to be safe and to be associated with the most robust beneficial effects. Berberin Berberine can be useful in obesity treatment and prevention through a range of mechanisms, including effects on PEPCK, the gut microbiome, AMPK and glucose metabolism. A review found that berberine can elicit clinical benefits for various diseases at standard doses and has low toxicity. The (possibly relatively small but useful) anti-obesity effects (as well as effects on associationed issues such as via effects on insulin receptors) are thought to partly stem from its effects on the microbiome, such as enrichment of butyrate-producing bacteria which can upregulate GLP-1 and PYY. Berberine can modulate the diversity of the gut microbiome at the dose of 500 mg/day. Forskolin Forskolin increases cAMP levels. Results from clinical trials "lead to speculation that forskolin might be helpful in the management of overweight". While it apparently reduced body fat levels in people with obesity, additional trials with high quality are required. Oleuropein Oleuropein, as contained in olive leaf extract, has anti-obesity properties, which may make it useful as a supportive treatment. Caloric restriction mimetic Accumulating evidence demonstrated anti-obesity impact of caloric restriction mimetics (CRMs) like spermidine. Such nutraceuticals exert effects similar to caloric restriction. However, more studies are needed and some CRMs may not have effects useful for the treatment or prevention of obesity – for resveratrol in specific "current evidence does not fully support its use to prevent or treat age- or obesity-related diseases". Conjugated linoleic acid Conjugated linoleic acid is claimed to help reduce obesity but it is ineffective for this use. ECA stack The ECA Stack cannot be marketed in most developed countries but used to be marketed as a weight loss aid; it provided modest short term weight loss but evidence for the long term was lacking. Additionally there was a risk of adverse effects on the cardiovascular, mental, digestive, and nervous systems. Pyruvate Pyruvate, which is found in red apples, cheese, and red wine, is sometimes marketed as a weight loss supplement, but as of 1999 has not been thoroughly studied and its weight loss effect has not been demonstrated. Side effects Some anti-obesity medications can have severe, even, lethal side effects, fen-phen being a famous example. Fen-phen was reported through the FDA to cause abnormal echocardiograms, heart valve problems, and rare valvular diseases. One of, if not the first, to sound alarms was Sir Arthur MacNalty, Chief