The modern medical community has long battled against depression, pouring significant resources into the search for an effective therapy that will provide lasting relief to patients living with painful emotionally and behavioral symptoms. Considerable progress has been made, with antidepressant therapies offering symptom relief for millions of patients every year. However, many patients fail to find complete and durable healing from existing psychotropic therapies, and even those who find their symptoms alleviated may experience intolerable side effects from treatment. Meanwhile, psychotherapeutic modalities present similar variable efficacy and many patients face significant barriers to access. As a result, the quest for better treatment options remains ongoing. Soon, however, patients may have a new option for effectively addressing depression with minimal side effects: berberine.
For nearly 5000 years, berberine, a plant alkaloid, has been used as an anti-inflammatory and antibiotic in Chinese traditional medicine. In the modern era, the medical community has taken an interest in berberine on account of its wide spectrum of biological activity; berberine can modulate neurotransmitter systems in the brain, induce or inhibit liver enzymes, kill bacteria, reduce the rate of cellular metabolism, and help to regulate blood sugar, among many other properties relevant to human health. Due to its ability to affect multiple systems in the brain, researchers have suggested that it could be beneficial in Alzheimer’s disease, schizophrenia, and anxiety. However, initial investigations into berberine and depression have been especially compelling, with preliminary results suggesting that berberine supplements may serve as an impressively effective antidepressant.
Berberine Alleviates Depression Symptoms in Mouse Models
In a 2017 study on berberine therapy in mouse models of depression, berberine appeared to reduce levels of despair as measured by performance on forced swim tests. In these tests, mice are placed into a pool where they cannot escape or stop treading water without starting to drown. Healthy mice will try to escape vigorously until they are exhausted, at which point they revert to treading water until they have recovered enough energy to try vigorously escaping once again. Depressed mice take far more time in between escape attempts when compared to healthy mice. In the study, researchers found that depressed mice took up to 30% longer to recover in comparison to healthy mice and berberine-treated depressed mice. In other words, berberine allowed the depressed mice to maintain the hope of escape to a similar extent that a healthy mouse could.
In an earlier study published in the European Journal of Pharmacology, berberine also had a profound impact on mice induced to exhibit the symptoms of severe depression. Specifically, berberine appeared to alleviate the highly inhibited motor activity associated with catatonic depression to a statistically significant degree. In this study, researchers were able to observe the biochemical impact of berberine on the brain, providing critical insight into its potential therapeutic mechanisms. Following administration of berberine, mice experienced a 31% increase in norepinephrine secretions, a 47% increase in serotonin secretions, and a 31% increase in dopamine secretions across the brain. These effects were durable over the course of 12 days of once-daily berberine treatment, indicating that consistent treatment can lead to persistently elevated neurotransmitter concentrations. It’s important to note that low concentrations of these neurotransmitters in the brain have not been established to be causative of depression; rising concentrations might be a side effect of another mechanism which was responsible for relieving the mice’ symptoms (as is the case with all antidepressant medications). However, a strong correlation between neurotransmitter concentrations and depression does exist, and the results demonstrate that berberine supplementation may be used to modulate neurotransmitter activity.
Multiple Mechanisms of Depression Relief
Berberine likely has a handful of biological mechanisms which make it an effective therapy for depression. Researchers don’t have any concrete answers, but the present evidence suggests that in addition to its ability to modulate neurotransmitters, berberine reduces inflammation in the brain, promotes neuronal growth, and diminishes the damage that depression may cause to organ systems outside the brain. These capabilities are found in other antidepressants and play a critical role in both short-term symptom relief and long-term recovery, but the basic science regarding how they alleviate depression remains elusive. Nonetheless, scientists are trying to clarify the underpinnings of berberine’s multidimensional potential as a therapeutic.
Researchers suspect that berberine causes new neuronal growth by forcing the brain to upregulate its production of certain chemicals. In particular, berberine appears to cause the upregulation of brain-derived neurotrophic factor (BDNF), a protein that prompts neurons to reinforce neuronal connections and also to form new synapses. Depression and stress reduce the production of BDNF, though researchers are uncertain regarding the exact role it plays in the pathology of depression. Nonetheless, by increasing neurons’ production of BDNF, berberine may cause neurons to repair the damage caused by atrophy of neuronal tracts during depression, thus contributing to remission and recovery.
Other research in mouse models of depression induced by chronic and unpredictable mild stress suggests that berberine may decrease inflammation in the brain. Neural inflammation leads to reduced functionality of brain cells, which means that it could also disrupt the brain’s ability to self-regulate and subsequently lead to depression. Thus, controlling inflammation might be a viable method for mitigating depression. To reduce inflammation, berberine appears to interact directly with the immune cells of the brain, forcing them to decrease their secretion of core proinflammatory molecules like tumor necrosis factor alpha (TNFa), interleukin 1 (IL-1), and inducible nitric oxide synthase (iNOS). Once the level of inflammation starts to drop, depression may abate. However, the hypothesized link between inflammation and depression has many gaps independent of any data regarding berberine; researchers don’t believe that inflammation is the only cause of depression, as taking anti-inflammatory medications doesn’t cause symptoms to fade. It is also possible that berberine’s ability to push depression into remission is not solely the result of its direct effect on the brain.
In rat models of depression caused by unpredictable mild stress, researchers found that berberine therapy led to the repair of gut tissue sections which had been damaged as the result of depression. When depressed, the rats lose weight, accumulate damage to their intestinal mucosal lining, withdraw from other rats, move less frequently and with less vigor, and spend less time grooming themselves. While these symptoms do not always map perfectly onto human symptoms of depression, researchers assume that the rats are exhibiting the anorexia, lethargy, and withdrawal which can occur in depressed human patients. By visually comparing dissected sections of the rats’ intestinal tracts, researchers were able to determine that rats that were treated with berberine exhibited fewer traces of recent depression-induced mucosal damage. Furthermore, the rats which were treated with berberine started to regain weight after treatment began, whereas the other depressed rats continued to lose weight and experience more intestinal degradation. In other words, berberine appears to help repair physical damage caused by depression. While it is possible that berberine reduced depressive symptoms via direct neurological mechanisms and simultaneously induced gastrointestinal healing, growing understanding of the gut-brain axis suggests that restoring gastrointestinal health could alleviate psychiatric symptoms due to the complex, reciprocal connection between the gut and the central nervous system. As such, the reversal of gastrointestinal damage may play some role in alleviating depression, even if it is not the central mechanism of berberine’s antidepressant effects. At the very least, it suggests that berberine may offer multiple protective benefits for patients with depression.
The Future of Berberine and Depression Treatment
Researchers are just getting started on berberine. Should scientists ultimately answer these key questions and prove its efficacy in human patients, berberine may become a first-line depression treatment. Given the current flurry of interest into the chemical’s capabilities and its growing availability as a nutraceutical supplement, patients and clinicians probably won’t have to wait much longer.
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