Actovegin Review: Benefits, Side Effects, Dosage, and the Sports Scandal Explained

Although the exact Actovegin mechanism of action is not yet fully understood, studies have already established a number of effects of the mixture:

Actovegin uses include the treatment of vascular and metabolic disorders of the brain, circulatory disorders and their consequences (trophic ulcers), burns and wounds, and fetal growth disorders in pregnant women.

The nootropic complex is manufactured by the Japanese company Takeda Pharmaceutical, which has been in operation since 1781. It is one of the leading healthcare providers worldwide.

Among the first users of Actovegin Takeda were athletes and cyclists. Then, sportsmen began to discover the applications of Actovegin in bodybuilding. They mostly use Actovegin in case of muscle sports injuries. 

Actovegin is also commonly used by patients with cerebrovascular disorders and by the elderly who suffer from mild cognitive disorders prior to dementia.

Doctors recommend Actovegin for widespread use. For example, in the form of Actovegin ointment, the substance is used to treat dermatologic pathology due to its ability to accelerate tissue healing.

Meanwhile, the main forms of administration are Actovegin solution and Actovegin pills. Neurological diseases are the primary indication for its use. As part of complex therapy, it can be applied in the following cases:

Additionally, Actovegin activates glucose transporters GLUT1 and GLUT4, which, for instance, in cerebrovascular diseases, may facilitate glucose transport across the blood-brain barrier. The presence of such a mechanism was confirmed in a clinical study by D. Ziegler et al. (2009), in which Actovegin administration in patients with polyneuropathy on the background of type II diabetes mellitus significantly reduced the level of glycosylated hemoglobin (HbA1C) compared to placebo.

Since Actovegin modulates intracellular glucose transport, lipolysis is activated. The possibility of using Actovegin for the treatment of diabetes mellitus and metabolic syndrome is under consideration.

Recently, several studies have been conducted to investigate the neuroprotective effects of Actovegin and its ability to enhance neuronal survival.

An in vitro study conducted in cultivated primary rat hippocampal neurons demonstrated the neuroprotective and regenerative properties of Actovegin. Normally, the number of cultivated neurons decreases dramatically due to apoptosis. However, after 10 days in culture under optimal conditions, an Actovegin dose-dependent increase in the number of viable neurons (2.4 times that of the control) was observed.

Similar effects are noted in the peripheral nervous system of rats with severe symptoms of diabetic neuropathy. Administration of Actovegin at a dose equivalent to the clinical dosage for humans resulted in a decrease in peripheral neuronal degeneration caused by diabetes mellitus. At the end of the study, Actovegin increased intraepidermal nerve fiber (IENF) density by 32% and restored the reduced rate of nerve impulse conduction in sensitive fiber by up to 91%.

Actovegin's antioxidant effect is achieved through the presence of superoxide dismutase and magnesium ions in its composition, which enhances the activity of glutathione synthetase, thereby converting glutathione into glutamine.

Actovegin benefits include enhancing glucose absorption, cellular metabolism, and tissue respiration. This results in the activation of regeneration processes. 

Ultimately, Actovegin nootropic can enhance physical performance and stamina as well as have a calming effect on the nervous system.

In a study of Actovegin's effect on age-related memory impairment, after 2 weeks of drug therapy, a statistically significant improvement was observed in attention, memory, and cognitive processes. Moreover, even a single administration of the drug improved ielectrophysiological indices of brain function.

A study  involving 120 patients with cerebrovascular insufficiency and cognitive deficit showed that in long-term therapy of dyscirculatory encephalopathy with the syndrome of cognitive impairment, preference should be given to oral administration of Actovegin.

The possibility of using Actovegin, given its effect on glucose utilization, in type 2 diabetes mellitus (DM) patients with diabetic encephalopathy for the treatment of cognitive impairment is of great interest.

In a study of 60 patients with type 2 DM and varying degrees of cognitive impairment, intravenous administration of Actovegin at 400 mg for 3 weeks improved the total MMSE score, with the greatest improvement in memory. It can be assumed that the clinical efficacy of Actovegin in type 2 DM patients with cognitive impairment is primarily due to an improvement in cerebral metabolism.

In 2009, the American scientific journal “Diabetes Care” published a study evaluating the efficacy and safety of Actovegin in patients with diabetic polyneuropathy. The RCT involved 567 patients with type 2 diabetes mellitus. The study concluded that sequential intravenous and oral Actovegin treatment over 160 days improved neuropathic symptoms, VPT, sensory function, and quality of life in type 2 diabetic patients with symptomatic polyneuropathy.

W. Jansen and E. Beck conducted a controlled trial evaluating the effect of Actovegin in patients with diabetic polyneuropathy. One group of 35 patients received a placebo, and another group of 35 patients received Actovegin at a dose of 600 mg 3 times a day for 24 weeks [5]. Improvement in patients’ condition was observed with Actovegin treatment of hyperemia, and, as noted in the majority of patients, this effect was sustained for 8 weeks after the start of treatment. The optimal effect was achieved after 16 weeks of treatment. A reliable improvement compared to the placebo group was observed in almost all clinical parameters, including walking distance without pain, tendon reflexes, and surface and deep sensitivity. Patients in the Actovegin group felt better and had fewer complaints of psycho-emotional disturbances, which correlated with the improvement in their physical condition.

In 2017, a large-scale international prospective randomized placebo-controlled study  of Actovegin was conducted, which involved more than 500 stroke patients. The effect of the drug on the recovery process after ischemic stroke was studied (in particular, the ADAS-cog+ Alzheimer’s Disease Cognitive Assessment Scale and the Montreal Cognitive Assessment Scale, MoCA, were measured). The study lasted 12 months, with scores measured at 3, 6, and 12 months. In the third month, no statistically significant difference was observed between the placebo and Actovegin groups (the difference was 1.1 points on the ADAS-cog+ scale). By the sixth month, the difference on the same index was 2.3 points and was considered statistically significant. The treatment was discontinued. By the 12th month, the difference had increased to 3.7 points. The conclusion of the study states that Actovegin had a positive effect on cognitive impairment in stroke patients. Furthermore, more rigorous controlled studies are necessary to confirm this finding.

One of the most recent international randomized placebo-controlled trials was conducted between 2018 and 2020. The study enrolled 366 patients with Fontaine stage IIB peripheral arterial disease (PAD). The primary studied metric was the percent change in pain-free walking distance (ICD) from baseline at the 12th week. Based on the results, Actovegin showed statistically significant superiority over placebo. Actovegin also demonstrated safety comparable to that of the placebo group.

Regardless of the dosage form, the most common side effects include skin hyperemia and rash. An anaphylactic reaction is possible in case of hypersensitivity.

There are studies saying that Actovegin can be beneficial in case of the growth retardation of the fetus. However, the official Actovegin instructions clearly indicate that treatment with the drug in pregnancy is permissible only if the benefit exceeds the potential risk (!) to the fetus.

Other Actovegin contraindications include:

Actovegin originated as a generic of another drug, Solcoseryl, that has been produced by the Swiss company Solco since 1996.

The active ingredient of both preparations is deproteinized hemodialysate of calf blood, i.e., blood devoid of proteins and other particles larger than 5 kilodaltons. Solcoseryl is available as an ointment, while its generic is also available as Actovegin solution for injection and Actovegin tablets.

Actovegin is an antihypoxic compound with metabolic, neuroprotective, and microcirculatory effects. It is used in the therapy of diseases of the peripheral circulatory system and in the treatment of cognitive disorders, including dementia and post-stroke. A distinctive indication is the treatment of diabetic polyneuropathy.

Solcoseryl is used in combination therapy in disorders of metabolism and blood circulation in the brain (ischemic and hemorrhagic stroke, craniocerebral trauma) and pathologies of peripheral vessels. Solcoseryl is not prescribed during pregnancy.

In effect, the drugs are nearly identical in structure. Because of the common origin and similar indications, it is difficult to give an advantage to one of them. Only the attending physician can decide which one is better, Actovegin or Solcoseryl.

Actovegin is considered an ergogenic drug, although there is no evidence of its stimulatory effect on athletic performance. One hypothesized mechanism of action of this drug is an increase in tissue oxygen levels. Athletes take Actovegin, bodybuilding included, in order to improve their physical capabilities and to achieve:

Before taking Actovegin in sports, determine your goal. Thus, to accelerate recovery while preparing for competitions (as well as during and after them), it is possible to use schemes such as Actovegin 200 mg tablets three times/day or Actovegin intramuscular injections of 5 ml twice a day.

In conditions of hypoxia, the Actovegin drug is administered 80 mg parenterally for 14 days or in tablet form, 200 mg 3 times/day for 2 to 6 weeks.

Before administering the product parenterally for the first time, a test is necessary to determine whether it can cause an allergic reaction.

The most frequently recommended dosage is the Actovegin injection for athletic use, which is considered more effective than the Actovegin pill form. 

In 2000, Actovegin was at the center of a sports scandal. Participants of the Tour de France cycling race, including Lance Armstrong,  its seven-time winner, were accused of using it. Despite the fact that it is difficult to detect traces of the drug in the blood (our own blood contains approximately the same substances), the grounds for the accusation were open packages of Actovegin that were found during the inspection. However, further research revealed that the drug was deemed ineffective. The charges were dropped.

In 2016, the former cycling athlete Brandt-Sorenson pleaded guilty because he sold Actovegin to his fellow athletes, along with other performance-enhancing substances. Nick Brandt-Sorenson accepted a lifetime ban for his doping offenses. Brandt-Sorenson is now retired from competition. He is involved in designing made-to-measure, premium cycling apparel.

As of the writing of this article, Actovegin is excluded from the list of doping by WADA. And athletes continue to widely use it in various sports to improve performance and for rapid recovery.

Actovegin is not approved by the U.S. Food and Drug Administration (FDA) or by Health Canada and therefore is not marketed as a prescription medicine in the United States or Canada. However, the fact that it is not approved does not mean the FDA has formally banned it due to prion risk or any specific safety concern. Rather, it has simply not undergone the full marketing authorization process in those jurisdictions. Regulators in North America and Europe generally apply extra caution to injectable products derived from animal tissues, particularly since the discovery of bovine spongiform encephalopathy (BSE) (“mad cow disease”) and its human counterpart, Creutzfeldt–Jakob disease (CJD).

From a manufacturing standpoint, Actovegin is produced from a deproteinized hemoderivative of calf blood obtained by ultrafiltration, leaving only low-molecular-weight components (below about 5 kDa) in the final active substance. Prion proteins are much larger—on the order of tens of kilodaltons—which is one of the manufacturer’s arguments for a low theoretical risk of prion contamination. Nevertheless, like all medicines derived from bovine tissue, Actovegin is sometimes discussed in the context of a theoretical risk of transmissible spongiform encephalopathies (TSEs), though no such cases have ever been attributed to the product.

Following the emergence of BSE, the FDA issued a final rule on bovine spongiform encephalopathy defining “prohibited cattle materials” and banning their use in human food, dietary supplements, and cosmetics. These prohibited materials include specified risk tissues (SRMs) such as brain, skull, eyes, spinal cord, and certain vertebral tissues from older cattle, as well as material from non-ambulatory disabled cattle and cattle not inspected and passed. The rule clarifies that milk, hides, and gelatin or tallow processed under specific conditions are not considered prohibited materials.

Importantly, this regulation targets specific bovine tissues and does not constitute a blanket ban on all animal-derived medicines or bovine blood products:

For Actovegin specifically, the starting material, “Deproteinised hemoderivative of calf blood, Actovegin concentrate”, has been granted a Certificate of Suitability (CEP) by the European Directorate for the Quality of Medicines & HealthCare (EDQM). According to the EDQM database, the certificate number is R1-CEP 2004-235 – Rev 03, and its current status is Valid:

A CEP is not an “EMA approval” of the finished drug; rather, it certifies that the active substance complies with the European Pharmacopoeia monograph and that its TSE risk has been assessed in line with the European Medicines Agency (EMA) guideline “Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products” (EMA/410/01 rev.3). In other words, the TSE-risk control for the raw material has been evaluated through the CEP process, but it would be too strong to claim that the EMA itself has certified that the finished Actovegin product “meets all EMA requirements.”

To date, no cases of Creutzfeldt–Jakob disease have been reported in association with Actovegin use in the medical literature. Clinical trials in diabetic polyneuropathy, post-stroke cognitive impairment, and peripheral arterial disease have not revealed any unexpected safety concerns. Nonetheless, the long-term safety and efficacy of chronic Actovegin therapy have not been established to the same standard as many widely approved medicines, and the product remains unlicensed in North America and several Western countries.

Actovegin remains widely used in several European and Asian countries, particularly in neurology and vascular medicine. As with any biologic product derived from animal tissue, its use should always be based on local regulatory status, official prescribing information, and a careful individual assessment of benefits and risks by a qualified physician.

Along with anecdotal experiences a group of scientists from Cardiff University in the UK shared their study on Actovegin in terms of common sport-related injuries. In their small pilot study, they came to the conclusion that “players in the Actovegin treatment group were able to return to play 8 days earlier (95% CI -1.249 to -14.7510) compared to physiotherapy alone (p=0.033). No adverse reactions were recorded in any of the participants.” 

Actovegin's legal status is unclear in many parts of the world. The nootropic cannot be bought OTC in the USA, Canada, or the UK. However, the drug is used for medicinal purposes at the discretion of general practitioners in some European countries, in Russia and CIS countries, in China, and in South Korea.

Always be sure to do your research before purchasing any nootropic supplement to ensure you are getting a quality product.

Orally, without chewing, before meals, with a small amount of liquid.

According to the instructions, Actovegin solution can be taken intravenously or intramuscularly. The drug can also be added to infusion solutions. 

For infusion administration, 10 to 50 mL of the drug should be added to 200-300 mL of a basic solution (isotonic sodium chloride solution or 5% glucose solution). The infusion rate is about 2 ml/min.

For intramuscular injections, use no more than 5 mL of the drug, and inject slowly due to its hypertonicity. Depending on the severity of the clinical picture, initially 10-20 ml of the drug should be administered intravenously or intra-arterially daily. For further treatment, administer 5 mL intravenously or intramuscularly slowly, once daily or several times a week.

Generally speaking, Actovegin injections are more potent compared with the pill form. This is due to the fact that the pharmaceutical directly enters the blood flow, bypassing the gastrointestinal tract. The onset of action arrives faster. Hence, Actovegin injections are mainly used in acute conditions such as trauma or injury. The course of treatment is also shorter than with Actovegin pills.

However, Actovegin pills have their advantages too. The main one is the convenience of use. Pill administration does not require assistance from a medical professional, unlike IM or IV injections, which may necessitate medical intervention. Pills tend to have a more prolonged action, as the digestive process delays the absorption of the substance, resulting in slower action of Actovegin tablets. This may be particularly beneficial for patients with chronic illnesses.

As we can see, each form of the drug has its own advantages and disadvantages and is used in different situations. When making a choice, it is necessary to take into account the state of health and the presence of any pathologies as well. The correct form of the drug can only be prescribed by the attending physician, depending on the patient’s disease.