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Benfotiamine has been studied in laboratory models of diabetic retinopathy, neuropathy, and nephropathy. [10] A 2021 review of its use for diabetic polyneuropathy described two clinical trials which showed improvements in neuropathic pain and neuropathic symptoms scores, the latter of which showed a dose-response effect. [4]
Milnacipran was found to improve impulse control in rats, which has been linked to its activation of D 1-like receptors in the infralimbic cortex. [6] However, high doses of milnacipran did not show this effect, likely because of increased dopamine in the nucleus accumbens. [7]
Adverse effects found in clinical trials are usually limited to headache and gastrointestinal discomfort when high doses are used. While daily use can result in tolerance and paradoxical drowsiness, increasing the dose is strongly discouraged and side effects can include diarrhea, bladder infections, bronchitis, back pain, abdominal pain, insomnia, constipation, gastroenteritis, headache ...
The US Food and Nutrition Board set a tolerable upper intake level (UL) at 1,000 mg (1,500 IU) per day derived from animal models that demonstrated bleeding at high doses. [30] In the US, the popularity for vitamin E as a dietary supplement peaked around 2000, with popular doses of 400, 800 and 1000 IU/day.
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For example, the Food and Drug Administration recommends that adults on a 2,000 calorie diet get between 60 and 90 milligrams of vitamin C per day. [18] This is the middle of the bell curve. The upper limit is 2,000 milligrams per day for adults, which is considered potentially dangerous. [19]
However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus.
Side effects of guanfacine are dose-dependent. [29]Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache. [30]Common (1–10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes.
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