Actovegin

Actovegin contains only components under about 5 kilodaltons - the manufacturing process removes proteins - so what remains is a mixture of amino acids, small peptides, nucleosides, inositol phospho-oligosaccharides and electrolytes. The proposed mechanism is insulin-independent stimulation of glucose transport and enhanced oxidative phosphorylation, which would matter most in ischaemic or hypoxic tissue. Laboratory work also shows inhibition of poly-ADP-ribose polymerase and reduced oxidative stress and apoptosis in neurons. The honest position is that nobody knows which component is responsible for what, and that lack of a defined active ingredient is the main scientific criticism of the product. Its reputation in sport comes from intramuscular injection into and around injured muscle, popularised by clinicians treating elite footballers and sprinters.

Targets: Cellular glucose uptake, Mitochondrial oxidative phosphorylation, Poly-ADP-ribose polymerase, Oxidative stress pathways

• · Ampoules are 40 mg/mL, so 2-5 mL gives 80-200 mg. Manufacturer guidance is not to exceed 5 mL per intramuscular injection, and to give a 2 mL test dose first because of anaphylaxis risk.
• · Tablets are 200 mg; typical use is one to two tablets three times daily. The dose shown is per administration, not the daily total.

Work out your exact syringe units →

• commonInjection-site pain— Intramuscular volumes of several millilitres are uncomfortable.
• uncommonUrticaria, flushing and rash
• uncommonFever and sweating
• rareAnaphylaxis or anaphylactoid reaction— The reason a test dose is mandatory. This is a bovine blood derivative being injected into a human.

• Known hypersensitivity to any bovine-derived product.
• Decompensated heart failure, pulmonary oedema, oliguria or anuria - the injectable solutions carry a fluid and electrolyte load.
• Any tested athlete considering intravenous infusion - WADA prohibits intravenous infusions above 100 mL per 12 hours regardless of what is in them, though intramuscular Actovegin itself is not prohibited.

• conflictOther injectables in the same syringe — The manufacturer specifies it should not be mixed, given the undefined composition.

• · Observe for at least 30 minutes after the first dose for hypersensitivity.
• · Serum electrolytes if repeated intravenous infusions are used.

Approved and widely prescribed in Russia, Austria, Germany, China, South Korea and elsewhere. Not approved in the US, where importation has been blocked; not approved in the UK. Intramuscular use is permitted under WADA rules, but intravenous infusion volumes above 100 mL per 12 hours are prohibited.

• Ziegler et al. 2009, Actovegin in patients with type 2 diabetes and symptomatic polyneuropathy, randomised double-blind trial, Diabetes Care (trial)
• Guekht et al., ARTEMIDA randomised trial of Actovegin in post-stroke cognitive impairment (trial)
• Lee et al., update on the role of Actovegin in musculoskeletal medicine, Clinical Journal of Sport Medicine (review)

The proposed mechanism is insulin-independent stimulation of cellular glucose uptake and enhanced oxidative phosphorylation, which would matter most in tissue that is ischaemic or hypoxic. The inositol phospho-oligosaccharide fraction is the component usually credited with the insulin-like glucose transport effect, since inositol phosphoglycans are recognised second messengers in insulin signalling. Beyond that, laboratory work shows inhibition of poly-ADP-ribose polymerase (PARP) and reduced oxidative stress and apoptosis in neurons. PARP overactivation depletes NAD+ and drives cell death after ischaemic and oxidative injury, so inhibiting it is a coherent neuroprotective mechanism and it is the one most often cited for the stroke and neuropathy indications. The honest position, and it needs to be stated rather than buried: nobody knows which component does what. That is not a rhetorical criticism, it is a practical one. Without a defined active ingredient you cannot do dose-response pharmacology, you cannot standardise batches against a potency assay in any conventional way, and you cannot interpret a positive trial mechanistically. The positive trials that exist - and they are real - tell you that this preparation did something, not what. The sports medicine reputation comes from a different place entirely. Intramuscular injection into and around injured muscle, popularised by clinicians treating elite footballers and sprinters, is credited with faster return to play. That use rests on one small controlled study, extensive case experience and a great deal of reputation, and it is not what the randomised trials examined. One mechanistic point worth flagging for the sports context: injecting several millilitres of a fluid into an injured muscle has effects of its own, independent of what is in the fluid. Nobody has run that control.

The first thing is anaphylaxis, and it is the reason the test dose exists. This is calf blood ultrafiltrate injected into a human. The reaction rate is low, but a bovine-derived product carries a real hypersensitivity risk and a 2 mL test dose with 30 minutes of observation is standard practice rather than an abundance of caution. The second is the interpretive problem, which affects how you should read every claim about this product. Two large randomised trials came out positive. Nobody can say which of the hundreds of components produced the effect, which means the trials cannot be reasoned about mechanistically, cannot guide the design of a better version, and cannot easily be extrapolated to other indications. A positive trial of an uncharacterised mixture is a weaker piece of evidence than a positive trial of a defined molecule, even at the same p-value. The third is the gap between the trials and the use. The randomised evidence is in diabetic polyneuropathy and post-stroke cognitive impairment, with intravenous then oral dosing over months. The famous use is a handful of intramuscular injections into a hamstring over two weeks. Those are not the same intervention and the trial evidence does not underwrite the sports use. The fourth is availability and provenance. Actovegin is not approved in the US and importation has been blocked; it is not approved in the UK. Product obtained outside a legitimate supply chain in a country where it is licensed has no assurance of being what it says. The fifth is the fluid load. Repeated intravenous infusions carry a real fluid and electrolyte burden, which is why decompensated heart failure and oliguria are contraindications rather than cautions.

1. 80 mgBefore any course — A 2 mL intramuscular test dose - 80 mg at the standard 40 mg/mL ampoule concentration - given and observed for 30 minutes. This is manufacturer guidance and it exists because of the anaphylaxis risk with a bovine-derived product, not as a formality.
2. 200 mgAcute injury, first days — Up to 5 mL, so 200 mg, intramuscularly into and around the injured muscle. The manufacturer specifies not exceeding 5 mL per intramuscular injection. Sports courses are a handful of injections over one to two weeks.
3. 2000 mgNeurological indications, weeks 1-3 — 2000 mg daily by intravenous infusion for up to 20 days is the regimen used in both the diabetic polyneuropathy trial and ARTEMIDA. This is a hospital or clinic procedure, not a self-administered one.
4. 1800 mgNeurological indications, months 1-6 — Oral continuation at 1800 mg daily for 140 days in the polyneuropathy trial, or 1200 mg daily for six months in ARTEMIDA. Note that oral dosing is a fraction as potent per milligram given the gastrointestinal barrier, which is why the intravenous phase comes first.

• Cellular glucose transport — Attributed to the inositol phospho-oligosaccharide fraction; no defined ligand or constant

  Insulin-independent increase in glucose uptake, the mechanism most often cited for the effect in ischaemic and hypoxic tissue.

• Mitochondrial oxidative phosphorylation — Not a receptor interaction

  Increased oxygen utilisation and ATP production, which would be most relevant where oxygen supply is limited.

• Poly-ADP-ribose polymerase (PARP) — Inhibition demonstrated in laboratory work; component responsible unidentified

  Reduced NAD+ depletion and reduced apoptosis after oxidative and ischaemic injury. The most plausible neuroprotective mechanism.

• Oxidative stress pathways — Not characterised

  Reduced reactive oxygen species and lipid peroxidation in neuronal models.

• Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients Randomised, double-blind, placebo-controlled · n=567 · 23 weeks · 2009

  567 patients (281 actovegin, 286 placebo) given 2000 mg daily intravenously for 20 days followed by 1800 mg daily orally for 140 days - 160 days total. Co-primary endpoints were total symptom score of the lower limbs and vibration perception threshold. Symptom score improved significantly (p=0.0003 by area under the curve, p<0.0001 from baseline) and vibration perception threshold improved at day 160 (p=0.017), alongside improvements in sensory function and quality of life.

• ARTEMIDA: A Randomized Trial of Efficacy, 12 Months International Double-Blind Actovegin in post-stroke cognitive impairment Randomised, double-blind, placebo-controlled · n=503 · 52 weeks · 2017

  503 patients (248 actovegin, 255 placebo) after ischaemic stroke, given 2000 mg daily intravenously for up to 20 infusions then 1200 mg daily orally, for six months of treatment with six months of follow-up. Cognitive change at six months favoured actovegin, mean change from baseline -6.8 versus -4.6, treatment difference -2.3 (95% CI -3.9 to -0.7, p=0.005).

Sports use, days 1-3: injections given in the first days after a muscle strain. Nothing is expected immediately beyond injection-site soreness from several millilitres of fluid in an injured muscle. Sports use, weeks 1-3: return to play is judged here. This is the timeframe the reputation rests on and it overlaps almost exactly with the natural healing course of a grade 1 or 2 strain, which is why the case evidence is hard to interpret. Neurological use, days 1-20: the intravenous phase. Effects are not expected within it. Neurological use, months 3-6: where the randomised trials measured their endpoints. Both the polyneuropathy and stroke trials assessed at six months, and that is the honest timescale. This is not a compound with a fast subjective signal, which is worth knowing before assuming an early improvement is the drug.

The manufacturer specifies not mixing Actovegin with other injectables in the same syringe, and given the undefined composition that is a reasonable instruction to follow literally rather than interpret. In sports medicine practice it is frequently given alongside local anaesthetic and sometimes alongside other injectables around an injured muscle. That is a clinician-administered combination with no interaction data behind it. For tested athletes there is a specific rule worth understanding precisely: intramuscular Actovegin is not itself prohibited by WADA, but intravenous infusions exceeding 100 mL per 12 hours are prohibited regardless of what is in them. The 2000 mg intravenous regimen used in the neurological trials involves volumes well past that threshold. So the route determines the violation, not the substance. In diabetes, watch for additive glucose lowering with insulin or a sulfonylurea if the insulin-independent glucose uptake mechanism is real.

Against the peptides in this class: Actovegin has larger and better randomised trials than almost anything else here - 567 and 503 patients, published in Diabetes Care and Stroke - and simultaneously the weakest mechanistic characterisation of anything here. That is an unusual combination and it should make you uncomfortable in both directions. Against ARA-290 for diabetic neuropathy: ARA-290 is a defined molecule with objective nerve-fibre imaging endpoints in a 64-patient phase 2b. Actovegin has a 567-patient trial with symptom and vibration threshold endpoints and no defined active ingredient. Neither is approved for this in the US. They are strong in opposite ways. Against platelet-rich plasma for muscle injury: both are used in elite sport on reputation, both have thin randomised evidence for that specific use, and both are injected into muscle in volumes that could plausibly produce an effect on their own. The honest comparison is that neither has earned its reputation from trials. Against simply managing the injury properly: for a grade 1 or 2 muscle strain, progressive loading and time have a well-characterised recovery curve that overlaps the window in which Actovegin gets credit. That overlap is the central difficulty with the sports evidence.

$40–$250/month. Priced as a prescription medicine in the countries where it is licensed - Russia, Austria, Germany, China, South Korea and others. Ampoules and tablets are relatively inexpensive there; obtaining it elsewhere is a different and more expensive proposition. Order-of-magnitude estimate, not price-checked in the preparation of this entry.

• ?No active ingredient has ever been identified, so no pharmacokinetic parameter of any kind can be stated for the product as a whole.
• ?The oral regimen in the Ziegler 2009 trial is reported as 1800 mg daily; the tablet strength and exact divided-dose schedule were not confirmed in this session, and the Core record notes 200 mg tablets while the trial regimen implies larger units.
• ?The single small controlled study underpinning the muscle injury use was not resolved to an indexed publication in this session.
• ?Whether injecting several millilitres of any fluid into injured muscle produces an effect independent of the contents has never been controlled for.
• ?Batch-to-batch consistency of an undefined biological ultrafiltrate is a genuine open question that the trials do not address.
• ?Cost figures are estimates and were not price-verified in this session.

• Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I, Diabetes Care, 2009 · PMID 19470838

  The largest and best-conducted trial of this product. 567 patients, properly randomised and placebo-controlled, with positive results on structured endpoints - which sits awkwardly alongside the fact that nobody knows what the active ingredient is.

• ARTEMIDA Trial: A Randomized Controlled Trial to Assess the Efficacy of Actovegin in Poststroke Cognitive Impairment Guekht A et al., Stroke, 2017 · PMID 28432265

  A 503-patient randomised trial in a major journal with a positive cognitive endpoint. Worth reading alongside the composition problem, because the two facts are hard to reconcile.

• Predictors of response to treatment with actovegin for 6 months in patients with type 2 diabetes and symptomatic polyneuropathy Ziegler D et al., Journal of Diabetes and its Complications, 2017 · PMID 28438471

  Secondary analysis identifying who responded, which is more useful clinically than the headline result.