[EricPaul]

The Benzodiazepines
Toxicity, Cognitive Impairment, Long-Term Damage
& The Post-Withdrawal Syndrome
Dr R F Peart BSc, PhD
December 2000

Abstract
There is a great deal of misinformation, mythology and ignorance surrounding the benzodiazepines, their uses and problems. The attitude of denial by many has a severe impact on patients trying to get help from doctors, treatment for dependency, DLA and other benefits, and help for legal actions.

This paper is an attempt to bring together apparently diverse aspects in a format that hopefully will be informative and a source of further information for those seeking help and compensation for the destruction of their lives.

Contents

1. Introduction

2. Elimination Half Lives and Accumulation

3. Individual Variability and Dependence

4. Toxicity

5. Adverse Reactions and Events

6. Toxic Poisoning

7. Medical Literature

Section A - Cognitive Impairment/Long Term Damage - Reference List and Extracts

Section B - Long-Term Damage/Post Withdrawal Syndrome - Reference List and Extracts

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1. Introduction
Any drug acting upon the central nervous system (CNS) whether it is an analgesic, stimulant or depressant has a potential for causing toxic side effects, cognitive impairment, neurological disorders and dependence.

The benzodiazepines are depressants of the CNS and have five major therapeutic actions, anxiolytic, hypnotic, muscle relaxant, antiepileptic and amnesic i.e. they are very non-specific drugs. Recipients of these drugs will be subject to all of these actions, whether required or not, and to adverse reactions associated with each therapeutic action. Over 500 different adverse reactions to the benzodiazepines have been reported to the MCA (UK) and the FDA (USA) and not surprisingly many are directly linked with the therapeutic actions e.g. rebound anxiety, rebound insomnia, musculoskeletal problems, epileptic fits and severe memory problems. Because of the wide range of therapeutic actions, and the fat-soluble nature of the benzodiazepines few parts of the body and brain are exempt from adverse reactions. Some patients have dozens of these adverse reactions occurring at the same time or over a given period. No wonder many are mis-diagnosed as having schizophrenia, dementia, chronic fatigue syndrome, or muscular dystrophy. It seems that they will enhance any psychological or physical problem existing prior to ingestion of these drugs, in addition to the many new problems they create.

2. Elimination Half-life and Accumulation
Accumulation of the benzodiazepines in the body and brain is a severe problem with long-term use of many of the benzodiazepines -- e.g., diazepam, chlordiazepam, chlordiazepoxide, flunitrazepam and flurazepam. This is a result of long elimination half-lives of up to 250 hours and of the formation of active metabolites giving levels for diazepam about six times the daily dose in two weeks and eight times in four weeks. For a given drug the half-life can vary by up to a factor of three between individuals. Metabolic changes in the elderly with kidney or liver problems cause much slower elimination rates -- e.g., for diazepam half-lives of 400 hours have been measured leading to very high accumulation levels (x20). The benzodiazepines without active metabolites can also produce significant accumulation levels -- e.g., nitrazepam and lorazepam with half-lives of 18 to 57 hours and 12 to 34 hours respectively producing levels of about 4 and 3 times the daily dose respectively with an ingestion period of one week.

A severe consequence of the accumulation of and toxicity of benzodiazepines is the effect on babies born to mothers who have ingested these drugs. They readily cross the placenta and allowing for the measured levels in the umbilical cord, the increased bioavailability, and the weight of the foetus, the level of exposure per unit weight of the foetus is many hundred times that of the daily dose level of the mother. It is not surprising that many babies are born addicted to these drugs, suffering from floppy infant syndrome and other problems. There is sufficient evidence to postulate a causal link between benzodiazepines (and some other drugs) and the Sudden Infant Death Syndrome although the authorities are very quick and keen to deny such a possibility.

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3. Individual Variability and Dependence

There is a wide variability in the patterns of response to benzodiazepines among individuals, in both therapeutic and adverse reactions, both wanted and unwanted. Individual variability is determined largely by genetic programming of drug metabolism and responsiveness. A clear-cut example of these phenomena is the 30-fold variation in plasma concentration in patients given the same oral dose of diazepam. This variability is dependent on both genetic and environmental factors such as race, sex, age, smoking, disease and concomitant drug treatment. Wide inter-individual response to these drugs was frequently recorded in research studies and clinical trials in the 1960s, but has seldom been commented upon in recent decades.

There is one area where this variability has a strong impact -- i.e., the probability of an individual becoming dependent on these drugs. It can readily explain why some become dependent in a few weeks (shortest recorded case - seven days) and others on similar doses may take more than a year or more. This pattern is no different than that for dependence to other drugs acting on the CNS, but the speed of onset for benzodiazepines appears to be quicker than most, especially alcohol (5 mg diazepam = 2 units of alcohol).

In essence, chronic dependence is the repeated taking of the drug to alleviate the adverse reactions caused by that drug. In everyday terms it is taking "the hair of the dog that bit you". Those who are more sensitive to unwanted adverse reactions will become more quickly dependent on these drugs especially if the link between the drug and adverse reaction is not recognised by the patient and the doctor (as happens very frequently). There are "101" reasons why individuals start taking drugs and continue to take them prior to chronic addiction, but only one to explain how dependence occurs with drugs having widely different and sometimes opposite therapeutic actions. /In other words - pharmaceutical actions cause adverse reactions - therapeutic actions alleviate adverse reactions./

Resort to half-baked ideas like personality traits and characteristics is not necessary or appropriate. Such an explanation will be less than satisfying to the members of the medical profession and the drugs industry whose thinking is rooted in the 19th century, and revolves around mental and moral issues. It is however far more acceptable to the 13,000 BMA members dependent on alcohol, prescribed drugs and hard drugs (BMA conference, Birmingham 1998).

4. Toxicity

The toxicity of drugs can be related to total dosage -- i.e., the larger the dose the greater the toxic effects; e.g., overdose and death. Most drugs can produce toxic reactions in the normal or therapeutic range, especially those that accumulate in the body with repeated doses. Toxic effects due to overdose are generally a harmful extension of the drugs normal pharmacological reaction and are largely predictable and preventable. Toxic reactions that occur with normal doses are often unrelated to known pharmacology and are responsible for most of the adverse reactions reported for the benzodiazepines.

Toxicity resulting from a drug may be divided into four types (Spilker B., 1992):

Type 1. Toxicity results from an excess of an undesired pharmacological effect. Many of the benzodiazepines adverse reactions are in this category because in general they are presented for only one of the main therapeutic actions e.g. if diazepam is prescribed as a muscle relaxant then the dependence, withdrawal, memory problems, fits, anxiety, etc. are of this type.

Type 2. Toxicity results from an excess of a desired beneficial pharmacological effect for which the drug is used e.g. hangover effect for hypnotics.

Type 3. Toxicity results from effects not observed at therapeutic doses. These are generally predictable and observed in overdose e.g. coma. The safety index of a drug is defined as the ratio between the minimum toxic dose and the maximum effective dose, the larger the ratio the greater the safety. The barbiturates generally have a higher value than the benzodiazepines (but not as high as the blown up estimates of the drug industry) but the individual variability of the benzodiazepines has caused deaths at a few times the therapeutic dose.

Type 4. Toxicity is unexpected (paradoxical reactions). These are idiosyncratic events and often may be the opposite of the intended and anticipated response. For some drugs these occur at low rates but for the benzodiazepines they occur relatively frequently -- e.g., rebound anxiety, rebound insomnia, muscular tension, aggression and hostility. These occur so frequently that they can no longer be
described as unexpected.

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5. Adverse Reactions and Events
Adverse reactions include any undesirable effects that occur, e.g.:


1. Physical symptoms
2. Psychological symptoms
3. Physical signs
4. Laboratory values from tests and biological samples
5. Laboratory values from tests on the patient's EEG etc.
6. Other factors relating directly to deterioration of the quality of life and social interactions


The frequency of toxic adverse reactions is not given in data sheets or literature in the UK. Their frequencies are given in some international data sheets e.g. the Spanish data sheets (data supplied by the drug companies) give a wide range of adverse reactions for many benzodiazepines. These reactions include:


Greater than 25%: drowsiness, confusion and ataxia.

From 10 - 25%: sedation, depression, disorientation, dysphagia, dysarthia, poor concentration, trembling, changes in libido, incontinence, nausea, vomiting, diarrhoea and hyper-salivation.

From 1 - 9%: hepatitis, dermatitis, urticaria, puritis, leucopoenia, anterograde amnesia, paradoxical excitation, changes in vision, diplopia, nystagmus, hearing changes and eosinophilia.

Less than 1 %: respiratory depression, hypertension, hypotension, bradycardia, tachycardia and palpitations.


6. Toxic Poisoning

It is interesting to note that the most frequently reported adverse reactions in Canada (about 50% of adverse reactions for single benzodiazepine ingestion) is encephalopathy i.e. organic brain disease. One of the manifestations of this illness is toxic psychosis or toxico mania which the World Health Organisation has defined as a chronic state of intoxication produced by repeated consumption of a drug harmful to the individual or to society.

The characteristics are:

1. Uncontrollable desire or necessity to continue consuming the drug and try to get it by all means.
2. Tendency to increase the dose.
3. Physical and psychic dependence as a result.


Many long-term therapeutic addicts will readily identify with toxico mania, especially those addicted to long half-life benzodiazepines. This aspect of the benzodiazepine problem which put simply is toxic poisoning produces an altered state of consciousness with an altered state of perception of self, others and one's environment and relationships. In many ways this syndrome is similar to that produced by chemical poisoning -- e.g., organo-phosphates. The lack of self-awareness can take many years to change, often requiring much information, knowledge and counselling to achieve it. /*nb after discontinuation of drugs many have an enduring personality change./

7. Medical Literature

The medical literature contains thousands of papers on toxic effects and resulting adverse reactions and effects. Listed below are some of the topics in the VOT archives with the number of papers in brackets:


1. Dependence and withdrawal (500)
2. Adverse reactions, side-effects and paradoxical reactions (220)
3. Cognitive impairment, memory and brain problems (140)
4. Pregnancy, neonates, infants (120)
5. Toxicity, poisoning, suicides, deaths (100)
6. Driving problems, accidents, injuries (80)
7. Elderly (60)


Many of these papers were published in the 1960s and 1970s and they contain most of the information on benzodiazepine problems that has only recently been accepted and included in data sheets and patient information leaflets. Some problems are still not included. On the other hand, most information was published in overseas adverts, journals and data sheets.

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Sections A and B contain a selection of extracts from representative and key papers on cognitive impairment, long-term damage and the post-withdrawal syndrome.

Section A: Cognitive Impairment and Long-Term Damage
The many papers published in the 1960s and early to mid 1970s on this subject were largely single dose therapeutic dose studies or low-dose studies for periods of a few weeks. They showed a range of deficits in cognitive function, psychomotor performance and short-term memory problems with no development of tolerance. It was not until the late 1970s and early 1980s (when therapeutic dose dependency was belatedly accepted), that cognitive function and other tests on long-term benzodiazepine users (up to 10 years) were studied both during use and in acute withdrawals. From the mid-1980s to mid-1990s there was an increasing number of studies looking at damage after long-term use and at follow-up periods after discontinuation of up to six years. Several of these studies involve CT scans of the brain looking for structural changes.

Summary

1. Benzodiazepines produce impairment of cognitive functioning and psychomotor performance e.g. reaction time, vigilance, arousal, judgement, reasoning, speed and accuracy of information processing, visual spatial ability, co-ordination, short-term and post drug long-term memory, 'blackouts' and
learned tasks.

2. These effects are independent of abuse, dependency, non-dependency, normal, healthy, young or old subjects. Impairment increases with chronic use. Development of tolerance to these effects is very slow.

3. CT brain scans show a difference in ventricular cerebral spinal fluid space dimensions between benzodiazepine users and non-users, and also between high and low benzodiazepine users.

4. The functional brain damage causes increased morbidity, increased mortality and social deterioration.

5. Subjects are generally not aware of their reduced capacity or the fact that they are not functioning well in every day life.

6. In general much of the impairment is slowly reversible. Some aspects show improvement after six years, some are semi-permanent or permanent.

Key papers: 1, 4, 10, 12, 17, 20, 21, 24, 25, 28, 29, 37, 38, 40.

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References and extracts

1. Di Mascio A. et al. (1968) Behavioural Toxicity of Psychotropic Drugs Connecticut Med. 32, 8, 617-620. Reaction time, judgement, concentration and visual acuity are impaired by benzodiazepines.

2. Kleinknecht R. (1975) Review of Effects of Diazepam on Cognitive and Psychomotor Performance. J. Nerv. Mental Dis.161, 399-411. 23 studies (1970-75) Mainly young healthy volunteers after a few days ingestion showed impairment in 6 areas of cognitive function.
3. Liljequist R. et al. 1978 Effects of Diazepam and Chlorpromazine on Memory Functions in Man. Europe J. Clin. Pharmacol.13, 339-343. Single doses, 2 weeks treatment. Impairment of acquisition, reaction time, co-ordination and memory. Impaired transfer from short to long term memory.

4. Grant I. (1978) Organic Impairment in Poly Drug Users, Risk Factors. Amer. J. Psychiatry,135, 2, 178-184. Extensive use (up to 10 years) of CNS depressants (incl. Benzodiazepines) causes neuropsychological impairment detectable 3 months after cessation of drug taking and may be long lasting.

5. Lucki I. et al. (1980) Chronic use of Benzodiazepines and Psychomotor and Cognitive Test Performance. Psychopharmacology, 88, 426-433. Behavioural and cognitive tests on chronic users (5yrs) gave results that are similar or worse than a control group with diagnosed anxiety disorders (no pills). /[So much for the effectiveness of benzodiazepines - RFP]/

6. Hendler N. et al. (1980) Comparison of Cognitive Impairment due to Benzodiazepines and Narcotics. Amer. J. Psychiatry,137, 828-830. Cognitive impairment due to benzodiazepines is marked, no effect due to narcotics at clinical doses.

7. Bergman H. et al. (1980) Neuropsychological Impairment and Exclusive Abuse of Sedatives or Hypnotics. Amer. J. Psychiatry,137, 2, 215-17. Chronic use for 5 to 10 or more years. Tests 3 to 10 months after withdrawal showed significant decrease in neuropsychological performance and intellectual impairment compared with a control group.

8. Scharf M. (1982) Lorazepam, Efficacy, Side Effects and Rebound Phenomena. Clin. Pharmacol. Ther., 31, 2,175-179. Lorazepam (4mg) used in 18-night sleep study with insomniacs. Rebound insomnia, rebound anxiety, severe hangover and impaired functioning, including anterograde amnesia.

9. Petursson H. et al. (1983) Psychometric Performance during Withdrawal from Long-Term Benzodiazepine Treatment. Psychopharmacology, 81, 345-349. Chronic use of benzodiazepines results in selective and chronic psychological deficits including fine motor control and co-ordination. Rebound effects measured during withdrawal. Likelihood of cerebellar damage.

10. Block R.I. et al. (1984) Alprazolam and Lorazepam Effects on Memory Acquisition and Retrieval Processes. Pharmacol. Biochem. and Behaviour, 20, 233-241. Both benzodiazepines produced marked memory impairment of acquisition and retrieval for long-term memory (pre-drug). /[This study supports the anecdotal reports of hundreds who claim that their retrograde memory was impaired for many years after stopping the benzodiazepines - RFP]/

11. Romney D.M. et al. (1984) A Brief Review of the Effects of Diazepam on Memory. Psychopharmacol. Bull., 20, 313-315. Review of about 30 papers. Supports memory loss being due to a consolidation process of impairment -- i.e., short- to long-term memory transfer. Queries use of psychotherapy whilst patient is on diazepam.

12. Lader M. et al. (1984) Computerised Axial Brain Tomography in Long-Term Benzodiazepine Users. Psychological Med., 14, 203-206. Benzodiazepine users have larger ventricular brain ratio than control group.

13. Angus W.R. (1984) Effects of Diazepam on Patients Memory. J. Clin. Psychopharmacol., 4, 4, 203-206. Has detrimental effect on short-term and long-term memory. It interferes with consolidation process of information transfer -- i.e., short- to long-term storage. Dose 5-30 mgs/dly, patients 21-74 yrs.

14. Mac D.S. et al. (1985) Anterograde Amnesia with Oral Lorazepam. J. Clin. Psychiatry, 46,137-138. Young healthy volunteers, 2mg Lorazepam, single dose. Deleterious effect on short-term recall of verbal information.

15. Lucki I. et al. (1985) Psychomotor Performance Following Long-Term Use of Benzodiazepines. Psychopharmacol. Bull., 21, 93-96. Chronic users (6 yrs) for 5 different benzodiazepines on equivalent of 10-30 mgs. dly of Valium, compared with a group of anxious patients not on benzodiazepines. Very little difference except for impairment of delayed recall for Benzodiazepine users. /[Benzodiazepines ineffective - RFP]/

16. Pomara M. et al. (1985) Increased Sensitivity of the Elderly to the Central Depressant Effects of Diazepam. J. Clin. Psychiatry, 46, 5,185-187. Groups of old and young healthy volunteers. Single 2.5 mg dose. Impaired immediate and delayed recall memory and psychomotor performance for elderly is much greater than for the young.

17. Curran H.V. (1986) Tranquillising Memories. A Review of the Effects of Benzodiazepines on Human Memory. Biolog. Psychology, 23,179-213. Review of 1973 - 1985 papers, about 90 papers on 20 different benzodiazepines. Most studies are short-term of single dose. All show amnesic problems and cognitive deficits.

18. Cole S.O. (1986) Effects of Benzodiazepines on Acquisition and Performance: A Critical Assessment. Neuroscience and Biobehaviour Revs., 10, 265-272. Review of up to 100 papers. Benzodiazepine produced impairment of learned tasks (behaviour) as well as an acquisition impairment of different (new) tasks.

19. Brosan L. et al. (1986) Performance Effects of Diazepam During and After Prolonged Administration. Psycholog. Med., 16, 561-571. Repeated doses for 3 weeks. Reduced performance while on drug and for 3 weeks afterwards e.g. reduced reaction time and reasoning.

20. Borg S. (1986) Dependence and other Long-Term Effects Associated with Benzodiazepines. Lakartidningen, 83; 321-326. Withdrawal symptoms occur after 1-2 weeks of benzodiazepine ingestion, 15% become dependent with short term use (weeks). Benzodiazepines cause functional brain damage similar to that seen with alcohol abuse. Increased mortality and marked social deterioration. Whether brain damage is permanent requires further research.

21. Borg S. (1987) Sedative Hypnotic Dependence: Neuropsychological Changes and Clinical Course. Nord. Psyhiatr. Tidsskr., 41, Suppl.15,17-19. Neuropsychological impairment present in patients, independent of abuse, dependence or non-dependence. Impairment still present after abstinence of 1, 4 and 6 years.

22. Smiley A. (1987) Effects of Minor Tranquillisers and Antidepressants on Psychomotor Performance. J. Clin. Psychiatry, 48, Suppl.12, 22-28. Review of studies of the effects of benzodiazepines on tracking, reaction time, vigilance and divided attention. Diazepam clearly impairs performance for several hours after dosing. No evidence of tolerance for up to 3 weeks. Effects are the same for groups of anxious and normal subjects.

23. Golombok S. et al. (1987) A Follow Up Study of Patients Treated for Benzodiazepine Dependence. Br. J. Med. Psychol., 60,141-149. Examination of patients from 1-5 years after discontinuation, 54% had withdrawn successfully in spite of continuing psychiatric symptoms.

24. Schmauss C. et al. (1987) Enlargement of Cerebral Spinal Fluid Spaces in Long-Term Benzodiazepine Users. Psychological Med.,17, 869-873. Large difference in CSF spaces between high- and low-dose benzodiazepine users for 5-6 years.

25. Lader M. (1987) Long-Term Benzodiazepine Use and Psychological Functioning. The Benzodiazepines in Current Clinical Practice. Roy. Soc. Med., 1987, 55-59. Patients perform poorly on tasks involving visual spatial ability and sustained attention. They are not aware of their reduced ability. Only after they have withdrawn do they realise that they have been functioning below par.

26. Larson E. et al. (1987) Adverse Drug Reaction Associated with Global Cognitive Impairment in Elderly Persons. Anns. of Inst. Med., 107, 169-173. Patients on long-term/long half-life benzodiazepines diagnosed with dementia. After discontinuation 30% re-diagnosed -- i.e. no dementia after 1 year follow-up.

27. Lavender S. (1988) Psychophysiology and Anxiety: Current Issues and Trends. Pharmacological Treatment of Anxiety, 145-51. Benzodiazepine-induced neurophysiological impairment, in worst cases permanent.

28. Golombok S. et al. (1988) 'Impairment in Long Term Benzodiazepine Users' Psychological Med., 18, 365-374 Patients on benzodiazepines not functioning well in everyday life and not aware of reduced ability. Recognition of below par functioning after withdrawal. Cognitive impairment greater with chronic medication.

29. Bergman H. et al. (1989) Dependence on Sedative Hypnotics, Neuro-Psychological Impairment, Field Dependence and Clinical Course in a 5 yr Follow Up Study. Br. J. Addiction, 84, 547-553. Cerebral disorders present 4-6 years after drug discontinuation - permanent? CT scans show dilation of ventricular system in brain.

30. Danion J.M. et al. (1989) Diazepam Induces a Dissociation Between Explicit and Implicit Memory. Pharmacology, 99, 238-243. Healthy volunteers, double blind study. Diazepam impairs explicit memory (new events/recent information) but not implicit (knowledge-based memory). Organic Amnesia-like Korsakoff's Syndrome.

31. Penetor D.M. et al. (1989) Triazolam Impairs Learning and Fails to Improve Sleep in a Long-Range Aerial Deployment. Aviation, Space and Envir. Med., June, 594-597. Ability to recall recent verbal information impaired 8 hrs after ingestion of triazolam.

32. Curran H.V. (1991) Benzodiazepines, Memory and Mood: A Review. Psychopharmacol., 105,1-8. Effect of benzodiazepines on anxiety, cognitive function and arousal. Detailed discussion on memory processes affected by benzodiazepines. Slow tolerance to memory impairment, i.e. tolerance not fully developed.

33. Lader M. (1992) Benzodiazepines and Memory Loss: More Than Just Old Age. Prescriber, 3,13. Benzodiazepines cause memory losses, or 'blackouts'. They impair speed and accuracy of information processing.

34. Slazman C. et al. (1992) Cognitive Impairment Following Benzodiazepine Discontinuation in Elderly Nursing Home Residents. Intl. J. Geriatric Psychiatry, 7, 89-93. Group of patients on short half-life benzodiazepines for 18 months. After 1 year discontinuation impairment in short-term memory and alertness. Impairment slowly reversible.

35. Bowen J.D. (1993) Drug Induced Cognitive Impairment. Drugs and Ageing 3 (4), 349-357. Benzodiazepines have a high risk of cognitive impairment. A common cause of delirious and a confounding factor in dementia.

36. Anon (1993) Learning and Memory Impairment in Older Detoxified Benzodiazepine Dependant Patients. Mayo Clinic Proc., 68, 731-737. Benzodiazepines have an accumulative effect on memory that did not necessarily diminish with time after detoxification.

37. Moodley P. et al. (1993) Computed Axial Brain Tomograms in Long Term Benzodiazepine Users. Psychiatric Research, 48,135-144. Differences in the density of some areas of the brain between benzodiazepine and non-benzodiazepine users.

38. Tata P.R. et al. (1994) Lack of Cognitive Recovery Following Withdrawal from Long-Term Benzodiazepine Use. Psycholog. Med., 24, 202-213. Modest recovery of cognitive deficits after 6 months cessation of benzodiazepines compared with pre -and post-withdrawal and a follow-up.

39. Binnie C. (1994) Cognitive Impairment - Is It Inevitable? Seizure, 3 Supple. A. 17-22. Most anti-epileptic drugs, including benzodiazepines, cause cognitive impairment.

40. Patten S.B. et al. (1994) Neuropsychiatric Adverse Drug Reactions. From Canadian Adverse Data Base (65-94) Intnl. J. Psychiatry in Med., 24 (24), 45- 62. Over half of all reports (for single benzodiazepines) were for encephalopathy (organic brain disorder).

41. Tonne U. et al. (1995) Neuropsychological Changes During Steady State Drug Use. Acta Psychiatr. Scand., 91, 299-304. Neuropsychological deficits only partly reversible on discontinuation at 1 yr follow up.

42. Anon (1996) Intellectual Impairment and Acquired Intellectual Deterioration in Sed/Hyp Drug Dependent Patients. Dept. of Psychology and Psychiatry Clinic, Stockholm University, Sweden. Every second patient on sed/hyp drugs showed signs of intellectual impairment.

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