33 replies to this topic

[dunbar]

I read something on a psychiatry site about methyl-folate being helpful against depression.
Does anyone know what would be better as an add-on to a SSRI? Methyl-Folate or Sam-E or both?
And is it safe to combine these things with antidepressants? Are there any possible risks?

[blood]

I take both (methyl-folate, SAMe) with Effexor. I haven't noticed any serious negative effects.

(SAMe did give me digestive issues, when I took it in high doses. I only take 400 mg/ day now, before bed, and have no issues with it.)

[Tom_]

There is some evidence for both. However the evidence for them is incredibly weak and they are regulated to fourth-line treatments. SAM-e is mentioned in passing in the maduley prescribing guidelines at a dose of 1600mg oral or 400mg IM. Its a shit idea though.

[username]

Why is it a shit idea? You know why your statements bother me?
You don't pay any attention to the effects vs. side effects. None.
When you have a substance with practically no side effects, why not give it a try? What do you have to lose? It doesn't mean that you have to say no to meds. But it's worth a try.
It costs money and esp. SAMe is expensive, but if you're willing to pay that, what's the downside?

SAMe helps me a lot. And even if it didn't and it was placebo or it's something else I'm taking: I have osteoarthritis and had to take over 100mg of diclofenac pretty much every day. I was able to reduce that dosage significantly. I also take curcumin for that.

Don't just say it's a shit idea. You're biased like everyone on this planet, but believe that your views are entirely objective. I disagree since you tend to ignore side effects of meds that force people to stop taking them while advising people not to take substances that have fewer side effects and can work.

http://examine.com/s...syl Methionine/
That's a good article on SAMe

SAMe caused my digestive problems. It took over a week for that to subside. Not entirely, but for me it's worth it. I don't care.

[Tom_]

Dumbar wants to take it for mental health problems, I have no knowledge of its research in pain disorders and rheumatology.

I am aware however there is no/or very little evidence to support safety or efficacy in depressive disorders.

I pay attention to efficacy vs side effect burden. The only difference is I strongly support evidence based medicine and the general perception among people on this board is the pharms used have worse side effects than supplements. When I see some evidence supporting that I'll happily accept it, as I would happily accept pharms cause less side effects vs supplements.

The whole idea of evidence based research is that it eliminates human bias. It doesn't do it perfectly (after all humans are doing it) but its the closest we have.

Once you can show me convincing evidence x, y or z supplement is as reasonable a choice as x, y or z drug I'd happily suggest it.

Ignoring side effects of meds doesn't impact objectivity, I don't understand your point.

There will always be tolerance issues when people take supplements or drugs in doses or w/e that the body doesn't have naturally and sometimes it might outweigh the benefits of taking them. If you look at the research for antidepressants, mood stabilizers and antipsychotics you will find out from the acute phase of the illness until they are returned to good health or at least reasonable health the drop out rates are low, typically below 10%, even for Clozapine (excluding those that get lukopenia and are forced to come off them). Its when people get well around week 12 when they suddenly decide to come off them because they feel well but have side effects. Then they get ill again and it turns into a cycle. Where as toughing out side effects they were content to deal with when ill for typically no more than another six months (in depression/anxiety syndromes) would significantly reduce there chances of getting ill again.

[username]

I believe that not only evidence is important when you choose a treatment, but also how many side effects it has.
When something has no to few side effects, it is okay to take despite the fact that it might not have as much evidence as other treatments with more side effects.
That doesn't necessarily mean that it doesn't work. It just means that there need to be more studies.
A treatment that people can only stand for a couple of weeks is a questionable treatment.
And in regard to evidence: There are people who do disagree with you, e.g. the scientists from examine.com
And, finally, I'm not even suggesting that you have to use these substances as monotherapy. There ARE studies using them in addition to antidepressants that show that they do help the antidepressant to work better compared to placebo. Of course, the doctor should know about the patient taking supplements additionally to the antidepressant or antipsychotic or whatever.


I guess we have to agree to disagree. I'm also quite biased because the change I have seen in myself with freely available supplements has been tremendous and cannot be explained by the simple placebo effect. Severe depression and auditive and visual hallucinations don't just get better on their own. I wasn't willing to take the antipsychotic because I had so many side effects that I would rather die than to be on that medication for a long period of time.

Edited by longschi, 16 February 2014 - 05:54 PM.

[dunbar]

I have read that Sam-E is as effective as TCA in some studies this sounds definitely promising.
The question is does Sam-E only exist as supplement or also as prescription drug?

[Tom_]

I agree, something people can't tolerate is a pointless treatment. I'm suggesting psychiatric medication generally has an acceptable tolerance profile. You seem to be missing my point. EBM also shows that people can tolerate medication, its not just about showing efficacy.

I have certainly not seen any evidence that SAM-e is as effective as TCA's. Please can I see these studies.

This is a conclusion from a paper written in the clinical nutrition journal:

Fairly strong evidence exists(I don't call class C evidence fairly strong but I can agree to disagree) that oral and parenteral SAMe are effective for the treatment of major depression. Some studies have suggested a faster onset of action for SAMe than for conventional antidepressants (others have shown a slower or non-existant onset). SAMe may be used alone or in combination with other agents and may even accelerate the effect of conventional antidepressants (speculation as far as I'm aware). SAMe appears to be well tolerated and has relatively benign side effects (same as an SSRI then). Thus, SAMe may be especially useful in patients who experience side effects from conventional antidepressants. The use of SAMe has not been shown to have toxic side effects; however, as mentioned earlier, there have been reports that SAMe may cause increased anxiety and mania in patients with bipolar depression. Recommended doses range from 400 to 1600 mg/d, although some persons may require doses > 3000 mg/d to alleviate depression.
In summary, on the basis of previously published evidence, the best candidates for SAMe or other natural antidepressants may be mildly symptomatic patients for whom a delay in adequate treatment would not be devastating. At the other end of the spectrum, patients who have failed multiple trials with conventional remedies or who are highly intolerant of side effects may also be good candidates (not the case here). The use of SAMe in conjunction with conventional antidepressants also appears to be a viable application in patients who achieve only a partial response to conventional antidepressants alone. However, clinicians must be careful about recommending the use of SAMe to patients who take other medications, because its interactions with other drugs are not well elucidated (vital point). More research is needed to determine optimal doses(400-3000+ is massively variable and could lead to some nasties), and head-to-head comparisons with newer antidepressants should help to clarify SAMe’s place in the psychopharmacologic armamentarium.
I'm not saying it doesn't have potential, I'm saying until everything else has been tried it shouldn't be used.

Edited by Tom_, 17 February 2014 - 01:11 PM.

[BlueCloud]

I am aware however there is no/or very little evidence to support safety or efficacy in depressive disorders.

You haven't looked very hard then
http://www.ncbi.nlm..../pubmed/2183633
http://www.ncbi.nlm..../pubmed/3046382
http://www.ncbi.nlm....pubmed/15538952
http://www.ncbi.nlm..../pubmed/7941961
http://www.ncbi.nlm..../pubmed/6367496
http://www.ncbi.nlm....pubmed/16021987


Now , whether it should be used as a first line treatment or not is debatable ( in Dunbar's case it shouldn't, as he is a very special case...hmm). I would say it could be used if the depression is not extreme, as its side-effects are truly insignificant compared to almost any SSRI/SNRI , so you might as well start with the most tolerable option, and move to other options including SSRIs if it doesn't work.
( I wouldn't however recommend it to people who are very prone to anxiety, as it is a cofactor for the PNMT enzyme wich increases the conversion of norepinephrine into epinephrine. I loved Sam-e for its energizing and mood lifting effects, but it quickly raised my anxiety levels as well and made me often irritated and angry )

EDIT : Also, just for fun, here is a brand new study that contradicts both of us by comparing SAM-e and Escitalopram , and concluding that both of them are barely better than placebo ! Shows that one shouldn't be too hang up about "number of studies", especially when it comes to supplements that are not backed by multi-billion dollar companies to finance the studies ( ever heard of "publication bias" ? )
http://europepmc.org...ct/MED/24500245

OBJECTIVE: To examine the comparative antidepressant efficacy of S-adenosyl-l-methionine (SAMe) and escitalopram in a placebo-controlled, randomized, double-blind clinical trial.

METHOD: One hundred eighty-nine outpatients (49.7% female, mean [SD] age = 45 [15] years) withDSM-IV-diagnosed major depressive disorder (MDD) were recruited from April 13, 2005, to December 22, 2009, at the Massachusetts General Hospital and at Butler Hospital. Patients were randomized for 12 weeks to SAMe 1,600-3,200 mg/d, escitalopram 10-20 mg/d, or placebo. Doses were escalated at 6 weeks in the event of nonresponse. The main outcome measure was the 17-item HamiltonDepression Rating Scale (HDRS-17). Tolerability was assessed by the Systematic Assessment for Treatment of Emergent Events-Specific Inquiry (SAFTEE-SI).

RESULTS: All 3 treatment arms demonstrated a significant improvement of about 5-6 points in HDRS-17 scores (P <.001 for all), and no significant differences were observed between the treatment arms (P >.05 for all). Response rates in the intent-to-treat sample were 36% for SAMe, 34% forescitalopram, and 30% for placebo. Remission rates were 28% for SAMe, 28% for escitalopram, and 17% for placebo. No comparisons between treatment groups attained significance (P >.05 for all). Tolerability was good, with gastrointestinal side effects (19% for stomach discomfort and 20% for diarrhea) as the most common in the SAMe arm. Significant differences were observed between treatment groups for dizziness, anorgasmia, diminished mental acuity, and hot flashes (P <.05 for all).

CONCLUSIONS: The results fail to support an advantage over placebo for either the investigational treatment SAMe or the standard treatment escitalopram for MDD.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00101452.

Edited by BlueCloud, 17 February 2014 - 03:52 PM.

[BlueCloud]

. I wasn't willing to take the antipsychotic because I had so many side effects that I would rather die than to be on that medication for a long period of time.

I was given an antipsychotic a long time ago, as my depression was very treatment-resistant. Can't remember wich one it was exactly ( Haldol ?) , but it was the first time I literally wanted to kill myself to make the side-effects stop. It was horrifying. It went into the garbage bin very quickly.

Edited by BlueCloud, 17 February 2014 - 03:33 PM.

[username]

SAMe appears to be well tolerated and has relatively benign side effects (same as an SSRI then).

Sorry, but I had to laugh at that statement. You're not serious, are you? SAMe is a joke when it comes to side effects compared to SSRIs.
Millions of people who have taken these meds would wholeheartedly disagree with you.

Edited by longschi, 17 February 2014 - 07:14 PM.

[blood]

( I wouldn't however recommend it to people who are very prone to anxiety, as it is a cofactor for the PNMT enzyme wich increases the conversion of norepinephrine into epinephrine. I loved Sam-e for its energizing and mood lifting effects, but it quickly raised my anxiety levels as well and made me often irritated and angry )

In contrast to your experience, I found SAMe to be somewhat soothing.

(Incidentally, TMG, also a methyl donor, did seem to induce feelings of irritability in me when I first tried it.)

[nupi]

Sorry, but I had to laugh at that statement. You're not serious, are you? SAMe is a joke when it comes to side effects compared to SSRIs.
Millions of people who have taken these meds would wholeheartedly disagree with you.

SAMe reliably gives me splitting headaches while not doing anything useful. SSRI have no such drastic side effects (and they actually do, you know, work). So not everyone agrees to your millions, really.

Edited by nupi, 20 February 2014 - 02:26 PM.

[username]

Studies show that SSRIs have plenty of side effects, which is why people stop taking them. This is not comparable to SAMe.
One case doesn't mean it's universally true.
It can be true for some, of course.
I guess I'm also biased because I had the exact opposite experienc as you.

[airplanepeanuts]

( I wouldn't however recommend it to people who are very prone to anxiety, as it is a cofactor for the PNMT enzyme wich increases the conversion of norepinephrine into epinephrine. I loved Sam-e for its energizing and mood lifting effects, but it quickly raised my anxiety levels as well and made me often irritated and angry )

In contrast to your experience, I found SAMe to be somewhat soothing.

(Incidentally, TMG, also a methyl donor, did seem to induce feelings of irritability in me when I first tried it.)

I also find SAMe soothing. ( A colleague asked me if I took 'calming pills' the month I started with it) On the other hand it makes me a little bit more angry. The mood lifting effect is subtle but good. Unlike TMG it doesn't bother my stomach nor do I get any other side effects from it. And I also feel it's good for the joints even though they weren't bothering me to begin with.

[Godof Smallthings]

SAMe appears to be well tolerated and has relatively benign side effects (same as an SSRI then).

Sorry, but I had to laugh at that statement. You're not serious, are you? SAMe is a joke when it comes to side effects compared to SSRIs.
Millions of people who have taken these meds would wholeheartedly disagree with you.

To be fair, you would also find millions who have been helped by SSRIs, too. I am one of them - I was on citalopram for 10 months when I was 23. It definitely helped me get through a crippling depression during my university years.

As for the side effect profile, we need to take into account that pharmaceutical drugs go through a very long and costly process of evaluation, during which ALL suspected side effects *must* be reported. The fact that SAMe and many supplements appear to have a low side effect profile is mainly because they are not subjected to the same process as pharmaceutical drugs (although of course, as with any substance, there is bound to be huge variation in actual side effect profiles for individual supps, and it is quite possible SAMe would have a low one. This would all be much clearer if supplements were subject to the same evaluation criteria as pharma drugs). This is a point that really needs to get through to everyone who thinks they can take anything that is a supplement almost risk free. This is not the case.

If you stick to normal doses of herbs commonly used in cooking, then yes, the side effects are indeed very minor. But as soon as substances are isolated and extracted from those herbs, we end up with a different concentration and a different overall effect (the substances in the herb interact, and it is not clearly evaluated or understood exactly how for most of them, since there is no requirement to do trials - hence fewer trials are made).

It's a huge fallacy to trust the supplement makers any more than you trust the pharmaceutical companies. In the end, any company is in it for the money, and contrary to much of the opinion in the 'alternative health camp' there is no reason at all to believe that those who peddle supplements are any more morally advanced than those who peddle pharmaceutical substances. All of them are human operating within a capitalist system where profit is the raison d'être for starting a business in the first place.

Despite what I have written, I experiment with supplements myself to assess their effects, I grow my own medicinal herbs and eat them every day, but I am fully aware that this experimentation involves the risks of some unforeseen side effects. But those are risks I am willing to take.

Edited by Godof Smallthings, 21 February 2014 - 04:32 AM.

[Godof Smallthings]

I am no expert on SAMe, but I would be careful with methylfolate, since too high levels of circulating folate are associated with an increased risk of some types of cancer. There is much research on folate and methylation at the moment, and it appears to be a lot more complicated than anyone understands at the moment. Better to wait for a more solid understanding of the underlying systems.

[Duchykins]

People taking SAMe or other methyl donors and are having the anger/anxiety side effects may want to try a bit of nicotinic acid to gobble up excess methyl. I would not suggest taking it regularly though, since you may inadvertently lower methyl too much, making you feel tired and brain foggy, and this can happen very quickly

This may not help those who are feeling agitated, irritable due to raised dopamine or norephinephrine levels, though

Edited by Duchykins, 21 February 2014 - 05:27 AM.

[dunbar]

This is confusing. How much methylfolate would be considered safe? Or are there no safe dosages?
I was just thinking if this helps against depression then I should take it.

And can anyone brief me on methyl. Is this something good or bad? What does it do in the body?

[blood]

Straight-forward article on methyl-folate & depression from LEF:
http://blog.lef.org/...depression.html

[protoject]

SAMe appears to be well tolerated and has relatively benign side effects (same as an SSRI then).

Sorry, but I had to laugh at that statement. You're not serious, are you? SAMe is a joke when it comes to side effects compared to SSRIs.
Millions of people who have taken these meds would wholeheartedly disagree with you.

Seems I react badly to SSRIs- though years ago, I didn't Btw, I havent taken them for extended periods except once when I took prozac for like 2 months at a dose way higher than normal and it barely did anything. This was about 6 years ago.

Anyway since then I tried a few on my own accord with the side effects not being worth it.

But I think it's pertinent for me to mention that I was very hopeful about methylfolate and so bought some. And it really did a horrible job on me. It made me feel the exact OPPOSITE of how I wanted to. it made me return to my severe MOOD SWINGS of my teenage years and deep depressive feelings, wanting to cry. I'm a 27 year old man and it is looked down upon in my society to cry as a man. I'm not saying it's wrong, but I'm really beyond stuff like crying these days, maybe once a year to be honest. So the fact that I took methylfolate and this shit happened is no joke to me.

Same effect occured at very low doses to larger doses, except worse with the larger dose of course. Also the side effect didnt go away for a few days. I have a handy supply of niacin and wasn't really sure it helped. I think the methyfolate set something off in my brain that was bad. I really don't like the idea of guinepigging myself on it again. But if I do I'll let you know if the niacin "mopped up" my methyls.

Which, and I may be biased and uneducated for saying this, but I think the whole "niacin mops up the methyls" is something repeated again and again due to Dr Ben or whatever the dude's name is. I don't know why but his whole site and everything seems like a huge gimmick of quackerey to me somehow (though it could be a false alarm. I just see so much BS these days that I start thinking non-BS is BS)... Maybe I'm just a dumbass who knows nothing about MTFHR genes but when I asked him for studies examining the effects he pretty much told me that if I understood how it works then I wouldn't need evidence.

I dont know, something smells funny.

Edited by protoject, 28 February 2014 - 07:17 AM.

[protoject]

too high levels of circulating folate are associated with an increased risk of some types of cance.

Folate or folic acid?

[username]

High doses of methylfolate (15mg) increased the response rate of antidepressants and people who are depressed have lower folate levels. That's pretty much the prupose of taking it when you're depressed. Obviously, this is far from having strong evidence.
Zinc is also worth a try. People who are depressed have lower zinc levels and those with treatment-resistant depression have even lower zinc levels.

Edited by longschi, 28 February 2014 - 09:38 AM.

[presently]

For me, methylfolate started the process of coming out of a hopeless two-week depression which may have been triggered by playing with acetylcholine/racetam stuff. After a couple of days of painful stiff muscles and headache that came and went in quick cycles, intuitively accepted as a healing process rather than a setback, I started methyl-B12 with additional improvement and followed some of the other suggestions in this long thread:

http://forums.phoeni...dden-story.142/

The thread picks up steam as the participants contribute their speculation and refinements to the approach. By the end, consensus arises about the role of methylfolate in assisting absorption of non-denatured B12. It's mostly "broscience", which has definite limitations, but at least it's not tainted by pharmaceutical-industrial complex sponsorship. The backstory may be good enough to convince the most hardened anti-placebo skeptic!

I've had chronic pain and fatigue since being poisoned by fluoroquinolone antibiotics, and this protocol has been helping rapidly with the pain and fatigue as the cycles level out. In addition, my brain fog has lifted in a way I was hoping the nootropics would accomplish, but they never quite did. My depression left within an hour of my first test dose of methylfolate (approximately 0.25 mg) and not caring and wanting to die has been replaced by a rich tapestry of situationally-appropriate patience and irritability for the last two weeks. Works for me, so far, and YMMV, due to personal variations in epigenetic polymorphisms and/or credulity.

[BioFreak]

I think folate or SAMe are primarily effective if the body has a deficit of them, either by not eating enough (folate), or having a problem with it's metabolism.

Too much folate can be dangerous as others have pointed out -> cancer.

Folate should mainly play a role in mental problems because it is needed to make tyrosine out of phenylalanine, and l-dopa out of tyrosine. It's also, together with SAMe needed to produce adrenalin from noradrenalin.

Also, both are needed to produce melatonin.

Those pathways alone could cause a lot of problems, if they are not working. I am sure they are not the only pathways, but pretty important ones for mental problems.

SAMe however is very expensive, which makes me wonder if supplementing with a sulfur donor (methionine) and a methyl donor (MSM) would be an alternative.

Tyrosine / l-dopa supplementation massively increases sulfur requirements, dependent on dosage. So people supplementing with them would deplete their sulfur levels, and in the process lower SAMe, as well as decreasing the effectiveness of those amino acids, because the catecholamine metabolism would be inhibited at those points where SAMe plays a role.

Also, folate is important in homocysteine metabolism. It can for example convert homocysteine back into methionine which then could be converted into SAMe. Basically folate makes sure(amongst other things) that homocysteine does not accumulate, and recylces it so it can be used in the sulfur cyle, which also glutathione is dependent on.

So reducing homocysteine is good for health in general, and increases the supply of sulfur for other processes.

My oppinion? Make sure you get enough folate, b6 and b12 to keep homocysteine low.
Supplement with a sulfur donor if you also take phenylalanine, l-dopa or tyrosine.
(the body should be able to convert methionine into cysteine and vice versa, so your options are those two amino acids)
Supplement with a methyl donor such as MSM.(Might be enough of a sulfur donor, if you do not supplement with catecholamine precursors, since it does also work as a sulfur donor, but additional steps are required to synthesize cysteine or methionine which are needed for other processes that want sulfur - so basically, less efficient, with a better side effect profile, and my choice if there is no massive sulfur requirement)

That way, you should have as much SAMe as your body is able and willing to produce. If that is not enough, experiment with additional SAMe, in ADDITION to what I mentioned before, to save money. Also, this will result in a better health profile by actively reducing homocysteine.

If both folates and SAMe's anti depressive mechanisms are through their respective functions in the synthesis of neurotransmitters mentioned above, their effectiveness may be limited to the amount of neurotransmitters that your body is willing to produce under the best of circumstances.

If that is not enough, other strategies to increase neurotransmitters further may be needed(serotonin / catecholamine precursors, which make a whole stack necessary to work properly, or reuptake inhibitors, or mao inhibitors), or other ways to fight depression(cAMP increase for example). Their effective dosage should be lower though, if you optimized your neurotransmitter metabolism.

[1kgcoffee]

I am no expert on SAMe, but I would be careful with methylfolate, since too high levels of circulating folate are associated with an increased risk of some types of cancer. There is much research on folate and methylation at the moment, and it appears to be a lot more complicated than anyone understands at the moment. Better to wait for a more solid understanding of the underlying systems.

Synthetic folic acid, which is not found in nature, can be cancer promoting when it goes unmetabolized. Important to know for people who are undermethylators as their bodies cannot process it efficiently -check your 23andme to know for sure. AFAIK, naturally occuring folate has not been shown to promote cancer. If you are an undermethylator and get only enriched wheat folic acid in your diet, lacking folate containing leafy greens, then you could actually be deficient in folate. Folic acid is useless until it is converted to folate. What do you need folate for? DNA repair? What happens when your DNA doesn't get repaired efficiently? Cancer. You could make the argument that methylfolate in undermethylators with poor diets is possibly more of a cancer preventative if they're not already eating tons of leafy greens. Though I can see how methyfolate might aid the development of existing cancer at consistent and incredible super-RDA doses, if you're healthy and taking ballpark RDA then... for myself it is worth taking.

If you have the willpower then go a step further and cut out all folic acid containing enriched foods.

Edited by 1kgcoffee, 22 March 2014 - 09:35 PM.

[username]

The United States enriches their flour with folic acid. I don't think any other country does this?
It's very hard to tell what food fortification actually causes. When you look at the evidence it's likely that folic acid fortification leads to increased cancer rates.
In Jaminets' Perfect Health Diet (worth checking out) it says that the increased cancer rates can be explained by the fact that folic acid is not metabolized fully. I don't believe folate will increase mortality/cancer rates as folic acid does.
Higher amounts of folate made me irritable. I currently take 1mg of methylfolate. I wish there was more research on this.

[airplanepeanuts]

I think folate or SAMe are primarily effective if the body has a deficit of them, either by not eating enough (folate), or having a problem with it's metabolism.

I dont't think so. Especially with supplementing SAM-e it feels like oversaturating to me (but not in a bad way).

I think it's more plausible that methy-folate only works against depression if there is a deficit. Either because of difficulties in metabolism or just because because deficit is common. Deplin is promoted as an Add-on drug to antidepressants.

[BioFreak]

Maybe that is because your body can not produce enough by itself even if it wants to, i.e. because of a sulfur deficit.
You could test it by supplementing with cysteine or MSM(with msm higher doses are required vs cysteine, and if you have massive sulfur requirements (i.e. by using large dosages of catecholamine precursors), msm alone might not be enough. Source: Experience).

Either way, as long as it helps you, its a good thing.

[drg]

L-methylfolate seems like a really great alternative med for depression.

 

http://www.drugs.com...epression.html 

there are 40+ user reviews and some experiences.

Dose: 15mg per day or more?

 

Side effects: unlikely, it is a bio-available form of folic acid, which is natural to the body

 

I see no reason not to try this out if you have depression.