other cns depressants increases the risk of suicide in drug misusers. benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among 'drug misusers'. carcinogenicity there has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. in the second u.s. national cancer study in 1982, the american cancer society conducted a survey of over 1.1 million participants. a markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. fifteen epidemiologic studies have suggested that benzodiazepine or nonbenzodiazepine hypnotic drug use is associated with increased mortality, mainly due to increased cancer death. the cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. it has been hypothesised that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. while initially u.s. food and drug administration reviewers expressed concerns about approving the nonbenzodiazepine z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs. a 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk. brain damage evidence in a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. these results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder. a publication asked in 1981 if lorazepam is more toxic than diazepam. in a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain ct scan examinations. some scans appeared abnormal. the mean ventricular-brain ratio measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. there was no significant relationship between ct scan appearances and the duration of benzodiazepine therapy. the clinical significance of the findings was unclear. in 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage. in 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged cerebrospinal fluid spaces with associated cerebral atrophy. cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users. however, a ct study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users. in 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically, neuropsychological function was found to be permanently affected in some people long-term high dose non-medical use of benzodiazepines. brain damage similar to alcoholic brain damage was observed. the ct scan abnormalities showed dilatation of the ventricular system. however, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened cortical sulci. the study concluded that, when cerebral disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent. a ct study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group. a study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities. withdrawal from high-dose use of nitrazepam anecdotally was alleged in 2001 to have caused severe shock of the whole brain with diffuse slow activity on eeg in one patient after 25 years of use. after withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam. professor heather ashton, a leading expert on benzodiazepines from newcastle university institute of neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. she has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the gabaa benzodiazepine receptor level. newer and more detailed brain scanning technologies such as pet scans and mri scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage. a 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, but the exact nature of the relationship is still a matter of debate. history benzodiazepines, when introduced in 1961, were widely believed to be safe drugs but as the decades went by increased awareness of adverse effects connected to their long-term use became known. recommendations for more restrictive medical guidelines followed. concerns regarding the long-term effects of benzodiazepines have been raised since 1980. these concerns are still not fully answered. a review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. the majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. there is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. in 2007, the department of health recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of evidence base for effectiveness and due to the risks of long-term use. the long-term effects of benzodiazepines are very similar to the long-term effects of alcohol consumption (apart from organ toxicity) and other sedative-hypnotics. withdrawal effects and dependence are not identical. dependence can be managed, with a medical professional of course, but withdrawal can be fatal. physical dependence and withdrawal are very much related but not the same thing. a report in 1987 by the royal college of psychiatrists in great britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. despite this benzodiazepines are still widely prescribed. the socioeconomic costs of the continued widespread prescribing of benzodiazepines is high. political controversy in 1980, the medical research council (united kingdom) recommended that research be conducted into the effects of long-term use of benzodiazepines a 2009 british government parliamentary inquiry recommended that research into the long-term effects of benzodiazepines must be carried out. the view of the department of health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, as well as the dangers of benzodiazepine drug addiction. in 1980, the medicines and healthcare products regulatory agency's committee on the safety of medicines issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. when asked by phil woolas in 1999 whether the department of health had any plans to conduct research into the long-term effects of benzodiazepines, the department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. in a house of commons debate, phil woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with. john hutton stated in response that the department of health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. in 2010, the all-party parliamentary group on involuntary tranquilliser addiction filed a complaint with the equality and human rights commission under the disability discrimination act 1995 against the department of health and the department for work and pensions alleging discrimation against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted benzodiazepine withdrawal syndrome, as well as denial of rehabilitation and back-to-work schemes. additionally the appgita complaint alleged that there is a "virtual prohibition" on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. the complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing. declassified medical research council meeting the medical research council (uk) held a closed meeting among top uk medical doctors and representatives from the pharmaceutical industry between the dates of 30 october 1980 and 3 april 1981. the meeting was classified under the public records act 1958 until 2014 but became available in 2005 as a result of the freedom of information act. the meeting was called due to concerns that 10–100,000 people could be dependent; meeting chairman professor malcolm lader later revised this estimate to include approximately half a million members of the british public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. it was reported that benzodiazepines may be the third- or fourth-largest drug problem in the uk (the largest being alcohol and tobacco). the chairman of the meeting followed up after the meeting with additional information, which was forwarded to the medical research council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. he felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in growth hormone occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. also raised were findings in animal studies that showed the development of tolerance in the form of a 15 percent reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug flurazepam and a 50 percent reduction in binding capacity after 30 days of a low dose of diazepam. the chairman was concerned that papers soon to be published would "stir the whole matter up" and wanted to be able to say that the medical research council "had matters under consideration if questions were asked in parliament". the chairman felt that it "was very important, politically that the mrc should be 'one step ahead'" and recommended epidemiological studies be funded and carried out by roche pharmaceuticals and mrc sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. the meeting aimed to identify issues that were likely to arise, alert the department of health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. the world health organization was also interested in the problem and it was felt the meeting would demonstrate to the who that the mrc was taking the issue seriously. among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. the chairman stated that the "withdrawal symptoms from valium were much worse than many other drugs including, e.g., heroin". it was stated that the likelihood of withdrawing from benzodiazepines was "reduced enormously" if benzodiazepines were prescribed for longer than four months. it was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. dr mason (dhss) and dr moir (shhd) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take. controversy resulted in 2010 when the previously secret files came to light over the fact that the medical research council was warned that benzodiazepines prescribed to millions of patients appeared