My "Cocktail" - Buzz's Place

This page has NOTHING to do with dogs (WHAT!?!?!?) or trombones (whew!!), but rather with my "fight" with my idiopathic peripheral polyneuropathy and to a certain extent, my diabetes Type 2. So if you don't need this information, scroll on.

The information I put here is under the caveat, that I'm NOT a doctor, although I do link to quite a few peer-reviewed studies concerning the various "stuff" I've found that has helped me. The important word here is "me". I make no claims, that this will help you. If it does, terrific. And as always, before diving into this yourself, consult your doctor(s).

Now I know you didn't ask this, but I'm gonna get it out there anyway. Many people would say in such a situation „I did my research...“. Well, I didn't. Why? Because my background in science is in the behavioral sciences, and I didn't have a white lab coat there. I didn't study implicitly the formats for researching and then writing up scientific findings. I DID however need to learn how to read peer reviewed studies and evaluate their methodological accuracy in terms of form. I learned (what too few authors of peer reviewed papers do, especially in the animal behavioral sciences,) to backtrack cites in papers to see if what the authors claim can be found in previous work is actually … found in previous work. That can help explain where the present work came for, what it's based upon. And because I'm not doing papers that depend upon statistical results and relevancies, I never had to delve into the voodoo of statistics. So … I didn't „research“ anything here. I only searched available papers, read those which supported my „hypothesis“ as well as those that refute it, collated, and presented my findings.

First the "why". I was first diagnosed with Idiopathic Peripheral Polyneuropathy in 1999 after having been in the hospital for a leg thrombosis and lung embolisms. The doctors said, there was no connection. ...um, ok... It did take several months for the first neurologist to come up with that diagnosis. His prognosis: "Sorry, no cure, no relief, suck it up, buttercup". Well, not quite so brutal, but effectively that. I was also diagnosed with diabetes Type 2 in 2014, which was provoked by taking Spiricort (glucocorticoid) to combat Polymyalgia Rheumatica and I have been taking Metformin since late 2014, when my diabetes Type 2 was first diagnosed - that is until recently (see below). In November 2018 I had a heart infarct, was treated with stents and since then have been taking the following prescription medications for diabetes control and lipid control:

Ezetimib/Rosuvstatin-Mepha 10 mg/10 mg – 1-0-0-0 (Mo,Mi,Fr, So.)

Forxiga 5mg – 1-0-0-1

Aspirin Cardio 100 mg – 1-0-0-0

Metfin 1000 mg – ½-½-0-1 (discontinued in April 2024 as a test - see below)

Side note: I'm not a sweets/desert eater. Since 1973 I've eaten low-carbs (<50gr/day) and since around 2014 lower carb (<25gr/day).

And in the course of the next many years since 1999, the neuropathy got progressively worse. I had no sense of the floor under my feet, but had stabbing pains, electric shocks, cramps, depending upon the day, burning or freezing sensations in my feet and what I "like" to call "vice-grip" - my feet being held in a constricting vice-grip. It got to be pretty unbearable. My daughter, who is a doctor, recommended that I consult another neurologist, which I did. This new neurologist did about 3 hours of manual and electrical tests and found, that I not only had it in my feet, but also in my hands ... but I had almost no symptoms in my hands. Up until around 2021, my only symptoms in my hands were "the droppsies", meaning I tend to drop stuff ... but no pain. This neurologist sent me on to the big neurological guru at the local hospital who also ran his hours of tests including a lumbar puncture. His conclusion ... the same as hers. So, back with the neurologist, she first prescribed Cymbalta (SNRI class) and Gabapentine (anti-convulsant). The first couple of weeks were ok, but then the side effects started and now I know, that I had about 50-60% of the side effects possible, including brain fog, fatigue (also extreme, like suddenly falling asleep, like in the car or at work), phantom tastes, cognitive disturbances, sexual dysfunction. She switched out the Cymbalta for Effexor XR, but there was no improvement. And the effectiveness of the pain relief wasn't great. I still had many absolutely miserable days.

I then started pouring through Google Scholar for peer reviewed papers on neuropathy treatments and came across many using completely other substances. Some were small pilot studies, others full blown double blind placebo studies. It soon became apparent, that there were several substances, some that were readily available "over-the-counter", that had a good empirical track record. I started my own "experiments". I bought a bunch of these substances and made a record of how I felt. I then would exclude one or the other and see if I seemed to get worse, different or better.

What you see below is what I've settled on that works for me. I also listed a couple of substances that DO have good empirical results, but didn't seem to make any difference in my case, for example Hemp Oil and CBD oil.

Neuropathy is however a moving target. The symptoms I had 2 years ago are not the same as I have now. Basically, I now (see below) rarely have any cramps or stabbing pains, but the feeling of my feet being encased in a vice of cotton gauze with no contact to external conditions is much less prevalent and the numbness which had progressed to my thighs, has receded. My neurologist said after her testing November 2018, that I only had about 1/4 the sensitivity I'd had the year before in my feet. And once again a huge reduction in sensation in November 2019. But then and even still now, I've retained almost all of the strength in my legs, calves and ankles. The doctor had also diagnosed Carpal Tunnel Syndrome, without any symptoms presenting ... in 2013. That changed in 2021 as CTS symptoms started up big time - had the CT reduction surgery in May 2021 on my right hand - doesn't seem to be necessary in my left hand.

My “cocktail” as my neurologist calls it:

1-1-1-1 =

1 before breakfast

1 before lunch

1 before dinner

1 before going to bed

R-Lipoic Acid 250mg – 1-1-1-0

Acetyl-L-Carnitine 750mg – 1-0-1-0

N-Acetyl Cysteine (NAC) 1000mg – 0-1-0-1

Omega 3 (fish oil) – 1-0-1-0

Magnesium 100mg – 1-1-1-0

L-Citrullin 1250 mg – 1-0-0-0

Benfotiamine 250 mg – 1-1-1-1

Dihydroberberine – 1-1-1-0

(B8) Myo-Inositol & D-Chiro-Inositol 2000mg – 1-1-1-1 (see below "News from March 2024")

I started Vitamin B1 Benfotiamine in August 2023 and the difference was immediate. Since the 2nd/3rd day, no more burning. No more pain. The "woolley sock-vice" feeling is decreasing. I've started taking the following, loosely based upon the study by Maladkar, M., Tekchandani, C. and Dave, U. (2014) listed below. It is one that is cited now in many meta studies having to do with investigating non-prescription neuropathy pain strategies:

Vitamine B6 P5P ca. 80mg (see section on B6 below) 1-0-0-0

Vitamine B7 Biotin 5 mg 0-0-1-0

Vitamine B9 Folic acid 1.7 mg 0-1-0-1

Vitamine B12 Methylcobalamin 1500 mcg 1-1-1-0

The above neurotropic B-vitamin dosages (plus other B-vitamins) constitutes what I read, to be my "load dosages". I will try these Vitamin B substances until the end of June 2024 and slowly, gradually start reducing them until I find my so-called "maintenance dosages".. reducing only a couple at a time and seeing if, there is a worsening of my neuropathic discomfort. For example, I'll reduce the Benfotiamine from 600mg/day to 500mg/day. If that goes well over 2-3 weeks, I'll drop the B9 Folic acid from 5.1mg/day to 3.4mg/day. And so forth. ADDENDA: Last June I tried reducing the neurotropic B vitamins and ... the symptoms crept back in. So with approval of my GP and neurologist, I'm staying at these levels and I haven't had a "bad feet day" since October or so. Symptoms gradually disappearing (as of December 2024).

I have taken these in the past as well and they might help some people, I did not find, that I “missed” them, when I stopped taking them, but your mileage may vary...

cold pressed hemp oil –1000mg capsules 0-0-0-3

CBD oil (12% CBD), drops – 6-0-0-0 (actually before breakfast)

Vitamin D3, 5000 IU – 1-0-0-0

Borage Oil 240mg (GLA = Gamma Linoleic Acid) – 1-1-1-0

N.B. - this “cocktail” applies to and works for me. If you feel, it might be beneficial to you, please look at the research below and discuss this “cocktail” as well as this research with your doctor, inasmuch as I’m not a doctor.

NEWs from February 2024

As of today, 6. February 2024, both my GP and my neurologist have seen copies of my above list of substances and have signed off on them, so to speak. Today my neurologist did some tests of my balance as well as skin surface sensitivity. Yes, my thighs are no longer numb!! The numbness is still present below the knees, but I can now feel vibrations and feather touches down to the high ankle area, where ... the sensations stop. But this is a HUGE difference to August 2023, where this all was, simply to touch, - non-existent. What's interesting is - the researchers as well as my neurologist don't really know the why's or how's of this. There are theories, but ... haven't really been empirically proven. Why? Because in all the trials, almost all the participants experienced subjectively a very large reduction in neuropathic pain as I have or better, but in about half of them, electro-conductivity tests did not show any actual physiological improvement. So why did those participants still experience pain reductions, just like those whose tests did show physiological improvements? No scientific consensus. My neurologist is sceptical if my nerves have regenerated, especially not after almost 25 years. But results of her tests are ... as they are. Vast improvement over last August.

Next step, starting in July 2024, I will start, tiny step by tiny step, reducing the dosages, as written above, until I reach a maintenance dosage.

NEWs from March 2024

Today (26 March 2024) I saw my GP for my quarterly blood work. Sometimes it’s the full panel, sometimes just HbA1c and fasting blood sugar level – like today. Good news (relatively). No raise in HbA1c – still at 6.9, which theoretically still is high, but he’s satisfied. He’d said, that if it went above 7.3 and stayed there for a „longer period“, we’d have to think about „other options“, including, as he put it, a weekly injection of „something“ – I don’t remember if he actually named a name, but I suppose it would be something from the Ozempic family.

I had been taking 2gr Metformin/day since around 2014/2015 or so - often with sporadic GI distress. And have fought my way through various statins, two of which caused my neuropathy to flair up. I was able to find a statin and a dosage that keeps my LDL down and my HDL up, but not too far. Am taking now Ezetimib/Rosuvstatin-Mepha 10 mg/10 mg, once a day, three days a week and my last LDLs were „perfect“ as he said. More below ...

In the meantime, there is a lot of literature showing that Metformin can inhibit cellular absorption of Vitamins B6, B9 (folate) and especially B12 – and one sign of this is … you guessed it … neuropathy. And my feet have gotten so much better since August 2023, when I started taking B1, B6, B9 and B12 – see below. So I got to thinking and investigating. What else has an empirically proven track record of reducing blood sugar, fighting insulin resistence as well as keeping LDLs down? And I „found“ two substances:

Berberine (various forms)

Myo-Inositol /with or without D-Chiro-Inositol.

Both have been shown to reduce HbA1c, fasting blood sugar levels, as well as reducing LDL levels and triglycerides. The jury is mixed concerning HDL – some studies showed increases in HDL (which, within limits is desireable) while others showed no change.

I started with Berberine while continuing to take Metformin – something that is even suggested for increase efficacy. Within 3 days I was having increased upper stomach pain and gas, which I often got from Metformin anyway, but also lower intenstinal cramping and increased need to … deficate. But my fasting sugar levels were a little lower: 6.2 - 6.5. After trying difference combinations of different forms of Berberine, with no improvements, I gave up, stopped taking Berberine and switched to Myo-Inositol/D-Chiro-Inositol (as recommended 40:1 ratio). A short time later I stopped cold taking Metformin. That afternoon my stomach problems stopped and have stayed away - for the last 3 weeks (as of this writing, April 28, 2024). None since then. After having added Dihydroberberine, my fasting sugar has stayed consistently between 6.2 - 6.5 as it often was with Metformin/Berberine during the day with no return of stomach distress. This is the same level I had obtained with the Metformin/Berberine combination which my stomach didn't tolerate, so, unless proven otherwise, it appears, that the Berberine/Myo- & D-Chiro-inositol combination could be the way to go.

I related this concerning inositol to my GP and we’ve decided to try this combination of Myo-Inositol/D-Chiro-Inositol for 3 months without Metformin, while continuing on with the other B Vitamins and the Ezetimib/Rosuvstatin-Mepha (for lipids) and then do a large blood panel. He also mentioned, that if the Myo-Inositol/D-Chiro-Inositol doesn't have the positive effects that the studies have shown on LDL, he would recommend a PCSK9-Inhibitor such as Evolocumab instead of the Ezetimib/Rosuvstatin.

I might add, that my feet have never felt so well as now. All burning is GONE. All cramping is GONE. All electric shocks and tingling is GONE. The numbness has receded from mid-thighs to upper-ankles with very present sensitivity in my heels – I can even feel the fabrik and seams of my socks and the backs of my shoes. The vice-grip around my feet have reduced by 90% left and about 50% right if I even notice it at all. And more importantly: I can DO stuff with other people while sitting down, standing around or walking and … not constantly be feeling my feet. They just work now pretty much as advertised.

Below I have listed

1) some studies concerning side-effects of Metformin concerning B vitamins

2) some studies comparing metformin with other substances concerning relative efficiency

3) Berberine and diabetes

4) Inositol (Myo- & D-Chiro-Inositol)

NEWs from June 25 2024

Well the lab results were not as good as hoped for. Not that the inositol/berberine isn't working, they just are not working better than Metformin. LDL was 1.7 3 months ago. Now LDL was 2.2. HbA1C was 6.9 three and six months ago, but was now 7.3. Not the first time it was 7.3. So I'm NOT stopping statins - they're not "bothering" my feet anyway as my feet are still getting better and better. And I will continue taking the inositol/berberine as I'm otherwise feeling better than with metformin. I've also got a Continuous Glucose Monitor I'm wearing for the next 4 weeks and sporadically thereafter. I will continue my very-low-carb eating habits and exercise. And I'l resist any attempts at getting me to take ozempic or similar - and my GP doesn't seem to be opposed to that.

Addenda – July10 2024

I wore a Constant Glucose Monitor (CGM), a FreeStyle Libre 3, for the past two weeks and the results, as confirmed by my GP, are a relief. Although not "sterling", I was within "normal" glucose ranges 93% of the time, only experiencing raises right after breakfast (always consisting of 75gr hard cheese, 75gr sliced meat and coffee) which then receded during exercise at the gym or while walking the dog thereafter. Also a slight raise about 2 hours after dinner (which usually consists of a salad and a chicken breast or 3-egg omelette and coffee) - this also receded somewhere around midnight and stayed well in normal range until getting up in the morning. My average GMI (analog to HbA1c) was 7.0, which is acceptable. And this without metformin, but with inositol and berberine. I picked up two more CGMs and also ordered 3 CGMs from another company, Sibionics. Tomorrow I go on a 5-day road trip and am interested in seeing how the added exercise and "enjoying edible life" combine to effect my blood sugar. Then we're home until 27th July and then take off again for 8 days - then I'll have both monitors. My GP recommended I up my Ezetimib/Rosuvstatin-Mepha to 4 times a week and see if I experience any side effects. If not, up them once again to 5 times a week and check my LDL and triglycerides in September again.

Addenda – December 18 2024

CGM levels of 4.0 - 8.0 mmol/L and +/- 6.0% (GMI), Carb level still generally @ <25gr/day. When I do "enjoy life" in a culinary manner, for example a birthday party or family get-together, the spikes do get rather large, up to 12.0 mmol/L but also come down again after a few hours, so I just watch how often these periods occur.
LDL @ 1.2. So the combination of statin and inositol/dihydroberberine appear to be working on both levels. Will try reducing the stains in the coming months and will be measured again in March 2025.
Neuropathic symptoms still slowly receding. That means that surface sensitivity is returning to my feet to the point that my podological treatments are actually partially uncomfortable. In other words, bad news is good news. But activities are rarely negatively affected by neuropathic discomfort.

Studies

Alpha Lipoic Acid:

Tingting Han, Jiefei Bai, Wei Liu and Yaomin Hu, (2012) A systematic review and meta-analysis of a-lipoic acid in the treatment of diabetic peripheral neuropathy, European Journal of Endocrinology (2012) 167 465–471, https://www.ncbi.nlm.nih.gov/pubmed/22837391

Craig J. McMackin, Michael E. Widlansky, Naomi M. Hamburg, Alex L. Huang, Susan Weller, Monika Holbrook, Noyan Gokce, Tory M. Hagen*, John F. Keaney Jr., and Joseph A. Vita, (2007) Effect of Combined Treatment with Alpha Lipoic Acid and Acetyl- L-Carnitine on Vascular Function and Blood Pressure in Coronary Artery Disease Patients, J Clin Hypertens (Greenwich). 2007 April ; 9(4): 249–255. , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734271/

Ziegler D, Reljanovic M, Mehnert H, Gries FA. (1999) Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30., https://www.ncbi.nlm.nih.gov/pubmed/10595592

D. Ziegler, H. Nowak, P. Kempler†, P. Vargha and P. A. Low, (2003) Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a meta-analysis, 2004 Diabetes UK. Diabetic Medicine, 21, 114–121, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-5491.2004.01109.x

Andrew J. M. Boulton, Peter Kempler, Alexander Ametov, Dan Ziegler (2013) Whither pathogenetic treatments for diabetic polyneuropathy? DIABETES/METABOLISM RESEARCH AND REVIEWS
Diabetes Metab Res Rev 2013; 29: 327–333., https://www.ncbi.nlm.nih.gov/pubmed/23381942

Z. X. Poh* and K. P. Goh (2009) A Current Update on the Use of Alpha Lipoic Acid in the Management of Type 2 Diabetes Mellitus, Endocrine, Metabolic & Immune Disorders - Drug Targets, 2009, 9, 392-398, https://www.ncbi.nlm.nih.gov/pubmed/19601918

Giorgia Melli, MD,PhD, Michela Taiana, MS, Francesca Camozzi, MS, Daniela Triolo, MS, Paola Podini, MS, Angelo Quattrini MD, Franco Taroni, MD, and Giuseppe Lauria, MD (2008) Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy, Exp Neurol. 2008 Dec;214(2):276-84. doi: 10.1016/j.expneurol.2008.08.013. Epub 2008 Sep 9., https://www.ncbi.nlm.nih.gov/pubmed/18809400

Foster TS, (2007) Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy., Diabetes Educ. 2007 Jan-Feb;33(1):111-7., https://www.ncbi.nlm.nih.gov/pubmed/17272797

Linus Pauling Institute Micronutrient Information Center, Lipoic Acid, last update 2012, https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid

Evangelos Agathos, Anastasios Tentolouris , Ioanna Eleftheriadou, Panagiota Katsaouni, Ioannis Nemtzas, Alexandra Petrou, Christina Papanikolaou and Nikolaos Tentolouris (2018) Effect of a-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy, Journal of International Medical Research 2018, Vol. 46(5) 1779–1790, DOI: 10.1177/0300060518756540, https://journals.sagepub.com/doi/full/10.1177/0300060518756540

Acetyl-L-Carnitine

Di Stefano G, Di Lionardo A, Galosi E, Truini A, Cruccu G. Acetyl-L-carnitine in painful peripheral neuropathy: a systematic review. J Pain Res. 2019 Apr 26;12:1341-1351. doi: 10.2147/JPR.S190231. PMID: 31118753; PMCID: PMC6498091. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498091/

Sima AA, Calvani M., Mehra, M., Amato, A. (2005) Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials., Diabetes Care. 2005 Jan;28(1):89-94., https://www.ncbi.nlm.nih.gov/pubmed/15616239

Youle M., Osio, M., ALCAR Study Group (2007) A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection., HIV Med. 2007 May;8(4):241-50., https://www.ncbi.nlm.nih.gov/pubmed/17461852

Sarah J.L. Flatters, Wen-Hua Xiao a, Gary J. Bennett (2006) Acetyl-l-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy, Neuroscience Letters 397 (2006) 219–223, https://www.ncbi.nlm.nih.gov/pubmed/16406309

Bianchi G, Vitali G, Caraceni A, Ravaglia S, Capri G, Cundari S, Zanna C, Gianni L., (2005) Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine., Eur J Cancer. 2005 Aug;41(12):1746-50., https://www.ncbi.nlm.nih.gov/pubmed/16039110

N-Acetyl Cysteine (NAC)

Mahmoud Ali Ismael, Sébastien Talbot, Cynthia L.Carbonneau, Christian M. Beauséjour, Réjean Couture, (2008) - Blockade of sensory abnormalities and kinin B1 receptor expression by N-Acetyl-l-Cysteine and ramipril in a rat model of insulin resistance, European Journal of Pharmacology Volume 589, Issues 1–3, 28 July 2008, Pages 66-72, https://www.sciencedirect.com/science/article/pii/S0014299908005098

M. Sagara, J. SatohR. Wada, S. Yagihashi, K. Takahashi, M. Fukuzawa, G. Muto, Y. Muto, T. Toyota, (1996) Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine, March 1996, Volume 39, Issue 3, pp 263–269, https://link.springer.com/article/10.1007/BF00418340

Pieper, Galen M.; Siebeneich, Wolfgang, Oral Administration of the Antioxidant, N-Acetylcysteine, Abrogates Diabetes-Induced Endothelial Dysfunction, Journal of Cardiovascular Pharmacology: July 1998 - Volume 32 - Issue 1 - p 101-105, https://journals.lww.com/cardiovascularpharm/Fulltext/1998/07000/Oral_Administration_of_the_Antioxidant,.16.aspx

Sherry Wolf *, Debra Barton, Lisa Kottschade, Axel Grothey, Charles Loprinzi, Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies, EUROPEAN JOURNAL OF CANCER 44 (2008) 1507–1515, https://www.sciencedirect.com/science/article/pii/S0959804908003353

Omega 3/6 (Hemp Oil forms and fish oil)

Ko, Gordon D. MD, CCFP (EM), FRCPC, FABPMR, FABPM; Nowacki, Nathaniel Benjamin BS†; Arseneau, Leigh ND; Eitel, Melanie RMA; Hum, Annie MD, (2010) Omega-3 Fatty Acids for Neuropathic Pain: Case Series, Clinical Journal of Pain: February 2010 - Volume 26 - Issue 2 - pp 168-172, http://journals.lww.com/clinicalpain/Abstract/2010/02000 Omega_3_Fatty_Acids_for_Neuropathic_Pain__Case.14.aspx

Peter Yee; Anne E. Weymouth; Erica L. Fletcher; Algis J. Vingrys, (2010) A Role for Omega-3 Polyunsaturated Fatty Acid Supplements in Diabetic Neuropathy, Investigative Ophthalmology & Visual Science March 2010, Vol.51, 1755-1764., http://iovs.arvojournals.org/article.aspx?articleid=2165464

Benfotiamine (and/or in combination, for example with "neurotropic B vitamins"):

Hakim, M., Kurniani, N., Pinzon, R. T., Tugasworo, D., Basuki, M., Haddani, H., Pambudi, P., Fithrie, A., & Wuysang, A. D. (2018). Management of peripheral neuropathy symptoms with a fixed dose combination of high-dose vitamin B1, B6 and B12: A 12-week prospective non-interventional study in Indonesia. Asian Journal of Medical Sciences, 9(1), 32–40. https://doi.org/10.3126/ajms.v9i1.18510 https://www.researchgate.net/publication/322193567_Management_of_peripheral_neuropathy_symptoms_with_a_fixed_dose_combination_of_high-dose_vitamin_B1_B6_and_B12_A_12-week_prospective_non-interventional_study_in_Indonesia

Hakim M, Kurniani N, Pinzon R, Tugasworo D, Basuki M, Haddani H, et al. (2019) A Review on Prevalence and Causes of Peripheral Neuropathy and Treatment of Different Etiologic Subgroups with Neurotropic B Vitamins. J Clin Exp Pharmacol 9: 262. doi: 10.35248/2161-1459.19.9.262 https://www.walshmedicalmedia.com/open-access/a-review-on-prevalence-and-causes-of-peripheral-neuropathy-and-treatment-of-different-etiologic-subgroups-with-neurotrop.pdf

Maladkar, M., Tekchandani, C. and Dave, U. (2014) Post-Marketing Surveillance of Fixed Dose Combination of Methylcobalamin, Alpha Lipoic Acid, Folic Acid, Biotin, Benfotiamine & Vitamin B6-Nutripathy for the Management of Peripheral Neuropathy. Journal of Diabetes Mellitus, 4, 124-132. http://www.scirp.org/journal/jdm http://dx.doi.org/10.4236/jdm.2014.42019

Baltrusch, Simone (2021) The role of Neurotropic B Vitamins in Nerve Regeneration, Biomed Res Int. 2021; 2021: 9968228. Published online 2021 Jul 13. doi: 10.1155/2021/9968228 https://www.hindawi.com/journals/bmri/2021/9968228/

Pinzon RT, Schellack N, Matawaran BJ, et al. (2023) Clinical Recommendations for the use of Neurotropic B vitamins (B1, B6, and B12) for the Management of Peripheral Neuropathy: Consensus from a Multidisciplinary Expert Panel. J Assoc Physicians India 2023;71(7):93–98. https://www.japi.org/y26464c4/clinical-recommendations-for-the-use-of-neurotropic-b-vitamins-b1-b6-and-b12-for-the-management-of-peripheral-neuropathy-consensus-from-a-multidisciplinary-expert-panel

Silviana, Meyvita, Tugasworo, Dodik, Belladonna,Maria (2020) The Efficacy of Vitamin B1, B6, and B12 Forte Therapy in Peripheral Neuropathy Patients, DOI: https://doi.org/10.14710/dimj.v2i1.9549

Geller M, Oliveira L, Nigri R, Mezitis SG, Ribeiro MG, et al. (2017) B Vitamins for Neuropathy and Neuropathic Pain. Vitam Miner 6: 161. https://www.hilarispublisher.com/open-access/b-vitamins-for-neuropathy-and-neuropathic-pain-2376-1318-1000161.pdf

Amorin Remus Popa, Simona Bungau, Cosmin MihaiI Vesa, Andrei Cristian Bondar, Carmen Pantis, Octavian Machiar, Ioana Alina DimulescuI, Delia Carmen Nistor Cseppento, Marius Rus, (2019) Evaluating the Efficacy of the Treatment with Benfotiamine and Alpha-lipoic Acid in Distal Symmetric Painful Diabetic Polyneuropathy, Revista de Chimie, Buchares, Original Edition- 70(9) DOI:10.37358/RC.19.9.7498, https://www.researchgate.net/publication/336529734_Evaluating_the_Efficacy_of_the_Treatment_with_Benfotiamine_and_Alpha-lipoic_Acid_in_Distal_Symmetric_Painful_Diabetic_Polyneuropathy

H. Stracke, W. Gaus, U. Achenbach, K. Federlin, R.G. Bretzel, (2008) Benfotiamine in Diabetic Polyneuropathy (BENDIP): Results of a Randomised, Double Blind, Placebo- controlled Clinical Study, 2008 Nov;116(10):600-5. doi: 10.1055/s-2008-1065351. Epub 2008 May 13. https://pubmed.ncbi.nlm.nih.gov/18473286/

Gidon J Bönhof, Gundega Sipola, Alexander Strom, Christian Herder, Klaus Strassburger, Birgit Knebel, Claudia Reule, Jan-Christoph Wollmann, Andrea Icks,7 Hadi Al-Hasani, Michael Roden, Oliver Kuss, Dan Ziegler, (2021) BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy. BMJ Open 2022;12:e057142. doi:10.1136/ bmjopen-2021-057142 https://pubmed.ncbi.nlm.nih.gov/35115359/

Vitamin B6 - the good, the bad, the ugly:

Harvard T.H. Chan, School of Public Health, Viatamin B6, https://www.hsph.harvard.edu/nutritionsource/vitamin-b6/#:~:text=Alcoholism-,Toxicity,greater%20than%201%2C000%20mg%20daily.

I never went to Harvard, but I did read this page about Vitamin B6 on the Harvard web site. So, don't believe me, but maybe consider what Harvard has to say. Some of the things that folks say, this page takes the time to straighten out.

First of all, the term “RDA”. Many people believe this to mean „Recommended Daily Allowance“, like from the FDA. They might say:
“Well, if the FDA recommends you not take more than 1.4mg/daily, don't because you risk getting neuropathy or your neuropathy will get worse."

But as Harvard points out, this is what “RDA” actually means is: „Recommended Dietary Allowance“ This has nothing to do with medicines or in this case, supplements (see “UL” below). This has to do with the amount of a substance, that is recommended to be ingested via food sources - ie dietary intake not therapeutic usage.

Harvard writes:
“The Recommended Dietary Allowance (RDA) for men ages 14-50 years is 1.3 mg daily; 51+ years, 1.7 mg. The RDA for women ages 14-18 years is 1.2 mg; 19-50 years, 1.3 mg; and 51+ years, 1.5 mg.“

How much is recommended for therapeutic dosages is something different – see “UL” below.

The next bit of nomenclature to know is „UL“ or „Tolerable Upper Intake Level“. Harvard writes:

„A Tolerable Upper Intake Level (UL) is the maximum daily dose unlikely to cause adverse side effects in the general population. The UL for adults 19 years and older is 100 mg daily, with slightly lesser amounts in children and teenagers. This amount can only be achieved by taking supplements. Even higher amounts of vitamin B6 supplements are sometimes prescribed for medical reasons, but under the supervision of a physician as excess vitamin B6 can cause toxicity.“ (See toxicity below)

So THIS is the „watch out“ amount to be wary of – around the 100mg. Some therapies use higher dosages, but always with the caveat, that such a therapy be supervised by a doctor.

So at what levels can (not must be) B6 be toxic? Harvard writes:

„Toxicity

It is quite unlikely to reach a toxic level of vitamin B6 from food sources alone. Vitamin B6 is a water-soluble vitamin so that unused amounts will exit the body through the urine. However, a toxic level can occur from long-term very high dose supplementation of greater than 1,000 mg daily.“

As you can see, there is a lot of wiggle room between the UL „Tolerable Upper Intake Level“ of 100mg/day and toxicity levels, which have been determine in concrete cases of >1,000mg/ daily taken „long term“.

Much has been written about the benefits and horrors of B6. Many steadfastly believe, it will absolutely cause neuropathy or at the very least make a present neuropathy worse. I've seen "people" go so far as claim it's a neurotoxin. Interesting, that it's included in the so-called "neurotropic B-vitamins" studies and the extended ones which usually also include other substances, usually anti-oxidents like R-Lipoic Acid, ACL or NAC. Here is a meta-study that examines various ways B6 has been therapeutically used, when it's been beneficial and under what circumstances it can cause neuropathy or make an existing neuropathy worse.

Muhamad, Raman, Alexandra Akrivaki, Georgia Papagiannopoulou, Periklis Zavridis, and Panagiotis Zis. (2023). "The Role of Vitamin B6 in Peripheral Neuropathy: A Systematic Review" Nutrients 15, no. 13: 2823. https://doi.org/10.3390/nu15132823

Another study examing "B6 Toxicity" (we probably need to discuss what constitutes toxicity):

Hemminger A, Wills BK. Vitamin B6 Toxicity. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 32119387. https://europepmc.org/article/nbk/nbk554500

Quoted from this study: "Pyridoxine toxicity typically manifests as neurologic symptoms, including paresthesias in the extremities and, in severe cases, difficulty with ambulation. This sensory neuropathy usually develops at doses of pyridoxine above 1000 mg per day*. There are some case reports of sensor neuropathies at doses of less than 500 mg per day in patients taking supplements for months. However, none of the studies had sensory nerve damage at a daily intake below 200 mg of pyridoxine per day.[3] A rare cause of vitamin toxicity is hypophosphatasia."

* - underline by L. Cecil

In other words, as usual consult your doctor before taking, especially your tolerance and "allowed" dosage.

In the study
Pinzon RT, Schellack N, Matawaran BJ, et al. (2023) Clinical Recommendations for the use of Neurotropic B vitamins (B1, B6, and B12) for the Management of Peripheral Neuropathy: Consensus from a Multidisciplinary Expert Panel. J Assoc Physicians India 2023;71(7):93–98. https://www.japi.org/y26464c4/clinical-recommendations-for-the-use-of-neurotropic-b-vitamins-b1-b6-and-b12-for-the-management-of-peripheral-neuropathy-consensus-from-a-multidisciplinary-expert-panel,
the following can be read concerning dosage of B6:

„The Filipino Neuropathic Pain Technical Committee has cautioned against the use of vitamin B6, in which high doses (>250 mg/day) may induce neuropathy. Even though neurological side effects of vitamin B6 are rare and may resolve after treatment cessation, a high daily dose of >500 mg/day and/or a long treatment duration (>6 months) should be avoided. Various studies and case reports have suggested an association between PN and the dose or duration of vitamin B6, but it is generally well-tolerated at 50 mg/day for up to 6 months. Vitamin B6 alone at 250 mg/day for a few weeks has been shown to reverse PN associated with isoniazid treatment, whereas a dosing schedule of 30 mg daily for 1 month has shown improvement in PN associated with vitamin B6 deficiency in patients with uremia."

This paper also is one of the few that makes clinical recommendations for initial "load dosages" of neurotropic B-vitamins and well as later "maintenance dosages" of the same. At no time do they recommend >100mg/daily of B6.

A review (meta-study) looking more specifically at the relative toxicity of B6, making his recommendation based upon the studies he's dug up, read, digested and discussed:

Carlos-Alberto Calderon-Ospina, Mauricio Orlando Nava-Mesa & Ana María Paez-Hurtado (2021) Update on Safety Profiles of Vitamins B1, B6, and B12: A Narrative Review, Therapeutics and Clinical Risk Management, 16:, 1275-1288, DOI: 10.2147/TCRM.S274122 https://www.tandfonline.com/doi/full/10.2147/TCRM.S274122

Some excerpts:

“Relevant original articles on neurotoxicity of vitamin B6 in humans obtained by our searches included seven case reports/series, one prospective study, and one case-control study _{(Table 1).Citation39-,Citation47} In half of them, neurotoxic side-effects of vitamin B6 were mostly due to very high doses and/or long-term treatment and resolved after treatment cessation._{Citation39–Citation41}Specifically, reported clinical neuropathy cases occurred in a timeframe of 2–24 months depending on the administered dose: after 12 months or longer with doses of ≤2,000 mg/day, and after less than 12 months with doses >2,000 mg/day._{Citation39–Citation46} The first clinical assessment study of pyridoxine-induced neurotoxicity in humans by Schaumburg et al_Citation47 included seven patients with severe sensory neuropathy in the extremities after taking 2,000–6,000 mg/day pyridoxine for 2–40 months. Four of these individuals were not able to walk. All symptoms, assessed through objective neurological diagnosis, improved after medication discontinuation._Citation47 Another case series report by Parry and BredesenCitation46 studied 16 patients with neuropathy (all assessed by history and examination, seven electrophysiologically confirmed diagnoses, two sural nerve biopsies) after taking 100–5,000 mg/day pyridoxine for up to 72 months. Patients with doses ≤500 mg/day showed neuropathy after 23 months on average, while those taking 5,000 mg/day developed symptoms on average after around 3 months. In contrast, none of the patients taking 50 mg/day for <6 months presented with neuropathy, but when the intake exceeded 6 months, 20% developed symptoms._Citation46 These results indicate an association between neuropathy and dose/duration of vitamin B6 use, suggesting that 50 mg/day for <6 months is safe. As here, in the publications describing cases with persisting symptoms after vitamin B6 discontinuation _{(Table 1),Citation42–Citation4}₅ it was unclear whether the neurological symptoms were only attributable to vitamin B6 treatment or were favored by underlying diseases or co-medication. The study from Dalton and Dalton_Citation41 deserves special attention because it is usually cited when the potential neurotoxicity of low doses such as 50 mg is discussed._Citation25 However, the study design has often been criticized, for example by the Food and Nutrition Board of the Institute of Medicine (IOM), because neurological symptoms were not adequately detailed and actual doses may have been underestimated due to parallel intake of vitamin supplements; thus, the study appears unsuitable for determining the upper limit._Citation35”

“We conclude that neurological side-effects due to vitamin B6 are rare, habitually reversible, and usually occur after taking high daily doses (>500 mg/day) and/or longer treatment (>6 months).” (emphasis L. Cecil)

But just to be more complete, perhaps it's not globally B6 that's the problemm but rather what type, ie: Pyridoxine HCL vs Pyridoxal-5-Phosphate (P5P, or PLP). According to the study below (and others), Pyridoxine HCL is the issue, not Pyridoxal-5-Phosphate when:

1) one takes >200mg/day of Pyridoxine HCL - some set the limit @ >1000mg/day

2) over months, if not years – see Carlos-Alberto Calderon-Ospina et al (2021) above

3) In Vrolijk et al (2017), they explained why Pyridoxal-5-Phosphate (P5P) doesn’t cause harmful side effects/B6-toxicity like Pyridoxine HCL does. I've also watched medical videos, some of which were talks at medical institutes or schools, which said the same. Interestingly, almost all commercially available preparations for neuropathy pain which include B6, ONLY do so in the Pyridoxal-5-Phosphate (P5P) form. Only one that I've found do so as Pyridoxine HCL.

Vrolijk MF, Opperhuizen A, Jansen EHJM, Hageman GJ, Bast A, Haenen GRMM. (2017) The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicol In Vitro. 2017 Oct;44:206-212. doi: 10.1016/j.tiv.2017.07.009. Epub 2017 Jul 14. PMID: 28716455.

„In conclusion, the present study strongly indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to the vitamer that is used in the supplements, namely pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-phosphate. As a consequence, the paradox arises that the symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency. Vitamin B6 supplements are used by a large number of people. The safety of vitamin B6 is debated and recently EFSA has lowered the upper limit for vitamin B6. The question is whether lowering the safe dose for vitamin B6 is the solution. Remarkably, even at relatively low dose, vitamin B6 supplementation has given rise to complaints. Our study indicates that the toxicity of vitamin B6 is not only determined by the dose, but by the vitamer in which it is taken. Perhaps it might be better to replace pyridoxine by pyridoxal or pyridoxal-phosphate as vitamin B6 supplements, which are much less toxic. In this way, the vitamin B6 paradox may potentially be prevented.“

So still - watch out what form - you take Pyridoxal-5-Phosphate (P5P) or Pyridoxine HCL you take. Stick with the Pyridoxal-5-Phosphate (P5P) at <100mg/day and you should be fine.

GLA (Gamma Linolenic Acid)

Harry Keen, FRCP, Jose Payan, FRCP, Jaffar Allawi, MD, James Walker, MRCP, Goran A Jamal, MD, Andrew I Weir, FRCP, Lesley M Henderson, MRCP, Elizabeth A Bissessar, MRCPI, Peter J Watkins, MD, Michael Sampson, MRCP, Edwin A M Gale, FRCP, John Scarpello, MD, Hugh G Boddie, FRCP, Kevin J Hardy, MRCP, Peter K Thomas, FRCP, Peter Misra, MB BS, Jukka-Pekka Halonen, MD and The γ-Linolenic Acid Multicenter Trial Group, (1993) Treatment of Diabetic Neuropathy With Gamma-Linolenic Acid, Diabetes Care 1993 Jan; 16(1): 8-15., http://care.diabetesjournals.org/content/16/1/8.short

G.A. Jamal, (1994) The Use of Gamma Linolenic Acid in the Prevention and Treatment of Diabetic Neuropathy, Diabetic Medicine, Volume 11 Issue 2, March 1994, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-5491.1994.tb02010.x

L. Hounsom, D. F. HorrobinH. TritschlerR. CorderD. R. Tomlinson (1998) A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy, Diabetologia June 1998, Volume 41, Issue 7, pp 839–843, https://link.springer.com/article/10.1007/s001250050996#citeas

Kathleen M. Halat, and Cathi E. Dennehy, (2003) Botanicals and Dietary Supplements in Diabetic Peripheral Neuropathy, Journal of the American Board of Family Medicine vol 16, Nr 1 47-57, http://www.jabfm.org/content/16/1/47.full.pdf+html

CBD:

A link collection of research dealing with CBD for chronic pain including several specifically for neuropathic pain: https://www.projectcbd.org/chronic-pain

Elizabeth J. Rahn and Andrea G. Hohmann, (2009) Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside, Vol. 6, 713–737, October 2009 © The American Society for Experimental NeuroTherapeutics, Inc., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755639/pdf/13311_2011_Article_60400713.pdf

Petzke · E.K. Enax-Krumova · W. Häuser, (2016) Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen, Schmerz. 2016 Feb;30(1):62-88, https://www.ncbi.nlm.nih.gov/pubmed/26830780

Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR., (2016) Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain., Curr Med Res Opin. 2007 Jan;23(1):17-24., https://www.ncbi.nlm.nih.gov/pubmed/17257464

Barnes MP, (2006) Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain., Expert Opin Pharmacother. 2006 Apr;7(5):607-15., https://www.ncbi.nlm.nih.gov/pubmed/16553576

Fine PG, Rosenfeld MJ, (2014) Cannabinoids for neuropathic pain, Curr Pain Headache Rep. 2014 Oct;18(10):451. doi: 10.1007/s11916-014-0451-2., https://www.ncbi.nlm.nih.gov/pubmed/25160710

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace, (2018) Medical Cannabis for Neuropathic Pain, Current Pain and Headache Reports (2018) 22: 8 , https://static1.squarespace.com/static/55862101e4b04f6516e14908/t/5ab7c3c970a6adbbb6b837fe/1521992650615/neuropathic+pain.pdf

G. Michael Allan, Jamil Ramji, Danielle Perry, Joey Ton, Nathan P. Beahm, Nicole Crisp, Beverly Dockrill, Ruth E. Dubin, Ted Findlay, Jessica Kirkwood, Michael Fleming, Ken Makus, Xiaofu Zhu, Christina Korownyk, Michael R. Kolber, James McCormack, Sharon Nickel, Guillermina Noël and Adrienne J. Lindblad, (2018) Simplified guideline for prescribing medical cannabinoids in primary care, Canadian Family Physician February 2018, 64 (2) 111-120;, http://www.cfp.ca/content/64/2/111

Metformin side Effects:

Porter KM, Ward M, Hughes CF, O'Kane M, Hoey L, McCann A, Molloy AM, Cunningham C, Casey MC, Tracey F, Strain S, McCarroll K, Laird E, Gallagher AM, McNulty H. (2019) Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults. J Clin Endocrinol Metab. 2019 Oct 1;104(10):4837-4847. doi: 10.1210/jc.2018-01791. PMID: 30920623.

Dawood MH, Abdulridha MK, Qasim HS. (2023) Assessing pyridoxine adjuvant therapy effects on blood glucose levels in type 2 diabetes: A randomized clinical trial. J Med Life. 2023 Oct;16(10):1474-1481. doi: 10.25122/jml-2023-0178. PMID: 38313181; PMCID: PMC10835547.

de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. (2010) Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. doi: 10.1136/bmj.c2181. PMID: 20488910; PMCID: PMC2874129.

Metformin comparative studies:

Bodepudi R, Seher S, Khan SA, Emmanuel S, Shantha Kumar V, Nerella R, Shaman Ameen B, Patel D, David John J, Khan S. Myoinositol Versus Metformin in the Treatment of Polycystic Ovarian Syndrome: A Systematic Review. Cureus. 2023 Jul 11;15(7):e41748. doi: 10.7759/cureus.41748. PMID: 37575860; PMCID: PMC10421410.

Zhao H, Xing C, Zhang J, He B. (2021) Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis. Reprod Health. 2021 Aug 18;18(1):171. doi: 10.1186/s12978-021-01207-7. PMID: 34407851; PMCID: PMC8371888.

Fruzzetti F, Perini D, Russo M, Bucci F, Gadducci A. (2017) Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017 Jan;33(1):39-42. doi: 10.1080/09513590.2016.1236078. Epub 2016 Nov 3. PMID: 27808588.

Berberine and Diabetes, Lipids:

Wang, L. , Liu, D. , Wei, G. and Ge, H. (2021) Berberine and Metformin in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Clinical Trials. Health, 13, 1314-1329. doi: 10.4236/health.2021.1311096.

Kong, W.-J., Wei, J., Zuo, Z.-Y., Wang, Y.-M., Song, D.-Q., You, X.-F., … Jiang, J.-D. (2008). Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism, 57(8), 1029–1037. doi:10.1016/j.metabol.2008.01.037

Liang Y, Xu X, Yin M, Zhang Y, Huang L, Chen R, Ni J. (2019) Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr J. 2019 Jan 28;66(1):51-63. doi: 10.1507/endocrj.EJ18-0109. Epub 2018 Nov 3. PMID: 30393248.

Inositol and Diabetes, Lipids:

Pintaudi B, Di Vieste G, Bonomo M. (2016) The Effectiveness of Myo-Inositol and D-Chiro Inositol Treatment in Type 2 Diabetes. Int J Endocrinol. 2016;2016:9132052. doi: 10.1155/2016/9132052. Epub 2016 Oct 11. PMID: 27807448; PMCID: PMC5078644.

DiNicolantonio JJ, H O'Keefe J. Myo-inositol for insulin resistance, metabolic syndrome, polycystic ovary syndrome and gestational diabetes. Open Heart. 2022 Mar;9(1):e001989. doi: 10.1136/openhrt-2022-001989. PMID: 35236761; PMCID: PMC8896029.

Capasso I, Esposito E, Maurea N, Montella M, Crispo A, De Laurentiis M, D'Aiuto M, Frasci G, Botti G, Grimaldi M, Cavalcanti E, Esposito G, Fucito A, Brillante G, D'Aiuto G, Ciliberto G. (2013) Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial. Trials. 2013 Aug 28;14:273. doi: 10.1186/1745-6215-14-273. PMID: 23981814; PMCID: PMC3765513.

Greff D, Juhász AE, Váncsa S, Váradi A, Sipos Z, Szinte J, Park S, Hegyi P, Nyirády P, Ács N, Várbíró S, Horváth EM. Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2023 Jan 26;21(1):10. doi: 10.1186/s12958-023-01055-z. PMID: 36703143; PMCID: PMC9878965.

Tabrizi R, Ostadmohammadi V, Lankarani KB, Peymani P, Akbari M, Kolahdooz F, Asemi Z. (2018) The effects of inositol supplementation on lipid profiles among patients with metabolic diseases: a systematic review and meta-analysis of randomized controlled trials. Lipids Health Dis. 2018 May 24;17(1):123. doi: 10.1186/s12944-018-0779-4. PMID: 29793496; PMCID: PMC5968598.

Minozzi M, Nordio M, Pajalich R. (2013) The Combined therapy myo-inositol plus D-Chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. Eur Rev Med Pharmacol Sci. 2013 Feb;17(4):537-40. PMID: 23467955.