The active metabolite of progesterone has been found to enhance the binding of benzodiazepines to the benzodiazepine binding sites on the GABAA receptor. The cross-tolerance between GABAA receptor positive modulators, including benzodiazepines, occurs because of the similar mechanism of action and the subunit changes that occur from chronic use from one or more of these compounds in expressed receptor isoforms. Abrupt withdrawal from any of these compounds, e.g., barbiturates, benzodiazepines, alcohol, corticosteroids, neuroactive steroids, and nonbenzodiazepines, precipitate similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased seizure susceptibility and anxiety. While many of the neuroactive steroids do not produce full tolerance to their therapeutic effects, cross-tolerance to benzodiazepines still occurs as had been demonstrated between the neuroactive steroid ganaxolone and diazepam. Alterations of levels of neuroactive steroids in the body during the menstrual cycle, menopause, pregnancy, and stressful circumstances can lead to a reduction in the effectiveness of benzodiazepines and a reduced therapeutic effect. During withdrawal of neuroactive steroids, benzodiazepines become less effective. Physiology of withdrawal
Withdrawal symptoms are a normal response in individuals having chronically used benzodiazepines, and an adverse effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA is the second-most-common neurotransmitter in the central nervous system (the most common being glutamate) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA.
Benzodiazepines have also been linked to an increased risk of road traffic accidents and falls in the elderly. The long-term effects of benzodiazepines are still not fully understood. Long-term benzodiazepine use is associated with attentional and visuospatial functional impairments. Withdrawal from benzodiazepines can lead to improved alertness and decreased forgetfulness in the elderly. Withdrawal led to statistically significant improvements in memory function and performance-related skills in those having withdrawn successfully from benzodiazepines, whereas those having remained on benzodiazepines experienced worsening symptoms. People having withdrawn from benzodiazepines also felt their sleep was more refreshing, making statements such as "I feel sharper when I wake up" or "I feel better, more awake", or "It used to take me an hour to fully wake up." This suggests that benzodiazepines may actually make insomnia worse in the elderly. Cause
Tolerance occurs to the muscle-relaxant, anticonvulsant, and sleep-inducing effects of benzodiazepines, and upon cessation a benzodiazepine withdrawal syndrome occurs. This can lead to benzodiazepines being taken for longer than originally intended, as people continue to take the drugs over a long period of time to suppress withdrawal symptoms. Some people use benzodiazepines at very high doses and devote a lot of time to doing so, satisfying the diagnostic criteria in DSM V for substance use disorder. Another group of people include those on low to moderate therapeutic doses of benzodiazepines who do not use their benzodiazepines differently than recommended by their prescriber but develop a physical tolerance and benzodiazepine dependence.