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Professor C Heather Ashton DM, FRCP
March 2001

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Question: Is the Post-Withdrawal Syndrome caused by benzodiazepines being "locked up" in tissues for years or is it the result of brain damage occasioned by long-term benzodiazepine use?

Answer: Benzodiazepines are fat soluble and do enter fatty tissues including the brain. But these tissues are in equilibrium with the blood, so that if the concentration in the blood is lower than that in fat, some will come out of the fat and re-enter the blood where it is metabolised and excreted. This will again lower the blood concentration, so more will leach out of the fat, and so on. So the body is more or less cleared, even of long half-life benzodiazepines, within 30 days. There is no evidence that benzodiazepines are "locked up" in tissues for years. I have looked into this question with an expert pharmacologist, Dr Clare Stamford of University College in London. There is a reference to this in the Manual (Chapter III, pp 33/34 in the UK version).

Long-term effects of benzodiazepines that persist after withdrawal are largely due to changes they have caused in GABA/benzodiazepine receptors, and not due to bits of drug being retained in the body. Of course lots of other factors, like post-traumatic stress disorder in people who have had a traumatic withdrawal experience, may also be operative in different individuals.

When writing the Manual I did attempt to find out from many sources, including Roche, whether anyone had measured benzodiazepine concentrations in tissues after withdrawal, even in animals. The answer was no. There was one post mortem study in geriatrics which found a surprisingly high concentration of benzodiazepines in muscles. But these were bedridden old people and there was no record of the doses of benzodiazepines they were taking or not taking before they died. Dr Clare Stamford at the University College in London, who has done a lot of rat benzodiazepine work, said that it was most unlikely that benzodiazepines could be sequestered for long periods of time in tissues as these are in equilibrium with blood and continually washed out.

Benzodiazepines are not known to be chemically bound anywhere like some metals – so it comes down to receptor changes that are only slowly reversible. The complete alleviation of long term symptoms with the benzodiazepine antagonist flumazenil seems to point in this direction (also mentioned in Chap III of the Manual). You could still get windows if your receptors were unstable, switching from one state to another. A similar thing, involving other receptors, is thought to account for rapid swings between mania and depression in so-called bipolar patients. You could call receptor changes brain damage if you wanted to, but I think they are reversible or potentially reversible; probably with receptors in different areas reversing at different rates, and some more readily than others.

The question of permanent damage is discussed in "Protracted withdrawal from benzodiazepines: The post-withdrawal syndrome" Psychiatric Annals 25, 174-179. This article is available here. The article clearly states that the evidence about permanent (structural) brain damage due to benzodiazepines is equivocal and there is at present no definite proof of this although some evidence is suggestive. However, occasionally people do have "withdrawal" symptoms which appear to be permanent and may persist till death. This has been reported in the medical literature by others and also observed by myself.

by Professor Heather Ashton
August 29, 2002

I agree that there is an abundance of people with very long-term problems and I have never denied that benzos can cause lasting, possibly permanent, neurological and other symptoms (see my articles on protracted withdrawal syndromes). What I have said is that there is no convincing evidence to date that they cause structural brain damage - e.g. death of neurons, brain atrophy etc. I think that long-lasting changes are probably functional, at the level of the GABA/BZ receptors which fail to revert to their pre-benzodiazepine state, often leaving the nervous system hyperexcitable (paraesthesiae, formication, muscle twitches, fasciculation, sensory hypersensitivity, tinnitus, jaw and dental pain, insomnia etc.) or generally unregulated/uncoordinated (cognitive) problems. Being functional changes, they are potentially capable of resolving which is why many people do notice gradual, if incomplete, improvement over the years.

Professor Lader himself carried out CAT scan studies on long-term benzodiazepine users and failed to find definite structural brain changes. As you know I tried several times unsuccessfully to obtain a grant for MRI studies in long-term benzo users who have withdrawn (combined with neurocognitive and EEG measurements), and to my knowledge no such study has ever been performed. Several correspondents have had MRI scans which have been reported as normal. On the other hand, I have of course seen many patients with long-lasting tinnitus, paraesthesiae, muscle spasms and joint pains etc. which are reported in my papers on protracted withdrawal. See especially the 1991 paper.

However, neither CAT scans nor MRI can reveal functional as opposed to structural changes. A search for structural changes would require very careful comparisons of brain volumes, hippocampal size, ventricular volume etc, in benzo users compared to age, sex and IQ matched controls; or else prospective longitudinal studies, again comprising benzo users with matched non-users over the long term. Cerebral blood flow measurements (fMRI) or PET (positron emission tomography) of GABA receptors might be more informative about functional changes, but have not been carried out.

Professor C Heather Ashton, DM, FRCP
School of Neurosciences, Division of Psychiatry,
The Royal Victoria Infirmary, Queen Victoria Road,
Newcastle upon Tyne NE1 4LP, England, UK

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