Magic bullet
In Greg’s Dilemma 1 and Dilemma 2, Greg outlined more than one dilemma linked to getting hooked to antidepressants and benzodiazepines. The responses to these posts were all over the shop – from pull yourself together, to entrust your life to God, to support for descriptions of positions others find themselves in. The responses also split in terms of what the response should be – should it be to outline steps that might be practical and helpful or was the issue as much about why we are voiceless and what can be done about that.
The clinical and neuroscience establishment view of antidepressants (Dr Junig) is caught in the image above – taken from an advertisement for one of the SSRIs just before launch. This will be a drug that goes exactly and only to where it is needed and does the job that is needed. This drug is a Magic Bullet.
This is the kind of image used to hypnotize Dr Junig and a lot of other doctors and even more the insurers and others in the business of covering our healthcare costs. Any other problems you have with these drugs are linked to the rest of your neurons which are clearly messed up or we wouldn’t have been giving you these wonder drugs in the first instance.
Methylene blue
The idea of a Magic Bullet came from the use of Methylene Blue to stain cells in the 1870s. This was a time when the idea that the key unit of the human body and of disease was the cell was a new idea and when bacteria were still not fully accepted as a cause for infections. Paul Ehrlich, using new dyes just created by chemical companies, was able to stain the germ that causes sleeping sickness (trypanosomiasis) with Trypan Red, and stain malaria parasites with Methylene Blue.
Methylene Blue also stained nerve cells, and helped prove they had long axons that acted as a means of communication between cells.
On the basis that it visibly acted on these cells, as early as the 1890s, Methylene Blue was tried out in malaria and in psychosis. The effects on malaria were not compelling although the parasite cleared from blood. The effects on psychosis were clear enough – it tranquilized – but not sufficiently striking it seemed to warrant continued use.
These are extraordinary hints however because Methylene Blue is essentially a phenothiazine – the structure from which Rhone-Poulenc’s chlorpromazine and the early major tranquilizers (antipsychotics) came. The striking benefits of chlorpromazine led other pharmaceutical companies to look for similar structures.
Geigy turned to Summer Blue and from this created the tricyclic antidepressants, most of which are serotonin reuptake inhibitors. From these drugs the SSRIs subsequently came.
But far from being highly specific drugs that go to one place only, Methylene Blue and Summer Blue coat nerve and other cells pretty completely as the image of cells stained with Methylene Blue below shows. These drugs may hit certain receptors but they certainly hit a lot of other things as well – likely including Sodium, Potassium, Calcium and TRP channels – see the Complex Withdrawal and PSSD section.
Moody blues
It was realized pretty quickly that the tricyclic group of drugs had some pain relieving properties. While we usually think of carbamazepine (Tegretol) as an anticonvulsant, it is in fact a member of the tricyclic class, and one of its most striking effects is the relief it produces in the severe facial pain of trigeminal neuralgia where soon after it was first used it became the drug of choice.
There are millions of people around the world who have been put in tricyclics or SSRIs for pain relief with amitriptyline, the second oldest tricyclic, now being among the most commonly used drugs. At first the hunch was that these drugs improved mood which made any pain more tolerable but it is now very clear that drugs like amitriptyline can have a direct analgesic effect. Who knows their effect on mood may be secondary to their pain (dysphoria) relieving effects.
In the Complex Withdrawal and PSSD section, one of the ideas put forward is that many of the problems people have come from antidepressant actions on peripheral nerves. This idea comes from a simple observation that anyone reading this can replicate for themselves. Within thirty minutes of having an SSRI most people can feel some genital numbness. This is not unlike the numbness that comes from rubbing a small amount of the local anesthetic lidocaine onto genital skin. This effect underpinned lidocaine’s use to manage premature ejaculation – a market that the SSRIs now occupy.
Lidocaine genital numbness seems to comes from its effects on Sodium channels. This thought led to the hypothesis that perhaps what is happening in Post-SSRI Sexual Dysfunction (PSSD) and in complex withdrawal is linked to disturbances of Sodium channels.
The local analgesic (lidocaine like) effects of amitriptyline are now so clear that it has in recent years been used as a local anesthetic in its own right.
In 2004, Jean-Pierre Estebe and Robert Myers published a paper looking at the safety of amitriptyline given as a local anesthetic. Their main findings are in the image below. Applied locally to nerves amitriptyline caused a dose dependent destruction of nerve fibers and their myelin sheaths in rats.
The nerves in these images are stained with Methylene Blue. The immediate effects of the lowest dose are seen on the upper left. The later effects of the higher dose are on the lower right. Nerve cells have been destroyed after exposure to doses that are in the clinical range. The black dots are fatty deposits where nerves once were.
Here is the full paper on Amitriptyline Neurotoxicity.
The meaning of blue
There is a temptation not to raise something like this, but in these days of crowd-sourced research someone is going to find articles like this and trying to explain them away after the fact will not be convincing.
The article doesn’t absolutely nail down beyond a shadow of doubt that some of the problems of dependence and protracted withdrawal and of PSSD come from irreversible nerve damage. But it certainly opens up this possibility.
There is good evidence that some people with PSSD can for instance have temporary relief from their problem suggesting that the disturbance of function is temporary rather than permanent.
There is enough here to warrant giving serious attention to people when they report ongoing difficulties. Helpful suggestions to Greg or anyone else need to take this into account.
Its probably worth bringing the article along to some prescribers – not to confront or antagonize them but to see if some can be recruited to finding answers. The answers might come from the one per cent of us who feel left outside the tent at the moment, but they are more likely to come if we can recruit some of the ninety-nine per cent still inside to engage with the issues.
Anne-Marie says
After reading this post I thought if they can do this with Amitriptyline then they should be doing this test with SSRIS also especially considering how common withdrawal and PSSD symptoms are.
Hopefully this is the beginning of finding out why this happens. I wonder if the nerve endings grow back or are they permanently dead and replaced by fat?. Maybe it depends on how great the damage is.
Very, very interesting post, in fact I think if most people knew this happened they would think twice before taking an SSRI.
mary says
As Anne-Marie asks, do the nerve endings grow back over time or are they permanently dead? Does it continue to happen with continued use or does it sort of reach saturation and then continues at that level of damage? I take it that this damage happens within the recommended prescribed dose? If a patient should take a massive overdose (e.g. a month’s supply) how much greater could the damage be in that instance?
Johanna says
Someone sent RxISK a question on Twitter: does this apply to “gabapentinoids”? I assume she means gabapentin (Neurontin) and its cousin pregabalin (Lyrica). These drugs were initially developed to control seizures, but are now used to control pain. They’re also used to treat depression, anxiety and bipolar disorder.
It’s a great question, especially given the fact that antidepressants are often used as painkillers too these days. (This refers to taking pills by mouth, NOT injecting or rubbing them directly on painful areas.) At least in the US doctors usually give small doses of amitryptiline (25-50 mg) in combination with other drugs for chronic pain; they use Cymbalta more, and in bigger doses. All these drugs seem to have wildly varying effects in different people. Some people use them to combat neuropathic pain, numbness-and-tingling, etc., while others find they cause it.
Any answers appreciated! I doubt we’ll get much from our doctors. Most are vaguely aware that amitryptiline is supposed to help pain, but usually offer it to chronic pain patients “to help you sleep” (it does make many people groggy). Many docs these days also give out Trazodone as a “sleeping pill” for the anxious, and cyclobenzaprine (Flexeril) as a “muscle relaxant.” They’re all tricyclics. It’s bad enough that the docs who prescribe them are ignorant of their possible psychological effects; seems that’s true of the physical effects as well. I swear, I think the fact that these drugs are old and cheap makes the average doc assume they couldn’t be very powerful …
Dr. David Healy says
Jo
Gabapentin and Pregabalin are both used for pain management but both also cause dependence and withdrawal problems. So what’s going on?
We have a new tool on RxISK org that may help anyone reading this to make up their own mind. You can now go in and put in a symptom like parosmia, or dysgeusia or any of the symptoms linked to peripheral neuropathy like tingling, paresthesiae, numbness, pain, burning sensation or the other symptoms linked to dependence such as food intolerance and see what drugs are linked to each of these.
There are discoveries there waiting for people to make – just seeing what drugs are linked to which features may help suggest ideas as to what is going on.
In the case of Gabapentin and Pregabalin while they are used for pain control they are also linked to burning sensations or pain syndromes of the type that are linked to peripheral neuropathy and many of the other features of SSRI dependence and withdrawal.
This is just the kind of information people need to have and perhaps show to doctors suggesting they try gabapentin or pregabalin to manage SSRI induced problems.
David
Johanna says
Great point — will invite the sister on “gabapentinoids” to take a look. I did have the experience of getting numbness and a pins & needles parasthesia in the legs from an antidepressant. The doctor offered to put me on Lyrica for this. Very casually, as if the Lyrica could just hop on an express train to my legs without affecting any other aspect of my mind or body. Seems to me like magical thinking, of the sort grownups are supposed to leave behind, even without an advanced degree in Science!
Karl says
I took Amitriptyline 10mgs my doctor gave me after I stopped Seroxat to help withdrawal insomnia which it did not just made me more agitated to be honest. But I’m sure it temporarily masked the worse off the withdrawal because when I stopped it all my symptoms especially physical got worse I haven’t taken any medication since.
One strange symptom I have been suffering which is terrible and I get often but can be brought on by food and if I stare at a computer screen to long is these terrible attacks severe pain in head with a mild gurning jaw it is terrifying can last hours but eventually passes it feels like I’m having some kind off seizure.I went on the train with my partner the other day and she was horrified to see me in this state.
I wonder David if you have heard off any one else in withdrawal experience severe headache attacks with gurning feeling in jaw/bruxism thought I’d ask you because gps are useless and couldn’t find any info on web it’s terrifying to be honest but does pass. I’m sure it must be seratonin related can’t believe I’m suffering this bad still four years off in March refuse to give up though.
Mr Sensible says
Johanna, I certainly think in the UK with our very cash strapped healthcare system cheap has an awful ot to do with amitryptiline’s current popular use as an off label cure all. I was in a pharmacy recently, not places that I usually frequent and was in hysterics when I saw the huge supply of the stuff behind the counter. I made a comment to the pharamcist about it being the cheap and nasty solution to apparently all ills, they did admit that its price does have a lot to do with its current popularity. A friend of mine recently got it for shingles and it didnt agree with them. As for myself getting venlafaxine for work stress back in 07, I’m pretty certain that whatever the reason the GP was prescribing venlafaxine it’s wasnt to save the UKs National Health Service any money(I off course wasnt aware at that point its cost compared with other ADs) and it didnt save the UK benefits system any money either when I ended up unemployable for nearly 4 yrs as a consequence. Great trick that from Wyeth, Pfzer now I believe, wreck someone’s life under the disguise of treating illness and get everybody else to pay for it.11 out of 10 for that one. By the way have any studies been done into what the economic impact of adverse reactions to ADs in fact is in terms of days off work, hospital admissions, increased GP appointments(remember also they get money when you make another appointment to go back and see them again about the bad reaction-bit self perpetuating isn’t it), lost productivity to employers. They can come up with figures for the econimic impact of alcohol abuse so surely they must be able to come up with figures for economic impact of adverse reactions to ADs. However as they say, Turkeys dont vote for Christmas.
Anne-Marie says
That’s not to forget the cost to the Criminal Justice System either. It costs £40,000 to just put someone in prison and approx another £40,000 to keep them there for a year. They can cost a lot more in damage than they probably cost to buy in a year for some people.
mary says
Yes, and the cost to the Benefits system for years following release, as your chances of being well enough for work never mind lack of opportunity due to a criminal record, is really low. ‘Doing time’ will probably have caused further deterioration in your mental state too, resulting in the need for more and more medication – becoming an added cost to the NHS. Your need for ‘support’ from the CMHTeam for years to come is another cost.
However, added together they are NOTHING compared to the cost to you as a person or to your family!
Mr Sensible says
There is a solution to the above problems, I believe its called amitriptilyne. By the way I estimate the cost to myself from my venlafaxine experience to be in region of £100k plus 2 parents in their 70s worried sick about their 40something youngest son they had not had to worry about for yrs and my mother due to ill health was a very dependent on me for day to day stuff, i had became unreliable. The stress and strain on my girlfriend, in my case our relationship became stronger as a result, that does not justify her our my suffering. Now I’m pretty certain if GPs who were the prescribers in my instance had to suffer the way I and those close to me suffered in the years after they would very quickly learn to be just a little bit more careful with such drugs. Remember drugs are like cars. A car is only as dangerous as the mechanic who’s servicing it and the person who’s driving it. The same applies to drugs, medically prescribed or ordered in brown envelopes off the internet from china(nothing’s really changed in Britain’s relationship with China in 150yrs its just the man in Shanghai now has a far bigger range of drugs to sell us than he did back in the days of the opium wars). If doctor does not in fact know what a drug is capable of doing then that makes it a very dangerous drug and if a patient is not properly informed of potential adverse effects, then that again makes for a very dangerous drug, put these two things together and there’s a pretty big chance of a very bad outcome and in my case there was.
Sally Macgregor says
Low dose amitriptyline (25-50mg) seems to be the first line approach to any chronic pain here: people I know have had it prescribed for:
cluster headache (excruciating type of migraine)
appalling pain caused by badly healed back fracture
osteoarthritis in hip and shoulder
lower back pain
arthritic knees
I have to say that it hasn’t worked in each and every case – other than helping the person with osteoarthritis sleep better – she takes it essentially as a sleeping pill. I’d be interested to hear about anyone who found it actually did help with pain? Until David mentioned it in the post – I assumed it was simply used as placebo/sleeping pill. No one has mentioned adverse effects at that low dose…although when it fails to control the pain, people usually get given tramadol or co-codamol (or Lyrica for neuropathic pain) as well, at which point disentangling what’s causing what becomes well nigh impossible.
I have yet to hear of anyone, except me, being prescribed it as an antidepressant now I think about it. Only for pain.
I took around 150mg – 200mg a day, as a 2nd line treatment when citalopram made me so sick. I guess amitriptyline was prescribed back then, because it was a very cheap tricyclic at the time but I don’t actually know- (didn’t work for me as an antidepressant either!) Prescribing guidelines are complicated here in the UK – depends on NICE, the local Clinical Commissioning Group which controls GPs’ budgets, whatever’s going cheap right now in any particular class of drug…particularly generics.
I’m not sure whether doctors think old cheap drugs are inferior – not all do, for sure. But as a new entrant to the world of mental illness back in 1997 I most certainly did. I assumed that if I’d managed to stomach an SSRI I would have got better pretty quickly – and that relying on hoary old 2nd rate drugs was why I got worse. Live and learn.
Wendy K says
Marijuana Relieves Chronic Pain, Research Shows–
Three Puffs a Day Helped People With Nerve Pain, Study Finds
By Kathleen Doheny
Reviewed by Laura J. Martin, MD
Aug. 30, 2010 — Three puffs a day of cannabis, better known as marijuana, helps people with chronic nerve pain due to injury or surgery feel less pain and sleep better, a Canadian team has found.
”It’s been known anecdotally,” says researcher Mark Ware, MD, assistant professor of anesthesia and family medicine at McGill University in Montreal. “About 10% to 15% of patients attending a chronic pain clinic use cannabis as part of their pain [control] strategy,” he tells WebMD. But Ware’s study is more scientific — a clinical trial in which his team compared placebo with three different doses of cannabis. The research is published in CMAJ, the Canadian Medical Association Journal. The new study ”adds to the trickle of evidence that cannabis may help some of the patients who are struggling [with pain] at present,” Henry McQuay, DM, an emeritus fellow at Balliol College, Oxford University, England, writes in a commentary accompanying the study.
NOTE FROM WENDY (the poster) I posted the above in hopes it helps someone…I personally do no use Canabis nor any other drug including prescription) drugs–very wary of the side effects (one bad experience was enough for me!) I rely on good nutrition, excercise, a good attitude, & vitamins & minerals. I discoverd that DHEA (derived from Wild Yams) improves my mood and energy level without side effects (for me anyway). Dosage is important (e.g not too much!) Do the research! I know everything is chemicals & chemisty, however I’ve been much better off with natural products than pharmaceuitcals.
Mr Sensible says
I find the whole marketing behind these drugs fascinating. Looks to me as though their just telling doctors exactly what they wish to here(or what they think they want to here). Manipulating people by telling them what they wish to hear does have a very good track record of success. As for the ‘Magic Bullet,’ Am I correct that it takes a certain type of magic bullet, a silver bullet to kill a werewolf? Rememmber that magic silver bullet that kills the werewolf would also kill anybody else.
Carla says
There are no words to describe how I am feeling, at the moment.
Betrayal and a sense of loss, is what I feel.
Millions of innocent people have been impacted by this ‘poison’.
Many have died and many are left with debilitating medical problems.
Big Pharma, lied to everyone.
I still don’t understand how they can keep most of their negative clinical data trials hidden in a vault.
These poisons are designed to kill the masses slowly.
To make some clinicians wealthy AND
Have most of the corrupt people eating out of their dirty ‘trough’.
This is HUMILIATING TO THE HUMAN RACE :’ (
annie says
Of course, Anne-Marie and Mary, are right about the overwhelming costs to the NHS/Jail ~System.
Up in front of ‘the beak’ must be a tumultuous experience, when ‘drugs’ are to blame.
Equally Up in front of the Non-System is the same.
Passed from one ignoramus to another and another, we have all been through the rabbit warren.
The only difference between some of us languishing in jail to some of us languishing in shreds was doing our research right at the beginning.
It doesn’t help with the drug damage, which is being worked on, but, it does help with our own psychological approach which I would hedge is 50% of our problem.
Those of us who were in the know way back when and kept our eyes firmly on the Terriers, I would say, have a greater chance of recovery than The Majority who have no idea that there is a Force striking through on their behalf.
I would find it very difficult to Catch Up if I was just entering this Can of Worms, as from 2002 ish Diehards have Crusaded for Us…..most people have no idea who they are……
THAT Place, all alone, is the Ordeal, let alone Buried Alive with Horrendous Effects and to come through All That Sane really is quite an extraordinary feat.
ALL that had to happen was for Doctors to Listen to their Patients…..as they are still not listening to their patients….then it has to be nailed with The Data and come up from behind…..we are on a quest to unbend several thousand doctors and a fraudulent industry and nobody said it would be easy and all credit to ‘all stories’ as that isn’t easy either.
We have been put in a position of Public Degradation.
Does that make them ‘feel better’ about ‘themselves’?
Carla says
How do we tackle this problem especially, in regards with the credibility of meds?
Rxisk , I believe needs to go ‘above and beyond’ the internet.
How do we get the message out there without upsetting the majority?
Barak Obama, is trying to change the gun laws in America and good on him for being so passionate about this issue.
We need to challenge the medicine laws and get the word out there that these poisons can also harm. We need to make people aware about the risks involved with ingesting medicines which are ‘deemed safe’.
It is not ok for those who are ingesting them to be complacent because ‘unforseen circumstances’ can happen to anyone.
The ripple effect needs to get louder and stronger.
The question is how do we do this?
Carla says
What if a poison has false labelling?
What if they say it is from Australia and it comes from China, then we would have to wonder how it gets on the pharmacists shelf.
It would be very embarrassing if one day someone finds out that the systems and processes are not as robust as they claim it to be?
Many want compensation when devious and misleading labelling has caused harm?
The same should apply for these poisons many have ingested.
If they cause harm and there is nothing on the label or pamphlet information and this type of harm has been occurring for 30+ years and they have known about this, then it is not only deceitful but misleading.
They have placed a black box warning for children.
What makes them think that suicidal tendencies does not occur for people above 25 years of age?
Shame on you ‘big guys’ for not mentioning this.
Many professionals know this is occurring.
Come forward and ‘speak up for your patients’.
Don’t hide behind that white cloak because it is not benefitting anyone.
Carla says
For the records: What if the product was made in Australia and the product was dodgy?
Australian safety standards would be considered very harmful.
Still waiting for answers………………………..!
They don’t reply.
Anxious says
Excuse me,according to you Amitriptiline can give PSSD?
Dr. David Healy says
probably
DH
Anxious says
But have you ever heard about someone who gets PSSD from amitriptyline or it is a pure speculation?
I need to know because I have severe anxiety and if SSRI are so dangerous I have to try some tricyclics…
(Mirtazapine and buproprione don’t help so much)
Dr. David Healy says
Most tricyclics are serotonin reuptake inhibitors. The sexual dysfunction for Antidepressants was first reported with amitriptyline. I have seen full blown PSSD with clomipramine.
DH
Noel Hershfield says
Still would like to see a randomised controlled study ,that shows that the adverse effects are seen with SSRIs compared to a control group on placebo.
Noel Hershfield says
Are the adverse effects seen in a placebo group? Any decent literature,or is this opinion?
Dr. David Healy says
Noel
Can you apply the point you are making to tardive dyskinesia and tell me what you come up with
David
Anxious says
And…even the MAO inhibitors give PSSD?
Dr. David Healy says
i am not sure this has been reported – but some MAOIs are also serotonin reuptake inhibitors and vice versa some SSRIs can be MAOI
DH