Valium

Valium, otherwise known as Diazepam or ‘Mother’s Little Helper’, was widely used for the treatment of anxiety, but was also used as a sedative-hypnotic, anticonvulsant, or for cholinesterase poisoning, substance abuse withdrawal, antihistamine overdose and chloroquine overdose. (Dodd-Butera and Broderick, 2005, p784). It falls under the benzodiazepine class of drugs, which rapidly displaced the more toxic barbiturates. Benzodiazepines work by binding allosterically to benzodiazepine-binding sites on GABA-A receptors, enhancing the inhibitory effects of GABA to promote relaxation. The first benzodiazepine, chlordiazepoxide, was synthesised in 1955 by the Polish American chemist Leo Sternbach. Diazepam, which Hoffman-La Roche released in 1963, under the brand name Valium, rapidly became America’s bestselling medication by 1968, peaking in 1978, until 1982.

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Importantly, in parallel with clinical trials of the time, Valium wasn’t tested in women, despite the heavy marketing (to be further discussed). In fact, a study of the amnesic effects of diazepam in 1970 states that to reduce individual differences they recruit 12 young, intelligent male volunteers (primarily dental students). While the subjects are all of a particular class and sex, there is no mention through the paper that it is an issue, nor that the results may not be generalisable to individuals of less intelligence, or women. (Clarke et al., 1970, p690). That being said, along with the increased recognition of the importance of sex in clinical trials and change in legislation in 1993, the effects of Valium in women in particular began being explored more readily. It was already known that oral contraceptives decrease the clearance of benzos, that benzos have slower elimination rates in women, and that testosterone has a modulating effect on benzo receptors, and research started looking at other important sex differences. (Pesce et al., 1994, p353). For example, as the effects of Valium are non-specific, weaning from the compound has severe and varied side effects, such as panic attacks and seizures, however, there may be sex differences in the intensity of withdrawal symptoms. In a study of mice, the intensity of diazepam withdrawal syndrome was lower in male than in female mice. This effect was interrupted in castrated male mice, where the withdrawal symptoms similarly increased in intensity, compared to uncastrated mice, suggesting sex hormones and testosterone in particular modulate the action of benzodiazepines. This effect was not seen in ovariectomised female mice, but injection of testosterone or oestrogen to castrated male mice reduced withdrawal symptoms, namely seizures. This again was not comparable in female mice. Diazepam also increased the body weight of all male mice, compared to female and control mice. (Pesce et al., 1994, p354). The study provided evidence of sex differences in diazepam mediated responses in mice, but whether this is generalisable to humans is debatable. Comparably, a study in rats revealed that the menstrual cycle (oestrous cycle in rats) may affect Valium’s efficacy and even render it useless at certain points in the cycle, highlighting again the effects of sex hormones on a drugs pharmacodynamics. (Silva et al., 2016, p72). They also found that the minimum dose required to induce Valium’s anxiolytic effects was higher in female than male rats, suggesting women may be undermedicated with Valium compared to men. Finally, due to its high lipid solubility, diazepam crosses the blood brain barrier and placental barrier, and is also present in breast milk. Hence, Valium is not recommended during pregnancy and breastfeeding. (Dodd-Butera and Broderick, 2005, p784). While there are no major teratogenic effects like thalidomide, at birth, infants display lower birth weight when their mother’s receive diazepam throughout pregnancy compared to those unsubject to diazepam. This finding was not evident at an 8 month follow up. However, performing a sex analysis revealed that the finding of lower weight was still true for female infants, but not male infants at 8 months old. (Czeizel et al., 1999, p162-5). Whether there are long-term consequences of foetal and neonatal administration of diazepam is questionable, but unlikely.