Moms Little Helper

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How did benzodiazepines become the most widely prescribed class of drugs in the world in just a decade?
What a drag it is getting old
‘Kids are different today,’ I hear ev'ry mother say
Mother needs something today to calm her down
And though she’s not really ill
There's a little yellow pill
She goes running for the shelter of a mother’s little helper.
So begins the Stones’ 1966 hit ‘Mother’s Little Helper’, a dark and catchy paean to Valium. The words are a social commentary on benzodiazepines, which had just hit the market a few years prior and become wildly popular, particularly among American housewives.
Since the late 1800s, drug manufacturers had been hunting for a new, non-addictive anti-anxiety medication. Previously, patients were given opiates – with predictably disastrous results. Then came barbiturates, which were also written off as too addictive. After that, doctors began prescribing anti-psychotic drugs known as phenothiazines, but those drugs triggered severe side-effects such as uncontrollable facial movements.
In the 1950s, the late Leo Sternbach – a research chemist – began tinkering with an unknown class of compounds: the BZDs, or benzodiazepines. Over several years, he tested some 40 BZDs but all proved ineffective. Finally in 1956, after adding methylamine (a colourless gas derived from ammonia) to one compound, he produced a white powder that made mice sleepy and calm. The Food and Drug Administration approved Librium, the first-ever benzodiazepine, in 1960 and Valium in 1963. 
Benzodiazepines latch onto a receptor in the brain, which then activates a neighbouring neurotransmitter known as GABA. GABA release makes people calm and sleepy. The drugs can trigger that GABA rush in minutes, allowing a user to feel calmer almost immediately. Initially, benzodiazepines were hailed as a medical miracle, and they soon became the most widely prescribed class of drugs in the world. Even though the drugs’ addictive properties have now become clear, they remain widely available and are often prescribed for longer than the recommended 2–4 weeks.
Tolerance to the drugs is thought to develop because benzodiazepines weaken the response of receptors in the brain. That means a benzodiazepine user needs to keep ramping up the drug’s dosage to trigger the same calming effect of GABA. The drugs are also non-specific: they act on multiple subunits of GABA, which govern different actions, such as anxiety, restfulness, motor control and cognition. So even if a person goes on the drugs to alleviate social anxiety, they are invariably altering how they think, sleep and even move. That, in turn, explains why a person coming off benzodiazepines may experience wholly new symptoms, such as panic attacks and seizures.
Malcolm Lader, a psychologist and pharmacologist at King’s College London in the UK, began looking at the benzodiazepine craze as a young scientist in the 1970s. He initially assumed that most people on the drugs had ramped up their dose to such a degree that they had become hooked; instead, he found that users had largely remained on the prescribed dosage. “People couldn’t believe that you could still be on your original dose…and still have problems when you try to come off,” he recalls.
In the 1980s, Lader and a team of researchers issued one of the earliest warnings against long-term benzodiazepine use. Since that time, decades of evidence have made clear that taking benzodiazepines comes with serious risks, yet they remain hugely popular. Antidepressants (e.g. Prozac) and cognitive behaviour therapy are effective anxiety treatments, but neither act immediately; antidepressants can also initially worsen symptoms. For many people, benzodiazepines always seem like the better option.
If you could take the high out of drugs, what would be the point in taking them? Sujata Gupta meets the unorthodox doctor who thinks he can block some of the world’s most addictive pills.
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Background
Discovery
Pharmacology
Mechanism of action
Prevention
Since the late 1800s, drug manufacturers had been hunting for a new, non-addictive anti-anxiety medication. Previously, patients were given opiates with predictably disastrous results. Then came barbiturates, which were also written off as too addictive. After that, doctors began prescribing anti-psychotic drugs known as phenothiazines, but those drugs triggered severe side-effects such as uncontrollable facial movements.
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