Why was the evidence ignored? · Medicines in the United Kingdom found that the drugs’ anti-anxiety effects didn’t last beyond four months. The committee recommended that prescriptions

Why Was the Evidence Ignored?

The Long History of Research Documenting the Harm From Benzodiazepines

Robert WhitakerSeptember 2017

I have written books on the history of psychiatry and the efficacy of its drug treatments, and I have received payments for these books.

I have the president of a non-profit organization, Mad in America Foundation, which operates a webzine and a continuing education program. We receive reader donations and funding from several private philanthropists.

I am a paid employee of the Foundation.

Disclosure Statement

Objectives

1. Describe the history of benzodiazepines: animal research that led to their discovery; and historical recognition of their addictive properties and withdrawal syndromes.

2. Describe how the clinical trials of Xanax revealed its addictive properties and the harm to patients upon withdrawal, and how this information was not disseminated to the public.

3. Describe the scientific literature regarding the short-term effects of benzodiazepines, and their long-term effects on the overall well-being of patients.

The Discovery of Librium, 1960

In animal tests, the compound chlordiazepoxide was found to make animals less aggressive and numb to pain. Rats remained non-combative even when given electric shocks to their feet. The animals also showed no signs of stress when given the drug before being exposed to the expectation of being shocked.

Yet Roche Markets Librium as a Curative Agent

“Librium is the biggest step yet toward ‘pure,” anxiety relief as distinct from central sedation or hypnotic action.”

This new benzodiazepine is “safe, harmless and non-addicting.”

M. Smith, Small Comfort (New York: Praeger, 1985), 110.

In 1963, Hoffmann-La Roche brought Valium to market (the second benzodiazepine to be approved by the FDA), and from 1968 to 1981, it was the best-selling drug in the Western World.

Momma’s Little Helper

In the 1960s, many patients wrote to the FDA telling of how they experienced odd experiencing odd and quite distressing symptoms when they tried to quit a benzodiazepine. They told of awful insomnia, anxiety more severe than they had known before, and a rash of physical symptoms—tremors, headaches, and nerves that “jangled like crazy.”

As one man wrote the FDA, “I was not sleeping and in general felt horrible. Sometimes I thought I would die and other times wished that I had.”

Patients Tell of Withdrawal Symptoms

A. Tone, The Age of Anxiety (New York: Basic Books, 2009), 171

In 1975, the U.S. Justice Department demanded that benzodiazepines be classified as schedule IV drugs under the Controlled Substances Act. This designation limited the number of refills a patient could obtain without a new prescription, which revealed to the public that the government had concluded that benzodiazepines were addictive.

The Benzodiazepines Are Classified as Addictive Drugs

The Benzodiazepines Fall from Media Grace

Vogue headline: “Danger ahead! Valium—The Pill You Love Can Turn on You.” A benzodiazepine, the magazine wrote, could lead to a “far worse addiction than heroin.”

Ms. magazine interviews patients on the horrors of withdrawal:

• “My withdrawal symptoms are a double-dose of the anxiety, irritableness, and insomnia I used to feel,” one user said.

• Said another: “I can’t begin to describe the physical and mental anguish that accompanied my withdrawal.”

New York Times: Some critics go so far to say that [Valium] is doing more harm than good, or even deny that it is doing any good at all for the great majority of patients. Some cry with alarm that it is far from being as safe as it is proclaimed, that it can be hideously and dangerously addictive, and may be the direct cause of addicts’ deaths.”

M. Smith, Small Comfort (New York: Praeger, 1985), 78. A. Tone, The Age of Anxiety (New York: Basic Books, 2009), 17 G. Cant, “Valiumania,” New York Times, February 1, 1976.

Two million Americans were said to be addicted to benzodiazepines, four times the number addicted to heroin.

Abuse of tranquilizers, said Betty Ford’s physician Joseph Pursch, was “the nation’s number one health problem.”

R. Hughes, The Tranquilizing of America (New York: Harcourt Brace Jovanovich,1979), 8.

U.S. and U.K. Governments Urge that Benzodiazepines Be Used Sparingly

• In 1979, Senator Edward Kennedy held a Senate Health Subcommittee hearing on the dangers of benzodiazepines, which he said had “produced a nightmare of dependence and addiction, both very difficult to treat and recover from.”

• In a review of the scientific literature, the White House Office of Drug Policy and the National Institute of Drug Abuse concluded that the drugs’ sleep-promoting effects didn’t last more than two weeks.

• In a review of the scientific literature, the Committee on the Review of Medicines in the United Kingdom found that the drugs’ anti-anxiety effects didn’t last beyond four months. The committee recommended that prescriptions be limited to short-term use.”

A. Tone, The Age of Anxiety (New York: Basic Books, 2009), 176. Committee on the Review of Medicines, “Systematic review of the benzodiazepines,” BMJ 280 (1980): 910–12.

Sales of Benzodiazepines Decline

103 million prescriptions in the U.S. in 1975

71 million prescriptions in the U.S. in 1981

Source: M. Smith, Small Comfort (New York: Praeger, 1985), 32.

“Now that benzodiazepines have been shown to cause drug dependence should their use be more closely controlled—or even banned?”

— British Medical Journal

Editorial, “Benzodiazepines on trial,” BMJ 288 (1984): 1101–12.

The Introduction of Xanax Revitalizes the Benzodiazepine Market

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Baseline Week 1 Week 4

AlprazolamPlacebo

Number of panic attacks

The Xanax Investigators Used This Data To Tell of the Drug’s Efficacy

C. Ballenger, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 413–22.

The Conclusions Drawn in the Abstracts of Articles

• “Alprazolam was found to be effective and well-tolerated.”

• “Patient acceptance of alprazolam was high.”

• The drug has “few side effects and is well-tolerated.”

C. Ballenger, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 413–22. R. Noyes, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 423–28. J. Pecknold, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 429–36.

And Now for the Rest of the Story

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Baseline Week 1 Week 4 Week 8

AlprazolamPlacebo

Number of panic attacks

The Study Assessed Efficacy Over an Eight-week Period, Not Four Weeks

C. Ballenger, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 413–22. R. Noyes, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 423–28.

At end of eight weeks (active treatment phase), there was no statistically significant difference on most of the rating scales, at least among those who remained in the study.

This was so even though nearly 25% of the placebo group had been withdrawn from benzodiazepines at the start of the study, and thus were in fact going through benzodiazepine withdrawal during the 8-week efficacy study.

Efficacy

Adverse events (in the alprazolam group)• sedation• fatigue• slurred speech• amnesia• poor coordination• impaired mentation• severe adverse events like mania, aggressive behavior in 4% of patients

C. Ballenger, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 413–22.R. Noyes, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 423–28.

The Study Also Had a Six-Week Drug-Withdrawal Phase

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Baseline Week 1 Week 4 Week 8 Week 9 Week 12 Week 13 Week 14

AlprazolamPlacebo

Number of panic attacks

Tapering begins

J. Pecknold, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 429–36.

Withdrawal Outcomes in Xanax Group• 39% deteriorated significantly, and had to resume taking a benzodiazepine.

• 35% suffered rebound panic and anxiety symptoms more severe than when study began.

• 35% suffered distressing symptoms they had never experienced before:

confusionheightened sensory perceptionsdepressiona feeling insects were crawling over themmuscle crampsdiarrheadecreased appetiteweight loss

In sum, by the end of the 14-week study, the drug-exposed patients were more phobic, more anxious, suffered more panic attacks, and were doing worse on a global scale that assess overall well-being.

J. Pecknold, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988): 429–36.

Xanax: A Drug That Creates Addicts

By study end, 44% of those randomized to alprazolam had been unable to get off the drug during the withdrawal period, and were now on their way to a lifetime of addiction.

The APA Joins With Upjohn to Promote the Prescribing of Xanax for Panic Disorder

• In 1988, Upjohn sponsored a “scientific symposium” at the American Psychiatric Association’s annual meeting, where an “expert panel” highlighted the four-week results.

• Robert Pasnau, who had been head of the APA in 1987, sent a glossy booklet on the “Consequences of Anxiety” to APA members, an “educational” effort funded by Upjohn.

• Former NIMH director Gerald Klerman, who had led the “steering committee” that had designed the alprazolam tests for Upjohn, and Shervert Frazier, also a former director of the NIMH, penned a “Dear Doctor” letter that Upjohn included in the promotional literature it sent to doctors about Xanax as a treatment for panic disorder.

P. Breggin, Toxic Psychiatry (New York: St. Martin’s Press, 1991), 344-53.

• Upjohn gave $1.5 million to the APA so it could mount an educational campaign to educate psychiatrists, health-care workers, and the public about panic disorders, which was said to be “under-recognized and undertreated.”

• The FDA approved Xanax as a treatment for panic disorder in November 1990.

• The NIMH identifies panic disorder as a priority concern and sponsors a conference on it in 1991, with its panel of experts designating high-potency benzodiazepines—e.g. Xanax—as one of “two treatments of choice.”

P. Breggin, Toxic Psychiatry (New York: St. Martin’s Press, 1991), 344-53. F. Pollner, “Don’t overlook panic disorder,” Medical World News, October 1, 1991.

Newspaper Reports Tell of an Exciting New Anti-Anxiety Agent

St. Louis Dispatch:

The new drug helped 70 to 90 percent of those with the debilitating disorder, which affected 4 million adults in this country.

Associated Press

“A biochemical malfunction in the brain is believed to be one of the causes of panic attacks. Xanax can block the attacks by interacting with several different systems in the brain.”

Chicago Sun Times

“Xanax is the fastest acting and least toxic” medication for the disorder, said Dr. John Zajecka, at Rush Medical College.

J. Randal, “In a panic?” St. Louis Post-Dispatch, October 7, 1990. H. Brown, “Panic attacks keeps thousands from malls, off roads,” Associated Press, November 19, 1990. R. Davis, “When panic is disabling,” Chicago Sun- Times, June 29, 1992.

In 1992, Xanax became the fifth most frequently prescribed medication in the United States.

“High Anxiety,” Consumer Reports, January 1993.

In a 1978 review of 78 double-blind trials, Kenneth Solomon at Albany Medical College in New York determined that benzodiazepines had proved to be significantly better than placebo in only 44 of them. At best, the collective results could be said to “hint at therapeutic efficacy.”

In a 1983 report, Arthur Shapiro at Mt. Sinai School of Medicine in New York City fleshed out this efficacy picture a bit more. In a trial of 224 anxious patients, Valium proved superior to placebo for the the first week, but then this advantage began to lessen. Based on the patients’ self-assessment of their symptoms, by the end of the second week there was no difference between the drug and a placebo, and by the end of six weeks, the placebo group was faring slightly better. “It is unlikely in our opinion that carefully controlled studies would consistently show significant benzodiazepine therapeutic anti-anxiety effects,” Shapiro wrote.

The Short-term Efficacy of Benzodiazepines

K. Solomon, “Pitfalls and prospects in clinical research on antianxiety drugs,”J Clin Psychiatry 39 (1978): 823–31. A. Shapiro, “Diazepam: how much better than placebo?” J Psychiatric Research 17 (1983): 51–73.

Risk-Benefit Reports of Short-Term “Effectiveness”

In a 1991 report, British investigators concluded that the short-term efficacy of the drugs, which diminishes after a few weeks, comes at a high cost. “Both psychomotor and cognitive functioning may be impaired, and amnesia is a common effect of all benzodiazepines,” they wrote.

In 2007, researchers in Spain assessed whether the adverse events negated the small efficacy benefit, and determined that the drop-out rates in clinical trials, a measure often used to assess the overall “effectiveness” of a drug, were the same for benzodiazepine and placebo patients. “This systematic review did not find convincing evidence of the short-term effectiveness of the benzodiazepines in the treatment of generalized anxiety disorder,” they concluded.

C. Gudex, “Adverse effects of benzodiazepines,” Social Science & Medicine 33 (1991): 587–96.J. Martin, “Benzodiazepines in generalized anxiety disorder,” J Psychopharmacology 21 (2007): 774–82.

Withdrawal Syndromes: A Brief Historical Review of the Early Literature

1961: Leo Hollister of Stanford University reports that patients withdrawing from Librium experienced odd symptoms.

1976: Physicians Barry Maletzky and James Kotter report that when their patients stopped taking Valium, many complained of “extreme anxiety.”

1978: Physicians at Pennsylvania State University write that patients withdrawing from benzodiazepines often experience “an increase in anxiety above baseline levels . . . a condition that we term ‘rebound anxiety.’ “

1981: British psychiatrist Malcolm Lader and colleagues report that “anxiety rose sharply during withdrawal, and to a point of panic in several patients. Patients commonly experienced bodily symptoms of anxiety, such as a choking feeling, dry mouth, hot and cold, legs like jelly, etc.”

B. Maletzky, “Addiction to diazepam,” International Journal of Addictions 11 (1976): 95–115. A. Kales, “Rebound insomnia,” Science 201 (1978): 1039–40. H. Petursson, “Withdrawal from long- term benzodiazepine treatment,” British Medical Journal 283 (1981): 643–35.

From the 1980s forward, British physician Heather Ashton, who ran a benzodiazepine withdrawal clinic published numerous articles detailing benzodiazepine withdrawal symptoms. They include:

rebound anxiety insomniaseizures tremorsheadaches blurred visionringing in the ears extreme sensitivity to noisefeeling of insects crawling own skin nightmareshallucinations headachesextreme depression depersonalization

These findings show very clearly that benzodiazepine withdrawal is is a severe illness . . . The patients were usually frightened, often in intense pain, and genuinely prostrated. . . . Through no fault of their own, the patients suffered considerable physical as well as mental distress.” — Heather Ashton

Withdrawal Syndromes: The Evidence is Fleshed Out (1980s forward)

H. Ashton, “Benzodiazepine withdrawal,” British Medical Journal 288 (1984):1135–40.

Protracted Withdrawal Syndromes: Will the Patient Ever Recover?

In her research, Ashton observed that a small percentage of patients, after tapering from a benzodiazepine, suffer a “protracted withdrawal syndrome. Their anxiety remains at elevated levels “for many months;” depression may deepen; and the odd perceptual symptoms—the depersonalization, the derealization, the sensation of insects crawling on the skin—may haunt them for an extended period of time.

H. Ashton, “Protracted withdrawal syndromes from benzodiazepines,” Journal of Substance Abuse Treatment 9 (1991): 19–28.

The Biology of Benzodiazepine Withdrawal

How benzodiazepines act on the brain

• Benzodiazepines affect the GABA neurotransmitter.

• GABA (gamma-aminobutyric acid) inhibits neuronal activity. When it binds with a neuron’s receptor, the neuron either fires at a slower rate or stops firing for a period of time.

• A majority of neurons in the brain have GABA receptors, which means that this neurotransmitter acts as a brake on the brain’s neuronal activity.

• A benzodiazepine binds to the GABA receptor, and thus enhances the normal GABA inhibition of neuronal activity. As a result, it suppresses central nervous system activity.

How the brain adapts to a benzodiazepine

• In response to a psychotropic drug, the brain goes through compensatory adaptations in an effort to maintain a homeostatic equilibrium (e.g., the normal functioning of a neurotransmitter pathway.)

• In this instance, the benzodiazepine is increasing GABA activity; in compensatory response, the brain decreases its output of GABA and decreases the density of its GABA receptors. The brain is trying to “restore normal GABA transmission,” British scientists explained in 1982.

• However, this means that the brain’s GABA system—which acts as the brake on neuronal activity—is now in an impaired state. The brake fluid is low (release of GABA) and the brake pads are worn (decrease of GABA receptors.)

P. Cowen, “Abstinence symptoms after withdrawal of tranquillising drugs,” Lancet 2, 8294 (1982): 360–62.

The GABA impairment leads to withdrawal syndromes

• When the benzodiazepine is withdrawn (or dosage decreased), the brain’s own braking system—because of its impaired state—can’t properly inhibit neuronal activity.

• As a result, the brain’s neurons may fire in a more helter-skelter pattern.

• This excess firing of the brain’s neurons, Ashton concluded, may “account for many of the effects of withdrawal.” The anxiety, the insomnia, the sensation of insects crawling across the skin, the paranoia, the derealization, the seizures—all of these vexing symptoms may arise from neuronal hyperactivity.

H. Ashton, “Benzodiazepine withdrawal,” British Medical Journal 288 (1984):1135–40.

Protracted withdrawal syndromes may occur if the GABA system fails to renormalize

• The supposition with slow tapering is that, as the dosage is lowered, the brain’s own GABA system will begin to return to normal.

• However, in certain instances (and particularly after extended use), the GABA system may fail to renormalize, and thus the brain’s brake on neuronal activity remains permanently impaired—or impaired for an extended period—following the withdrawal of the drug.

• If this happens, the neuronal activity will remain, and thus the protracted experience of withdrawal syndromes.

• In a small percentage of patients, the GABA system may be permanently impaired, and in that case, the only possible solution may be to go back on a benzodiazepine.

Outcomes with Long-Term Use

Symptoms of emotional distress • In 1991, Karl Rickels at the University of Pennsylvania School of Medicine

reported on a group of anxious patients who had tried to quit benzodiazepines three years earlier, and he found that those who had successfully gotten off the drugs were doing “significantly” better than those who had failed to do so.

• In 1995, Canadian investigators found that benzodiazepine usage led to a fourfold increase in depressive symptoms.

• In 1999, Rickels reported that web long-term users withdrew from benzodiazepines, they “became more alert, more relaxed, and less anxious, and this change was accompanied by improved psychomotor functions.”

K. Rickels, “ Long-term benzodiazepine users 3 years after participation in a discontinuation program,” American Journal of Psychiatry 148 (1991): 757–61. S. Patten, “ Self-reported depressive symptoms following treatment with cortico-steroids and sedative-hypnotics,” International Journal of Psychiatry in Medicine 26 (1995): 15–24. K. Rickels, “Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation,” Journal of Clinical Psychopharmacology 19 (1999): 107–13.

• In 2000, Ashton observed that those who stay on the drug long-term tend to become more ill: “Many patients find that anxiety symptoms gradually increase over the years despite continuous benzodiazepine use, and panic attacks and agoraphobia may appear for the first time.”

• In 2007, French researchers surveyed 4,425 long- term benzodiazepine users and found that 75 percent were “markedly ill to extremely ill . . . a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability.”

H. Ashton, Benzodiazepines: How They Work and How to Withdraw (Newcastle upon Tyne: University of Newcastle, 2000), 8. A. Pelissolo, “Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice,” Encephale 33 (2007): 32–38.

• Early on, researchers recognized that memory problems were associated with short-term use of benzodiazepine, and this led them to worry about their long-term effects on cognitive function. In 1976, David Knott, a physician at the University of Tennessee, warned that “I am very convinced that Valium, Librium and other drugs of that class cause damage to the brain. I have seen damage to the cerebral cortex that I believe is due to the use of these drugs, and I am beginning to wonder if the damage is permanent.”

• Over the next twenty- five years, reports of cognitive impairment in long- term benzodiazepine users regularly appeared in the medical literature. These studies told of people who were having trouble focusing, remembering things, learning new material, and solving problems. However, the patients “are not aware of their reduced ability,” Lader wrote.

Cognitive function

R. Hughes, The Tranquilizing of America (New York: Harcourt Brace Jovanovich, 1979), 17. Golombok, “Cognitive impairment in long- term benzodiazepine users,” Psychological Medicine 18 (1988): 365–74.

• In 2004, a group of Australian scientists, after reviewing the relevant literature, concluded that “long-term benzodiazepine users were consistently more impaired than controls across all cognitive categories,” with these deficits “moderate to large” in magnitude. The studies showed the “higher the intake, dose and period of use [of a benzodiazepine], the greater the risk of impairment.”

M. Barker, “Cognitive effects of long- term benzodiazepine use,” CNS Drugs 18 (2004): 37–48.

• In 1983, the World Health Organization noted a “striking deterioration in personal care and social interactions” in long- term benzodiazepine users.

• In a 1985 study funded by Hoffmann-La Roche, the manufacturer of Valium, University of Michigan investigators determined that taking this drug was “associated with poor quality of life, poor performance in work and personal life, low social support, perceived lack of internal control, poor perceived health and high levels of stress.”

• In her many studies, Ashton determined that long- term use led to “malaise, ill- health, and elevated scores for neuroticism.” Benzodiazepines, she said, contribute to “job loss, unemployment, and loss of work through illness.”

Overall societal function

WHO Review Group, “Use and abuse of benzodiazepines,” Bulletin of the World Health Organization 61 (1983): 551–62. . Caplan, “Social effects of diazepam use,” Social Science & Medicine 21 (1985): 887–98. H. Ashton, “Tranquillisers,” British Journal of Addiction 84 (1989): 541–46. H. Ashton, Benzodiazepines: How They Work and How to Withdraw (Newcastleupon Tyne: University of Newcastle, 2000), 12.

A History of Harm Done

1) Science tells a very consistent story, across decades, about benzodiazepines.

2) The drugs work by suppressing central nervous system activity.

3) For a short period (weeks), benzodiazepines may provide greater relief from anxiety and panic attacks than placebo. Then this benefit begins to wane, and disappears by the end of a month.

4) The harms from their use includes:• Adverse effects on cognition and mobility during short-term use• Withdrawal syndromes that often lead to worse symptoms than at

baseline• A small percentage of patients may experience protracted withdrawal

syndromes that last for months and even a year or more• Long-term use is associated with increased emotional distress, cognitive

impairment, and a decline in capacity to function in society.

“What seemed so good about the benzodiazepines

when I was playing with them was that it seemed

like we really did have a drug that didn’t have many

problems. But in retrospect it’s difficult to put a

spanner into a wristwatch and expect that it won’t

do any harm.”

—Alec Jenner, British physician who conducted first

trials of a benzodiazepine in the UK, 2003.