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The Strange Cases of ME Remissions Induced by SSRIs (Dr James / Dr Smith / Dr Le Fanu)


Senior Member
Southern California
I've come across something very strange and confusing. Two UK doctors in the 90s and early 2000s used SSRIs (Zoloft / Prozac) to bring a number of ME patients into remission. A third, Dr Le Fanu, conducted an informal trial with promising results. As far as I can tell Dr Smith and Dr James had a biological view of the disease with well defined patients.

Given how many people take SSRIs, and how poorly many ME patients react to it, I'm a bit confused.

From a document on Dr Smith's protocol.

For more than two decades, Dr Smith has used this regime as the basis of treatment of around 3,800 patients, all referred to his Essex clinic by GPs and specialists under contracts with several Primary Care Trusts throughout South East England. A spokesman for NHS South West Essex said the service, commissioned for a number of years, had been ‘well received by the patients who accessed it’. Indeed, his regular audits of the patients he has treated show that more than eight out of ten patients experience improvement in function and are satisfied with the outcome of therapy. An active and independent patient support group is highly supportive of his work.

From the same document. Dr Le Fanu, inspired by the SSRI results invited ME patients to try sertraline via his newspaper column.

Dr Le Fanu suggested that readers with CFS/ME ask their doctors to prescribe sertraline, and begin to take it, starting with the smallest possible dose and slowly increasing it. Of the 27 readers who responded, ten found the medication to unpleasant to continue, a further ten felt there had been a definite improvement after taking them for a year - and seven ‘are astounded at how much better they feel’, reporting not just the restoration of their energy levels to near normal but also a virtual elimination of all their other symptoms’.

Finally from a testimonial of a mother and daughter posted by @Jenny a while back:

From lying in bed all day listening to Radio 4, to riding a bike up steep hills or enjoying a night’s clubbing - how did we do it? This is another recovery story but with a difference.

My daughter, Sarah, and I had had ME for 8 and 6 years respectively when the recovery began. She was 16 when her illness started and I was 48. We had between us tried many treatments: diet [anti-candida and elimination], cold baths, massage, a healer [Seka Nikolic], geopathic stress analysis, osteopathy, homeopathy, acupuncture, herbs [Chinese and Western], vitamins and minerals, injections [magnesium, Vitamin C, gamma globulin, and interferon], galanthamine pills, anti-fungal pills, high dose antibiotics, anti-depressants [prothiaden and seroxat], relaxation techniques [Alexander and autogenic]; we had seen 3 consultants [2 NHS, 1 private]. All these helped other people, even cured them, but we seemed destined to be forever incurable - always in the two-thirds who were not improved in any research study. We were therefore seriously sceptical when we volunteered for one more research ‘experience’.

This is wherein lies the difference. I have returned to normal and Sarah is well on her way, simply by taking drugs. We were very suspicious of drugs and would have greatly preferred it, if the homespun remedies had done the trick, or, best of all, if our carefully controlled lifestyle had worked. They did not, but an SSRI has.

Dr. Ian James, Reader in Pharmacology at London’s Royal Free Hospital, set out to show that many ME patients could regain their health by taking Sertraline Hydrochloride [Lustral]. This drug is used with some graded exercise regimes, and to deal with depression. But Dr James excluded from his research anyone who was depressed, and told us to maintain our practice of doing less than we felt able to do. He had noticed that ME patients usually had ‘pupil wobble’ after a bright light had been flashed at their eyes. The pupil closed but then failed to open to the correct size; instead it wobbled away, letting in too much light & causing the hatred of brightness with which we were all too familiar. He used this to measure whether the drug was working before we could notice any changes. We had high tech pupillometry tests both before we took the Lustral and again after 6 weeks taking it. [We later learnt that an improvement in pupil wobble did indeed predict those who would later improve.]

Meanwhile we started to take the pills. This, however was easier said than done, because Dr James’ other discovery was how to prevent our bodies rejecting Lustral either immediately or 6 months later. He was the first doctor to point out to us that ME patients react badly to normal doses of drugs, although this made sense of various bad experiences we had both had during the illness. In order to deal with this problem we started on very small doses. The smallest Lustral pill is 50mg. We started on 12.5mg [Sarah took them every other day to be extra careful] and turned our kitchen table into something resembling a ‘drugs den’ as we crushed a pill & ‘cut’ it into 4 piles of white powder, which we then had to store for future days in tiny ‘wraps’.

We increased the dose very gradually every 4 days. But now came the hardest part-the 2 month’s wait to see if it would work for us. I became particularly worried that I might improve but not Sarah, a mother’s worst scenario.

One morning, about 7 weeks after taking the first pill, I woke from a heavy sleep and suddenly remembered that I always used to feel like that when I was normal! If you had asked me, I would have told you I had no sleeping problems with ME; but now I could make a comparison, I realised my sleep had been very light. The next few weeks were wonderful as, first, Sarah’s sleep changed, and then various symptoms, mostly in areas controlled by the brainstem such as cold heads, poor temperature controls throughout the body, disappeared.

Interestingly enough we had been in Dr Costa’s research project at the Middlesex Hospital to measure blood flow in the brain. This showed that people with ME had too little blood in their brainstem, but had normal flow elsewhere in the brain. Could it be that the virus which caused ME in us had damaged the brainstem controls, and that the extra serotonin made available by the Lustral was improving the neurotransmission in that part of the brain? We became euphoric and made many overoptimistic plans but the euphoria was short-lived and not the result of the Lustral.

It has, in fact, taken 4 years for us to recover, and we have not yet reached total normality. Some symptoms were unbearably slow to depart: weird headaches, sore throats and lack of stamina were in this category, along with our tendency to catch every viral infection which is ‘going the rounds’.

We are now able to lead almost normal lives. I stay up 14.5 hours a day & sit in court as a JP, often taking the Chairman’s role in a busy central London court. I have at last resumed my social life, go out in the evenings, have returned to my kitchen and to large-scale cooking. I cycle round London at full speed, swim energetically and, above all, I am free of the tyranny of unrelenting self-control, with calculations of whether ‘if I do that, will I have to go to bed for 2 hours etc.? We both became expert at the ‘energy calculus’ but we are so pleased to have reintroduced spontaneity into our lives. Sarah’s social life is understandably more hectic. She hit the London social scene last year and has been making up for lost time. It is sometimes hard for me to believe the transformation in her appearance & her energy. She was once thin, white-faced & immobile, whereas now she speeds around rosy-cheeked & chatty; she has returned to her classical studies and is planning to complete her degree.

So why is this treatment not offered to everyone? Dr James found that 1% could not tolerate Lustral despite starting with low doses. But he also found that 80% of his sample improved. This is an amazingly high percentage. He excluded all whose illness had a nebulous onset but even so the results surprised. Sadly Dr James died before he could see our full recovery, and we will never know how many of the sample recovered completely because the Medical School have no interest in finishing the research. They point out that Dr James did not have a control group, and say that the whole piece of research would have to be repeated to ensure it was worthy of ‘peer review’ and publishable. They have nobody who wants to do this and, as ME is not a priority area for the hospital, they will take no notice of ‘patient need’. I wonder if any hospital makes ME a priority? Are we all to depend on the passing interest of hospital doctors?
When Dr James died the hospital washed its hands of us, sending us back to our GPs who can continue to prescribe us the drugs, but who know less about the treatment than we do.

Luckily I kept notes of Dr James’ answers to my ‘what if’ questions and so we consulted these if we suffered a setback. But what about patients who were not so curious? Furthermore we now have a network of people who, having heard of our recovery from friends, consult us on the use of the drug. This is most unsatisfactory as we have no medical skills and cannot give such advice. Our present hope is that the Dept. of Health will soon reconsider research priorities as they affect ME.

We are very keen that as many people as possible have a chance to try this method of taking Lustral. It will not cure everyone but it will release some of you from the prison of ME out into the world again. Therefore we need someone urgently to redo this research – any suggestions?

Cynthia Floud
[This was written in 2000. I have now [2005] been off the pills for nearly 4 years [after 5 years on the pills]. This still amazes me. Sarah has just completed a degree at LSE and got a first. She stopped taking Lustral in mid 2004 after nearly 8 years. We are totally back to normal and can be as energetic as ever, without watching our step in any way.


Senior Member
This doesn't pass the common sense test.

These medications are so widely prescribed and probably most patients have tried them. If they worked so well, we would know about it.

There also was a trial of fluoxetine (Prozac) which was clearly negative.


Senior Member
The other side.
Nearly 20 years ago, when my GP was still under the impression I was suffering from depression, I was put on Fluoxetine (Prozac). I have no idea what the dosage was but I'd assume whatever it was standard for NHS GPs to prescribe as a starting dose. This was after I had been tried on several other SSRIs with bad results.

The results were fairly spectacular, I wasn't back to "normal" but in most aspects I was functional, I could walk, a little slower than most, but for several miles if i chose. i didn't feel ill, my head was clearer, it took a lot more to overload me e.g. I could walk through a busy town centre (but still not a shopping centre/mall type place) without significant issues etc.

The only problem was, when the tablet began to wear off the withdrawal was bad, for several hours a day, until it was time to take the next tablet, I was in a grey hell, everything hurt, light, noise, my skin, my joints, everything -- the only fix was to take another tablet, and the after 90 minutes or so I was okay again.

The time the tablets worked for gradually decreased over the next few months, to a few hours, with the rest of the time being spent in the grey hell, at some point during this time I decided it simply wasn't worth it, so decided to discontinue, pretty sure that was immediately before I became bedbound for several months.

The above post makes me wonder...should I have asked for an increased dose, or did I do the right thing? in the last 20 years I've never approached being as functional as I was then, but the side effects/withdrawal......so bad I can't have been doing anything good to myself by taking fluoxetine if it did that when it ran out.


Senior Member
Southern California
This doesn't pass the common sense test.

These medications are so widely prescribed and probably most patients have tried them. If they worked so well, we would know about it.

There also was a trial of fluoxetine (Prozac) which was clearly negative.

Yes I agree which makes it so confusing. Some possible explanations.
  • Long term use, starting at very low doseages for the sudden onset cohort Dr James describes is not often tried
  • The patients were misdiagnosed and had major depression (which is unlikely given their symptoms and slow improvement).
  • The patients spontaneously improved and attributed it to the SSRIs
  • The doctors overestimated their own success rate or saw what they wanted to
There is a possible SSRI mechanism of action that involves boosting serotonin and reducing IL-1b and TNF-a, but it's hazy.

What struck me as interesting was that Cynthia Floud had demonstrated low blood flow to her brain stem, and the dysautonomia related to that improved with sertraline.


ME/CFS since 1995; activity level 6?
Cornwall, UK
"Dr Le Fanu suggested that readers with CFS/ME ask their doctors to prescribe sertraline, and begin to take it, starting with the smallest possible dose and slowly increasing it. Of the 27 readers who responded, ten found the medication to unpleasant to continue, a further ten felt there had been a definite improvement after taking them for a year - and seven ‘are astounded at how much better they feel’"

I took Prozac near the beginning. I wouldn't be surprised if it contributed to my worsening, although it was not sertraline, and I was taking other things too. I took 20 mg. Details here: http://forums.phoenixrising.me/index.php?entries/health-notes-including-suicide-attempt-1995-6.2099/

me/cfs 27931

My story is anecdotal and perhaps coincidental. That said...

I experienced a partial remission on 200mg Zoloft (Sertraline) from 1992-95. My functioning was significantly improved (to perhaps 70%). Then I went into relapse and seemed to get no benefit from the Zoloft, so I was prescribed another antidepressant.

Note that at the time, all my symptoms were attributed to depression or considered "all in my head". My most disabling symptoms were neuro, with lesser immune and PEM disability than I experience today.

Zoloft is the only antidepressant (out of ~2 dozen) which I can correlate with a disease remission and improvement in functioning.

Recently, I've considered giving Zoloft another try to see if it improves my functioning.

Edit: I should note I had no response to Prozac.
Edit2: I experienced no benefit at Zoloft doses below 200mg.
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early 2000s used SSRIs
In about the second year of illness (c2002) there was a recovery story in the AfME mag of a mother and daughter who 'recovered' using Lustral (Sertraline). I tried it, starting at a really low dose (cut the tablets up) and very gradually increased the dose but was not able to get it anywhere near a 'normal' dose as it really made me feel even more ill. No improvement in any symptoms so stopped after around 6 months.


Senior Member
Somewhere near Glasgow, Scotland
it's just more bullshit to try and shore up the psych "it's all in the mind!" scumbags as their position crumbles and they are about to face the proverbial firing squad for negligence, corruption and abuse.
they are trying to fling enough crap at the issue to delay their comeuppance, or any help for us, so I have ZERO sympathy for them

Flouxetine and another such drug were HORRIBLE experiences for me, ugh and I believe they made me worse.


Senior Member
Other than a few timed when I tried changing antidepressants, I have been taking Zoloft for about twenty five years. I did not notice a change when I developed Fibromyalgia, but maybe I would have felt worse if I hadn't been taking it. I think this would be almost impossible to prove though.

Antidepressants also reduce pain. When I unknowingly reduced my dosage my pain increased. This was after getting Fibromyalgia.

It's very important to have an antidepressant prescrided by a competent psychiatrist.

Monitoring is crucial as ADs can affect people in different ways. I became hypomanic on Wellbutrin. That did not mean I didn't need an AD but that it didn't work for me.

Zoloft has been a wonder drug for me as it has controlled my depression. There's a difference between the depression of a chronic illness and clinical depression. Sometimes you can have both which makes it very difficult sorting out what is going on.
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Senior Member
Early on, I took imipramine (tofranil) for a couple of months. All it did was raise my resting heart rate to 120+ (sometimes as high as 130). I've always figured that that could not have been good for me, even though I was in my early 20's. I stopped taking imipramine when the psychiatrist I was seeing (who seemed to suspect that my dizziness and other symptoms were psychological) essentially "fired" me after I presented him with objective test results showing an inner ear balance disorder.
I've just browsed this Dr Smith's 103 page document explaining his theories and treatment protocol.

To save others time and temper, I'll attempt to outline what I've learned from it. I skipped a lot of his ramblings about causes being stressful lives with all sorts of sweeping generalisations not based on any science.

He was the MEA medical advisor for some years before Charles Shepherd, but fell out with the MEA when he decided that because it could be triggered by different viruses with different symptom patterns in the acute phase, including enteroviruses and Epstein Barr, but with the indistinguishable symptom patterns in the ME stage, he concluded it couldn't be caused by ongoing viral infection.

His theory now is central (ie brain) neurological dysfunction caused by the long term life stress (I think). He seems to dismiss his own and others muscle and gut findings as irrelevant. And he rambles on for pages about stress and lifestyle and personality type and other stuff which I mostly skipped.

He seems to have worked with Wessely and Chalder in the past, and thinks they have the same theory as he does (I think), and states that CBT and GET are successful treatments. Yet his own treatment seems to involve very strict pacing, not GET.


First phase - stabilise activity at a level than can be maintained every day, with very strict restrictions on mental as well as physical activity, eg in any hour, no more than 15 minutes of visual concentration - reading, TV, computer etc., and no more than 30 minutes of audio stimulation - eg listening to the radio or an audio book. Also distance per day walked kept to planned amount that is less than what a patient says they can do. So it's strict physical and mental pacing staying rigidly within energy envelope.

Second phase - once first phase is established an stable, get sleep pattern sorted with amitryptiline or other tricyclic antidepressant (TCA) starting with a small dose and working up to what suits the patients (usually 10 to 75 mg) taken an hour before bed. Regular bedtime, regular waking time using alarm clock. He says getting sleep sorted is a most essential part of the treatment.

Phase 3 - SSRI, usually Prozac, morning dose starting with tiny dose and working up gradually. With the warning that SSRI and TCA aren't usually both taken because they use the same biochemical pathway in the liver for detoxification, so regular blood tests are needed to make sure it's ok. He says this is the part of the treatment that actually does the curing of the brain biochemistry, and hence leads to ME cure.

Throughout these 3 phases keep to the strict pacing regime.

I think he also suggested cure was less likely if you'd been ill more than a couple of years, but I'm a bit vague about that. My concentration had gone.

The treatment can go on for several years. I don't know how he decides it's worked and is time to start taking patients slowly off the drugs (SSRI first), maybe it's when the patient feels better.

He claims great success rates.

My problems with this whole thing:
He says nothing about diagnostic criteria, except vague stuff about fatigue and other symptoms, so he could be treating patients suffering from stress/burnout/depression for whom permission to slow down and take time out of their stressful lives, plus some antidepressants, is likely to be helpful.

He says something about the Royal Free and other outbreaks, but I've forgotten, or it didn't make sense, but I got the impression he thought they were something different.

His theories about cause and perpetuating factors are pure speculation, not evidence based.

What he calls recovery may be patients finding a way to live at a slower pace and stay within their energy envelope, after several years of strict pacing.

Snow Leopard

South Australia
This is why we trust randomised controlled trials, not anecdotes.

Initial positive unblinded pilot studies (eg Behan 1994) failed to replicate in RCTs. It's a typical story of hype in medicine.

These RCTs for a variety of SSRIs show this class of drugs are not only ineffective for CFS symptoms, but also ineffective for depression in CFS patients compared to placebo! (whereas tricyclics and monoamine oxidase inhibitors have demonstrated efficacy for depression)
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Senior Member
These 1990s theories have to be understood within their historical context. Back then there was massive hype about these new drugs (SSRIs) and every problem known to man was about serotonin. Pharma was pushing SSRIs for everything and many doctors enthusiastically jumped on this wagon. Prior to SSRIs, prescribing antidepressants required psychiatric supervision so it was a relatively small market. With SSRIs now in the hands of desperate and mostly incompetent GPs who are constantly faced with various ill-defined and non-specific medical problems, it became evident that these drugs were able to cut across diagnostic categories and had some degree of effectiveness for all sorts of symptoms (probably mostly placebo in hindsight). If you read old literature you can just sort of laugh at how zealous psychiatry was about these drugs. It wasn't until around 2000, after 10+ years of indiscriminate clinical use by GPs, gynaecologists and other assorted relatively low IQ medical professionals that their true effectiveness and dangers were properly appraised and the bodies counted, so to speak.