial function in conditions of hypoxia. [4]

Dr Kalvins meldonium creator

Dr Kalvins found that one particular chemical – gamma butyrobetaine – is being deplenished under physical workloads. He created a synthetic analogue of this molecule by replacing one atom of silicon with that of nitrogen so that the new molecule would not decompose and could act as a transmitter from the central nervous system (CNS) to peripheral cells.

Meldonium under the brand name Mildronate was approved for commercial use in 1984 to improve performance during rehabilitation, psychological and physical overload. 

According to The Washington Post, Mildronate was used to help Soviet soldiers combat stress during the Afghan War. Some sources even claim that it was actually the initial purpose of Meldonium creation: the survival of the body in extreme situations, high physical and psycho-emotional stress, lack of oxygen, high or low temperatures, and so on. 

Today, Mildronate (Meldonium) is produced by the Latvian company Grindeks. And it is available to buy by the general public in some of the CIS countries without prescription.  

WHAT DOES MELDONIUM DO? PHARMACODYNAMICS 

The mechanism of action of Meldonium attributes it to the group of the so-called cytoprotectors. These are antihypoxants which provide protection and energy supply to various cells in the body under ischemia and increased stress. 

Meldonium is the active molecule of Mildronate®. It has a chemical structure similar to that of an amino acid and it is known as 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate. It has long been used to treat myocardial and cerebral ischemia. [4

Inhibition of the organic cation transporter/carnitine type 2 (OCTN2) by Meldonium is accompanied by a decrease in L-carnitine concentration. Reduced L-carnitine availability decreases acylcarnitine formation by carnitin-palmitoyltransferase-1 (CPT1). In addition, Meldonium reduces the formation of trimethylamine (TMA) from L-carnitine by the intestinal microbiota and promotes the excretion of trimethylamine-N-oxide (TMAO). This determines the cardioprotective, anti-atherosclerotic and anti-diabetic effects of Meldonium. [18

Meldonium inhibits γ-butyrobetaine hydroxylase and carnitine palmitoyltransferase I. As a result, transport of long-chain fatty acids (FA) from the cytosol to the mitochondria is reduced and redirected to the peroxisomes, where they are metabolized to medium- and short-chain acylcarnitines for further oxidation in mitochondria. This prevents the accumulation of toxic long-chain intermediate products in mitochondria and reduces mitochondrial reactive oxygen species (ROS) formation. [15] [18] [19]

Thus, Meldonium reduces the risk of mitochondrial damage mediated by long-chain fatty acid metabolism and shifts energy production from fatty acid oxidation to glycolysis, which requires less oxygen. This situation is more favorable in ischemic conditions. Meldonium reduces the concentration of methemoglobin and therefore promotes greater O2 transport by erythrocytes. [7]

In simpler terms:

  • Meldonium can optimize intracellular energy processes under increased stress;
  • Meldonium has the ability to restore the balance between cellular oxygen supply and demand;
  • Meldonium is known to eliminate the accumulation of toxic products of metabolism in cells, protecting them from damage.

WHAT ARE THE BENEFITS OF MELDONIUM?

Under ischemic conditions, Meldonium can restore the balance between the processes of oxygen delivery and its consumption in cells, and prevent the disruption of adenosine triphosphate (ATP) transport. At the same time it activates glycolysis, which proceeds without additional oxygen consumption. As a result of a decrease in the concentration of carnitine, gamma-butyrobetaine, which has vasodilatory properties, is synthesized intensively.

The mechanism of action determines the variety of Meldonium pharmacological benefits [8] [9] [10]:

  • Improved myocardial contractility, reduced frequency of angina attacks,
  • Increased tolerance to physical and mental stress and the ability to quickly restore energy reserves,
  • Better cerebral hemodynamics and cognitive functions, reduced asthenic syndrome,
  • Stimulating effect on the CNS,
  • Tonic effect and increased productivity.

WHAT ARE MELDONIUM EFFECTS FOR ATHLETES?

Mildronate is a popular and one of the most affordable choices among athletes. What is the use of Meldonium for bodybuilding? Why do athletes use Meldonium medication? And how does it influence the recovery process after physical exertion?

As the studies show the drug Meldonium helps cells to adapt faster to energy starvation, and improves metabolism. Thanks to Mildronate, metabolic processes in immune cells normalize, and this contributes to strengthening the body’s protective potential. 

Mildronate can protect cardiac muscle cells from oxygen deficiency. If there is a balance between the flow of oxygen to the tissues and the need for it in the cells, the body’s resistance to stress increases, exhaustion goes away; there is an increase in blood flow, slowing the process of cell death. 

Under the action of the drug, the heart muscle is able to contract more vigorously and infrequently, expanding the cardiac muscle tolerance to stress. In addition, Mildronate leads to reduction of brain damage; coordination of movements improves. Mildronate has a favorable effect on the blood vessels. 

Please note that there are side effects and contraindications which need to be taken into account when choosing the medication. Consultation with a doctor is needed before taking any medication. 

SHARAPOVA MELDONIUM SPORTS SCANDAL 

Mildronate gained popularity worldwide after Maria Sharapova meldonium scandal. The famous Russian tennis player confirmed that she has been taking Mildronate for several years. The investigation resulted in Sharapova drug suspension for several years. According to The New York Times post after being accused of drug use Sharapova essentially retired from the big-time sports.

meldonium sharapova

Still, Maria Sharapova was not the only one who has been taking the banned substance. A great number of other world and Olympic champions admitted taking it. Read Meldonium Wikipedia for more information. 

In response to doping accusations the creator of the drug, professor Kalvins claimed that Meldonium had never been found to have anabolic properties. Rather, it was designed as a cardioprotector that can protect the cardiovascular system of athletes under high physical workloads from ischemia. 

In one interview Dr Kalvinsh defined doping as a substance that can make a person perform above the norm, which makes it unsafe to use. Unlike doping compounds, according to Dr Kalvinsh, Mildronate does not have this effect. It only helps athletes reach their maximum and minimize undesirable consequences of intensive training processes on their health. The position of the Mildronate producer on the matter is provided on their official web-site. 

Nevertheless Meldonium has been on the World Anti-Doping Agency (WADA) list of banned substances since 1 January 2016 because of evidence of its use by athletes. And WADA officials refuse to cancel this decision. 

Interestingly, Trimetazidine which is a Meldonium equivalent in the US is also included in the list of substances banned by WADA. 

MILDRONATE (MELDONIUM) IN POST COVID-19 REHABILITATION – STUDIES

Today, new clinical data is appearing on the efficacy of Meldonium in coronavirus infection. And we have to mention some of the studies in this Meldonium review.

They mostly concern post-covid syndrome which is a complex of symptoms including vascular endothelium, development of coagulopathies with microthrombosis, angiopathies and organ and tissue lesions.

One of the studies [23] was conducted in 2020 by a group of researchers who aimed to evaluate the use of Mildronate as a metabolic corrector in patients with coronavirus pneumonia and chronic heart failure. The results showed a statistically significant reduction of hospitalization time in the Mildronate group compared to the control group. 

There was a significant decrease in C-reactive protein and D-dimer levels by the time of patients discharge. The drug was administered as follows: an IV injection of  solution (0.5 g/5 ml) of 1 g per day during the entire hospital stay, followed by outpatient oral capsules at a dose of 500 mg 2 times per day for up to 2 weeks. After 3 months, a significant improvement in quality of life and a decrease in the severity of asthenic syndrome were observed in the Mildronate group. 

In the work of E.Yu. Ebzeeva et al (2020) a positive effect of Mildronate was noted when prescribed as a corrector of post-covid asthenic syndrome. Meldonium was administered orally by 500 mg twice a day for 14 days. [24

Mildronate also has immunomodulatory effects at the level of cellular and humoral immunity, circulating complexes, on the production of interferon and increased antiviral immune response. It has been shown to increase the total of T-system values and the ratio of T-helper and T-suppressor populations. Besides it had an influence on the IgM and IgA, IgG levels. [2] [3] [7]

It was shown that the drug can induce interferon in mice when simultaneously injected with the antigen. And it shows a protective effect against the influenza virus when used in accordance with the therapeutic and preventive regimens. [1

When studying the immunoadjuvant action of Mildronate during vaccination with inactivated influenza vaccine in 1992 O.I. Kubar et al [25] concluded that the use of Mildronate contributed to a statistically significant increase in the effectiveness of vaccine prevention and an increase in the multiplicity of growth of specific influenza antibodies. 

HOW TO TAKE MELDONIUM (MILDRONATE)?

  • For the purpose of increasing tolerance to mental and physical overload, the recommended dosage is 250 mg of Mildronate pills 2–4 times per day. The standard duration of one course is between 14 and 21 days.
  • Before and during the athletic events, athletes are recommended to take 500–1000 mg of Mildronate prior to workouts, preferably in the morning. The standard duration of one course is between 14 and 21 days.
  • Mildronate solution is administered intramuscularly (i.m.), intravenously (i.v.) and parabulbar. The mode of administration, doses and duration of treatment are determined individually depending on indications, severity of condition, etc.

For more information check the official instructions.

WHAT ARE THE SIDE EFFECTS OF MELDONIUM?

According to the producer and some medical specialists Meldonium is low-toxic and does not cause severe adverse reactions compared to other drugs that are used by athletes. However some side effects are still possible. They may include: allergies, decreased blood pressure accompanied by headache, tachycardia, dizziness, and general weakness, etc.

Another reaction to Meldonium that is sometimes reported by athletes is a sense of addiction. It means that if an athlete who has been taking it consistently for a long period of time misses a dose, they may feel less self-confident during the competition. Nevertheless, there is no official data supporting these anecdotal Meldonium experiences. So, it may well be a placebo.  

CONTRAINDICATIONS TO MILDRONATE

  • Hypersensitivity to meldonium or other Mildronate components.
  • Increased intracranial pressure (in case of impaired venous outflow, intracranial tumors).
  • Pregnancy and breastfeeding.
  • Age under 18 y.o. (safety has not been confirmed).
  • Liver and/or kidney diseases.

IS MELDONIUM LEGAL?

Mildronate (Meldonium) is an officially manufactured compound in Latvia. It is a non-prescription drug in the dose of 250mg in countries like Russia, Ukraine, and some others. 

Meldonium is not licensed by the Food and Drug Administration (FDA) for use in the United States and is not authorized in the rest of Europe – which means that doctors in these countries cannot prescribe Mildronate. However, you can still buy it online for personal use.

WHERE TO BUY MILDRONATE (MELDONIUM)?

There are several forms of Mildronate that are officially manufactured: 

  1. Mildronate capsules 250mg,
  2. Mildronate capsules 500mg,
  3. Mildronate vials 5ml.

Here at CosmicNootropic store, you can buy all three forms of Mildronate with the fastest delivery and at a low price with volume discounts. 

Why order from us? Many products in our store can be shipped from our US warehouse. So you will get them within a week or less. Also, we have customer friendly Refund & Reshipment policy and Delivery terms!

MELDONIUM REVIEWS AND PERSONAL EXPERIENCES

There are many anecdotal reviews of Mildronate on Reddit. This one is devoted to discussing the effects of Mildronate as a mild stimulator and cognitive enhancer that may improve mood and reduce fatigue. It suggests that Meldonium may also have positive interactions with other nootropic compounds (presumably due to improved blood flow and absorption of the other compounds). Another thread is devoted to Meldonium for cardio

You may also find many anecdotal Meldonium reviews at the CosmicNootropic Mildronate product page.

THE OFFICIAL DRUG SHEET OF MILDRONATE

Mildronate® capsules 250-500mg | [PDF]

Mildronate® vials 5ml | [PDF]

MILDRONATE PRODUCER – GRINDEKS

Mildronate is manufactured by Grindeks. It is a Latvian company that was founded in 1946. The main activities of the company are research & development, production, and sale of original products, generics, and active pharmaceutical ingredients.

The company exports its products to more than 70 countries. The main markets are: the European Union, Russia and other CIS countries, the USA, Canada, Japan, Vietnam and others. 

There are 11 sites of manufacturing facilities where active pharmaceutical ingredients are produced. Mildronate (Meldonium) is one of the most famous and most exportable products in the company’s portfolio, which includes several therapeutic groups:

  • Drugs for the treatment of cardiovascular diseases;
  • Drugs that target the central nervous system;
  • Antitumor and gastroenterological drugs.

LICENSE AND STANDARDS

High-quality standards of Grindex are proved by certificates of EU GMP, RU GMP, FDA, PMDA, TGA, and others. The company also takes compliance with the principles of Guidance for Industry ICH Q10 Pharmaceutical Quality System. 

Grindex operates in accordance with the requirements of the following standards:

  • Quality management system: LVS EN ISO 9001;
  • Environmental management system: LVS EN ISO 14001;
  • Energy management system: LVS EN ISO 50001;
  • Occupational health & safety management systems: LVS EN ISO 45001.

MILDRONATE ANALOGUES & GENERICS

Meldonium generics are manufactured by other pharmaceutical companies in Europe (Serbia, Georgia and others), which compliments the effectiveness and safety of the original preparation. 

There is also a Mildronate analogue that is available at CosmicNootropic, which is called BrainMax. It is a synergy of Mildronate and Mexidol active substances with neuroprotective, anti-hypoxic, antioxidant, nootropic and anti-ischemic effects enhanced. Thus it can reduce clinical manifestations of cerebrovascular insufficiency, improve cognitive functions, normalize emotional state, reduce symptoms of stress, increase efficiency and tolerance to mental and physical exertion. 

Do you know other examples of effective stacks of substances? Share your experiences in the comments on Reddit.  

MELDONIUM REVIEW BIBLIOGRAPHY

  1. Kremerman I.B., Kalvinsh I, et al (1987). Interferon-Inducing and Anti-Influenzal Properties of 3-(2,2,2-Trimethylhydrazine)Propionate in an Experiment. https://pubmed.ncbi.nlm.nih.gov/2448958/.
  2. Glozman V.N., et al (1991). Use of Mildronate in Therapy of Seroresistant Syphilis https://pubmed.ncbi.nlm.nih.gov/1953172/
  3. Nikolaeva I.A., Prokopenko L.G. (1998). Immunomodulating Action of Energizing Drugs During Dosed Fasting. https://pubmed.ncbi.nlm.nih.gov/9819550/.
  4. Kalvinsh I, et al (2005). Mildronate: An Antiischemic Drug for Neurological Indications. https://pubmed.ncbi.nlm.nih.gov/16007237/
  5. Suslina Z.A., et al (2005). Neuroprotection in Ischemic Stroke: the Effectiveness of Mildronate. https://pharmateca.ru/ru/archive/article/6266
  6. Statsenko M.E., et al (2005). Mildronate in Complex Chronic Heart Failure Management among Patients in Early Post Infarction Period. https://russjcardiol.elpub.ru/jour/article/view/2344
  7. Sjakste N., Kalvinsh I. (2006). Mildronate: An Antiischemic Drug with Multiple Indications. https://www.researchgate.net/publication/264885788_Mildronate_An_Antiischemic_drug_with_multiple_indications
  8. Hegay S.V., et al (2009). Cytoprotector Mildronate in Correcting Myocardial Dysfunction among Stable Angina Patients after Coronary Revascularisation. https://russjcardiol.elpub.ru/jour/article/view/1338?locale=ru_RU
  9. Kuznetsova A.V., Teplyakov A.T. (2009). Evaluation of the Effect of Cardionat on the Effectiveness of Antianginal Therapy and the Functional State of the Myocardium in Patients with Coronary Artery Disease in Combination with Arterial Hypertension Associated with Type 2 Diabetes Mellitus. https://www.rmj.ru/articles/kardiologiya/Ocenka_vliyaniya_Kardionata_na_effektivnosty_antianginalynoy_terapii_i_funkcionalynoe__sostoyanie_miokarda_u_bolynyh_IBS__v_sochetanii_s_arterialynoy_ gipertenziey_associirovannoy_s_saharnym_diabetom_2_tipa/.
  10. Dzerve V. A. (2011). Dose-Dependent Improvement in Exercise Tolerance in Patients with Stable Angina Treated with Mildronate: A Clinical Trial “MILSS I”. https://pubmed.ncbi.nlm.nih.gov/22186118/
  11. Tyshchenko I.A., et al (2011). Mildronate Potential for Correcting Cognitive Dysfunction in Elderly Patients with Arterial Hypertension. https://russjcardiol.elpub.ru/jour/article/view/1129?locale=ru_RU
  12. Nedogoda S.V., et al (2012). Mildronate Effects on Cognitive Function in Elderly Patients with Arterial Hypertension. https://doi.org/10.15829/1728-8800-2012-5-33-38.
  13. Belovol A.N., Knyaz’kova I.I. (2012). Therapeutic Potential of Meldonium in Acute Coronary Syndrome. https://repo.knmu.edu.ua/bitstream/123456789/1730/1/48-53.pdf 
  14. Statsenko M.Ye., Turkina S.V., Shilina N.N. (2014). The Role of pFox Inhibitors in the Treatment of Patients with Acute Myocardial Ischemia. https://www.mediasphera.ru/issues/terapevticheskij-arkhiv/2014/1/030040-3660201419
  15. Speijer D., Manjeri G.R., Szklarczyk R. (2014). How to Deal with Oxygen Radicals Stemming from Mitochondrial Fatty Acid Oxidation. https://doi.org/10.1098/rstb.2013.0446.
  16. Lopushkova Yu.E., et al (2015). Influence of Meldonium as Part of Basic Therapy on Microcirculation Indices and Respiratory Function in Patients with Chronic Heart Failure and Chronic Obstructive Pulmonary Disease. https://cyberleninka.ru/article/n/vliyanie-meldoniya-v-sostave-bazisnoy-terapii-na-pokazateli-mikrotsirkulyatsii-i-funktsiyu-vneshnego-dyhaniya-u-patsientov-s/viewer.
  17. Schonfeld P., Wojtczak L. (2016). Short- and Medium-Chain Fatty Acids in Energy Metabolism: The Cellular Perspective. https://doi.org/10.1194/jlr.R067629.
  18. Dambrova M., Makrecka-Kuka M. et al (2016). Pharmacological Effects of Meldonium: Biochemical Mechanisms and Biomarkers of Cardiometabolic Activity. https://doi.org/10.1016/j.phrs.2016.01.019
  19. Porter C., Constantin-Teodosiu D., et al (2017). Muscle Carnitine Availability Plays a Central Role in Regulating Fuel Metabolism in the Rodent. https://doi.org/10.1113/JP274415.
  20. Fabritskaya S.V., et al (2017). Efficiency of Short-Term Therapy with Meldonium in Patients with Chronic Heart Failure of Ischemic Etiology and Type 2 Diabetes Mellitus. https://elibrary.ru/item.asp?id=29076299
  21. Poletaeva L.V., et al (2017). Possibilities of Medical Correction of Secondary Mitochondrial Dysfunction in Patients with Coronary Heart Disease and Comorbid Pathology. https://pharmateca.ru/ru/ archive/article/34751.
  22. Derevianchenko M.V., et al (2020). Effect of Meldonium on Arterial Stiffness and C-Reactive Protein Level in Complex Therapy of Chronic Heart Failure and Chronic Obstructive Pulmonary Disease. https://doi.org/10.18565/therapy.2020.5.94-101
  23. Vertkin A.L., et al (2020). Metabolic Support Opportunities in Coronavirus Infection. https://doi.org/10.18565/therapy.2020.7.146-155.
  24. Ebzeeva E.Yu., Ostroumova O.D., Mironova E.V. (2020). Efficacy and Safety of Mildronate in Treatment of Postinfectious Asthenic Syndrome (Clinical Examples). https://doi.org/10.33667/2078-5631-2020-2-61-66.
  25. Statsenko M.E. et al (2021). New data on well-known drug: focus on meldonium. https://www.mildronat.ru/wp-content/uploads/2022/02/2021_%D0%A1%D0%A2%D0%90%D0%A6%D0%95%D0%9D%D0%9A%D0%9E_%D0%92%D0%9C%D0%94_%D0%9C%D0%A1_14.pdf
  26. Oynotkinova O.Sh. et al (2022). The effect of SARS-CoV-2 on multi-organ damage and rehabilitation tactics in the post-COVID period. https://www.mildronat.ru/wp-content/uploads/2022/07/%D0%A0%D0%B5%D0%B0%D0%B1%D0%B8%D0%BB%D0%B8%D1%82%D0%B0%D1%86%D0%B8%D0%BE%D0%BD%D0%BD%D0%B0%D1%8F-%D1%82%D0%B0%D0%BA%D1%82%D0%B8%D0%BA%D0%B0-%D0%B2-%D0%BF%D0%BE%D1%81%D1%82%D0%BA%D0%BE%D0%B2%D0%B8%D0%B4%D0%B5.pdf
  27. Official web-site. [mildronat.ru]

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