Biohacking is often described as a citizen or do-it-yourself biology. For many biohackers with MS, this consists of making dietary or lifestyle changes to try and make small improvements to your health and well-being. However, more recently MS biohackers have become active in sourcing off-label medications, which are usually prescription-only medications (PoM), in the hope of them improving long-term MS outcomes. The two most commonly sourced biohacking PoMs that I have seen being used in real-life are simvastatin and metformin.
Simvastatin is being used to try and slow down smouldering MS in people with more advanced MS and is based on the MS-STAT trial that showed that high-dose simvastatin, 80-mg per day, slowed down brain volume loss and disability progression in subjects with secondary progressive MS (see Study 1 below). I personally don’t recommend patients take simvastatin for MS until we see the results of the phase 3 MS-STAT2 trial, which is currently running. Please note that despite statins being one of the most commonly prescribed medications on the market, they are not without side effects and controversy. I am personally concerned about the effect of CNS-penetrant statins, such as simvastatin, on cognitive function, not to mention the effects of high-dose statins on skeletal muscle function. So please let's try and be patient and wait for fr the MS-STAT2 trial to report out before jumping the gun.
Multiple Sclerosis-Simvastatin Trial 2 (MS-STAT2). ClinicalTrials.gov Identifier: NCT03387670
Increasingly I am finding that some of the more proactive patients of mine are also taking metformin a drug that is licensed to treat type 2 or adult-onset diabetes. These patients are able to purchase metformin on the internet, bypassing the need for a prescription from their family doctor and other HCPs involved in their care. The use of metformin in MS is based on the observation in animal models that it rejuvenates oligodendrocytes, i.e. making them younger, which promotes remyelination (see paper 2 below). In addition to this, there is emerging literature that metformin may be antiageing and a large number of biohackers take metformin as part of their anti-ageing regimen. Please note that metformin is now in clinical trials in people with MS including an exciting trial in the UK to see if it can synergise with clemastine to promote remyelination.
Trials of metformin in MS
A Phase I Double Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children With Multiple Sclerosis. ClinicalTrials.gov Identifier: NCT04121468.
CCMR Two: A Phase IIa, Randomised, Double-blind, Placebo-controlled Trial of the Ability of the Combination of Metformin and Clemastine to Promote Remyelination in People With Relapsing-remitting Multiple Sclerosis Already on Disease-modifying Therapy. ClinicalTrials.gov Identifier: NCT05131828
Drug Repurposing for Improving the Therapeutic Outcome in Multiple Sclerosis Patients. ClinicalTrials.gov Identifier: NCT05298670
We have all assumed metformin is safe. It, therefore, came as a surprise to see that preconception metformin treatment in fathers is associated with major birth defects, particularly genital birth defects in boys.
It looks as if these metformin-associated birth defects occur in the children of men who take metformin during sperm development, i.e in the three months prior to conception. Sons born to these men are more than 3x as likely to have a genital birth defect as unexposed babies. The genital defects, such as hypospadias, when the urethra does not exit from the tip of the penis occurred in 0.9% of babies whose biological fathers took metformin in the 3 months before conception. These findings may be important because 100’s millions of people worldwide take metformin, mainly for type 2 diabetes, but also as part of the biohacking movement, which includes pwMS.
It is important to stress that these findings need to be replicated and at present, this finding is simply an association between metformin exposure and congenital abnormalities and more research is needed to prove causation. However, this is a sober reminder that biohacking and taking PoM off-label may have undefined consequences that have yet to be uncovered.
I would be interested to hear about your own biohacking attempts and how many of you are doing it with or without the consent of your MS HCPs. I am aware that many HCPs are complicit in that they prescribe these medications to their patients knowing that these PoMs are not licensed to manage MS.
Paper 1
Background: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis.
Methods: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348.
Findings: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was -0·254% per year (95% CI -0·422 to -0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]).
Interpretation: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing.
Paper 2
The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.
Paper 3
Background: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.
Objective: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.
Design: Nationwide prospective registry-based cohort study.
Setting: Denmark from 1997 to 2016.
Participants: All liveborn singletons from mothers without histories of diabetes or essential hypertension.
Measurements: Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.
Results: Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).
Limitation: Information on underlying disease status was limited.
Conclusion: Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
MS biohackers beware