Anxiety & Depression
The Role of Inflammation
Evidence suggests that chronic inflammation may play a significant role in both conditions.
Studies have observed increased levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in individuals with depression and anxiety compared to healthy controls (Slattery et al., 2020; Miller et al., 2020). This suggests an ongoing inflammatory response might be contributing to their symptoms.
Scroll down to read about the research showing how the ingredients in our formula help Anxiety & Depression.
About Chronic Inflammation
Inflammation is a natural response of the immune system to fight infections and injuries. However, when inflammation becomes chronic or excessive, it can cause damage to the tissues and organs. Inflammation is involved in the development and progression of both types of diabetes, as well as their complications.
Mechanisms of Action
- Neurotransmitter Imbalance: Inflammation can disrupt the production and function of key brain chemicals like serotonin and dopamine, leading to mood imbalances and depression (Muller et al., 2013).
- Hormonal Disruption: Chronic inflammation can impact stress and sex hormone levels (cortisol, estrogen), playing a role in mood and cognitive function (Haroon et al., 2018).
- Brain Changes: Inflammation can damage brain cells and structures, affecting areas crucial for emotional regulation and mood stability (Miller et al., 2020).
- Gut-Brain Axis: The gut microbiome, which interacts with the immune system and brain, might play a role in mediating the influence of inflammation on mental health (Cryan & O’Mahony, 2011).
Mood Disorders & Inflammation
- Atypical Depression (AD): A 2017 study (Łojko et al., 2017) suggests that Inflammation appears to be more severe in people with major depressive disorder with atypical features compared to non-AD and healthy individuals.
- Major Depressive Disorder (MDD): In MDD there’s evidence of hormonal changes, increased pro-inflammatory cytokines in the bloodstream, and markers of oxidative stress.
- Bipolar Disorder: Benedetti et al., concluded that “Recent works have thoroughly supported the association between BD and a proinflammatory state which involves both the innate and the adaptive immune system.”
Wu et al., found that relationship between which inflammatory processes and markers are higher or lower and bipolar disorder are dependent on the state (manic or depressive). In their words, “in BDD, immune-inhibition is persistently predominant, while in mild-to-moderate BDM, immune system is activated but inhibited in severe BDM. The dynamic change of serum inflammatory markers suggests that alteration of peripheral inflammatory markers in BD is state-dependent instead of trait-marked.”
Sırlıer et al., found that there is correlation between the level of inflammation and the level of criminal activity of individuals with bipolar disorder (Sırlıer, 2023).
- Seasonal Affective Disorder (SAD): A 2015 study (Song et al., 2015) found that people with SAD showed increased inflammatory responses compared to healthy subjects. Light therapy improved both immune function and depressive symptoms in these individuals.
- Postpartum Depression: Bränn suggests that women with postpartum depression have elevated levels of certain inflammatory biomarkers.
References
- Neurotransmitter Imbalance: Inflammation can disrupt the production and function of key brain chemicals like serotonin and dopamine, leading to mood imbalances and depression (Muller et al., 2013).
- Hormonal Disruption: Chronic inflammation can impact stress and sex hormone levels (cortisol, estrogen), playing a role in mood and cognitive function (Haroon et al., 2018).
- Brain Changes: Inflammation can damage brain cells and structures, affecting areas crucial for emotional regulation and mood stability (Miller et al., 2020).
- Gut-Brain Axis: The gut microbiome, which interacts with the immune system and brain, might play a role in mediating the influence of inflammation on mental health (Cryan & O’Mahony, 2011).
Ingredients: the Sciene
1. Apigenin
A systematic review of the therapeutic role of apigenin in depression was conducted to evaluate the effects of apigenin on patients with depression. The review found that apigenin supplementation reduced depressive-like behavior and oxidative stress biomarkers such as reduced glutathione, lipid peroxidation, total antioxidant power, and coenzyme Q10 levels in depressed animals.
A recent study from 2023 on 40 male rats shows that treating the animals with API reversed anhedonia, reduced anxiety and immobility time in behavioral studies; reduced brain corticosterone and MDA levels but increased brain levels of glutathione and superoxide dismutase.
Safety: Regarding toxicity, the review recognized 20 mg/kg of apigenin as the dose suitable for minimizing the undesirable adverse effects in the STZ-mediated depression.
2. Berberine
A study from 2021 tests whether BBR ameliorates anxiety by modulating intestinal microbiota under estrogen-deficient conditions. Experimental anxiety was established in specific pathogen-free (SPF) ovariectomized (OVX) rats, which were then treated with BBR for 4 weeks before undergoing behavioral tests. Open field and elevated plus maze tests demonstrated that BBR treatment significantly ameliorated anxiety-like behaviors of OVX rats compared with vehicle-treated counterparts.
Another study tested the anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: Interaction with drugs acting at 5-HT receptors. These results suggested that berberine at 100 mg/kg had a significant anxiolytic-like effect, which was similar to that observed with 1 mg/kg diazepam and 2 mg/kg buspirone. The anxiolytic mechanism of BER might be related to the increase in turnover rates of monoamines in the brain stem and decreased serotonergic system activity.
Safety: Regarding toxicity, a review of the biological activity of berberine found that it exerts a protective effect on the central nervous system, which makes it a promising agent in disorders such as Alzheimer’s disease, cerebral ischemia, mental depression, anxiety and schizophrenia 2. However, the safety of berberine supplements has not been established. Taking high doses of berberine can lead to adverse effects such as gastrointestinal problems, liver damage, and drug interactions.
3. B Vitamins
A 2019 systematic review and meta-analysis of B vitamin supplementation on depressive symptoms, anxiety, and stress was conducted to examine and quantify the effects of B vitamin supplementation on mood in both healthy and ‘at-risk’ populations. The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress.
A cross-sectional, population-based survey that includes 7387 adults from 2021 found that a higher intake of dietary B vitamins, especially biotin (B7), was associated with a lower prevalence of depression, anxiety, and stress symptoms.
A double-blind study (2021) investigated the effects of supplementation for 1 month with a high-dose of B6 or B12, compared to placebo found that Vitamin B6 supplementation reduced self-reported anxiety and induced a trend towards reduced depression, as well as increased surround suppression of visual contrast detection, but did not reliably influence the other outcome measures. Vitamin B12 supplementation produced trends towards changes in anxiety and visual processing.
Safety: The National Institutes of Health states that the B vitamins are water-soluble, which means that the body excretes what it does not absorb. Therefore, it is unlikely that someone would consume too much of these vitamins through food alone. However, taking high doses of supplements can lead to adverse effects.
B9 - folic acid – folate
A systematic review of the therapeutic role of folic acid (B9) in depression was conducted to evaluate the effects of folic acid on patients with depression. The review found that folic acid supplementation reduced Hamilton Anxiety Rating Scale (HAM) scores in all subgroups.
A systematic review from 2022 identified 23 studies of folate supplements in various psychiatric disorders for critical review. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated.
A 2009 review coauthored by Mischoulon showed methyl folate supplementation to be effective as an adjunctive therapy with psychotropic drugs or as a stand-alone treatment for both men and women in: reducing depressive symptoms in people with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly people with folate deficiency, and reducing depressive and other symptoms in people with depression and alcoholism.
Safety: Clinical studies in humans also demonstrated that individuals taking levomefolic acid 400–500 μg orally for 24 weeks or 15 mg orally daily for 12 months or 1 month therapy orally followed by 2 months withdrawal for 24 months reported no difference in adverse effects compared with the placebo group [73], [133], [134], [135]. Based on the results of the above studies, levomefolic acid appears to be safe and well tolerated with minimal side effects in humans.
4. CBD
A systematic review of the therapeutic role of Cannabidiol (CBD) in mental health (2020) was conducted to summarize the clinical outcomes, study designs, and limitations for the use of CBD and nabiximols in the treatment of psychiatric disorders 1. The review found that CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate recommendation.
A meta-analysis by Nutrition Formulators (2021) found that there has been a great wealth of evidence to support the use of CBD for anxiety and stress in the last two years.
A two-year CBD research review (2020) shows significant positive impact on anxiety and stress. In a review of 76 articles spanning the past two years, more than 70% of cannabidiol (CBD) research on anxiety and stress showed positive outcomes. The analysis also showed a 66.6% positive improvement for clinicians using CBD as an alternative treatment for depression.
Safety: 2017 review of research Trusted Source showed that humans can safely tolerate up to 1,500 mg per day. For reference, typical 1-ounce bottles of CBD oil contain from 300 to 1,500 mg.
- i. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-019-0012-y
- ii. https://www.nutraingredients.com/Article/2021/02/04/Meta-analysis-spotlights-CBD-s-stress-relief-capacity
- iii. https://newsroom.mandccommunications.com/two-year-cbd-research-review-shows-significant-positive-impact-on-anxiety-and-stress
- iv. https://newsroom.mandccommunications.com/two-year-cbd-research-review-shows-significant-positive-impact-on-anxiety-and-stress
5. Chamomile
A systematic review and meta-analysis of randomized trials and quasi-randomized trials was conducted to evaluate the therapeutic efficacy and safety of chamomile for state anxiety, generalized anxiety disorder, insomnia, and sleep quality. The review found that chamomile was effective in reducing state anxiety and improving sleep quality, but not for generalized anxiety disorder or insomnia.
Another systematic review and meta-analysis from 2019 chamomile for the treatment of state anxiety, generalized anxiety disorders (GADs), sleep quality, and insomnia in humans. By using HAM-A scale, there was a significant improvement in GAD after 2 and 4 weeks of treatment and showed a significant improvement in sleep quality after chamomile administration.
A narrative review on the potential therapeutic benefits of chamomile in the acute care setting (2017) found that chamomile may be a promising herbal treatment for anxiety, depression, sleep quality, gastrointestinal dysfunction, diarrhea, colic, pain management, nausea, vomiting, and diabetes among hospitalized and postoperative patients.
Safety: Regarding toxicity, all those reviews found that chamomile is generally safe and well-tolerated, with no serious adverse events reported.
6. Curcumin
A meta-analysis from 2019, total of 9 articles found an overall significant effect of curcumin on depressive and anxiety symptoms with large effect size. Curcumin was well-tolerated by patients. Our findings suggest that curcumin, if added to standard care, might improve depressive and anxiety symptoms in people with depression.
Clinical Use of Curcumin in Depression: A Meta-Analysis from 2017 includes Six clinical trials with a total of 377 patients reviewed, comparing the use of curcumin to placebo. In patients with depression, the pooled standardized mean difference from baseline Hamilton Rating Scale for Depression scores supports the significant clinical efficacy of curcumin in ameliorating depressive symptoms. Significant anti-anxiety effects were also reported in 3 of the trials. Notably, no adverse events were reported in any of the trials.
A Narrative Review (2020) check Potential Mechanisms of Action and Current Evidence of the effect
Of curcumin on depression. The result shows that curcumin could embody the dawn of Nutriceuticals as anti-inflammatory and antioxidant components appear to be a possible alternative in the treatment of depression. As curcumin displays neuroprotective effects, especially against stress-induced toxicity, it also suggests the use of such molecules as prophylactic agents.
Safety: A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe.
7. Kava
The Efficacy of kava extract for treating anxiety test in this systematic review and meta-analysis from 2000. Superiority of kava extract over placebo was suggested by all seven reviewed trials. The meta-analysis of three trials suggests a significant difference in the reduction of the total score on the Hamilton Rating Scale for Anxiety in favor of kava extract.
A meta‐analysis 2003 was done on seven studies using the total score on the Hamilton Anxiety (HAM‐A) scale as a common outcome measure. The result suggests a significant effect towards a reduction of the HAM‐A total score in patients receiving kava extract compared with patients receiving placebo.
A systematic review and analysis of randomized clinical trials (2018) test the effectiveness and safety of Kava Kava for treating anxiety symptoms. Results point to Kava Kava as an all-around treatment for anxiety relief.
Safety: kava is generally well-tolerated and safe, but it can cause some side effects, such as headache, dizziness, gastrointestinal discomfort, and skin reactions. Kava can also interact with some medications, such as sedatives, antidepressants, and anticoagulants.
8. Lavender
Lavender is a plant metabolite that has been used for centuries for its calming and soothing effects. It can be taken orally, inhaled, or applied to the skin.
Several meta-analyses and systematic reviews have found evidence that lavender, especially in the form of Silexan, a proprietary extract, can reduce anxiety levels in various conditions, such as subthreshold anxiety, generalized anxiety disorder, and mixed anxiety and depressive disorder. Lavender can also improve health-related quality of life and sleep quality in anxiety patients.
A Systematic Review and Meta-Analysis from 2021 showed that Lavender was superior to placebo or no treatment in reducing anxiety, depression, and systolic blood pressure.
A systematic review and network meta-analysis (2020), results of 32 studies include in quantitative analysis show that Silexan (oral lavender) 80 mg as the favorable option for anxiety in long-term treatment.
clinical data and pharmacological background of seven clinical trials are included, of which five had a treatment duration of 6 or 10 weeks. The results show that patients with subthreshold (subsyndromal) anxiety or generalized anxiety disorder (GAD), an anxiolytic effect of Silexan was evident after 2 weeks. HAM-A total score reductions between baseline and end of treatment were significantly superior to placebo in patients with subthreshold anxiety and comparable with those achieved under lorazepam or paroxetine in patients with GAD. In addition, Silexan had beneficial effects on typical concomitant symptoms of anxiety disorders, such as impaired sleep, somatic complaints, co-morbid depression, or decreased quality of life.
Safety: Lavender is well-tolerated and safe, but it can cause some side effects, such as nausea, vomiting, constipation, headache, and skin irritation.
9. Lemon Balm (Melissa)
Lemon balm (Melissa officinalis L.) is a medicinal herb that has been used for centuries for its calming and soothing effects. A systematic review and meta-analytic approach were considered to investigate the effects of lemon balm on anxiety and depression in clinical trials and its side effects 1. The review found that lemon balm significantly improved mean anxiety and depression scores compared with the placebo, without serious side effects.
A systematic review and meta-analysis from 2021 were searched in 12 online databases. Based on meta-analysis results, lemon balm significantly improved mean anxiety and depression scores compared with the placebo, respectively, without serious side effects. Current evidence suggests that lemon balm may be effective in improving anxiety and depressive symptoms, particularly in the acute setting.
A recent randomized double-blinded placebo-controlled clinical trial (2023) Sixty participants received M. officinalis extract or placebo, of which 44 patients completed the 12-week double-blind clinical trial. After 12-week the mean change of depression and anxiety scores were statistically significant between the two groups.
Safety: lemon balm is generally well-tolerated and safe, but it can cause some side effects, such as nausea, vomiting, constipation, headache, and skin irritation.
10. L-Theanine
L-theanine is an amino acid found in green tea that has been associated with several health benefits, including improvement in mood, cognition, and a reduction of stress and anxiety-like symptoms.
A systematic review and meta-analysis of randomized controlled trials evaluated the effect of pure L-theanine intake, in the form of orally administered nutritional supplements, on stress responses and anxiety levels in human randomized controlled trials. The review found that supplementation of 200–400 mg/day of L-theanine may assist in the reduction of stress and anxiety in people exposed to stressful conditions. A systematic review of Five RCTs with L-THE (200-400 mg/day; up to 8 weeks) in a total of 104 participants met the inclusion criteria. The findings in four studies indicated significant improvements in reducing stress and anxiety.
Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial ( 2019) found that Stress-related symptom (i.e., depression, anxiety-trait, and sleep) scores decreased and cognitive function (i.e., verbal fluency and executive function) scores improved after four weeks of L-theanine administration. The reduction in sleep quality problems (disturbances in sleep latency, sleep disturbance, and use of sleep medication) was greater in the L-theanine administration compared to the placebo administration, while verbal fluency, especially letter fluency, was improved in the L-theanine administration among individuals who showed relatively low performance at pretreatment.
Safety: L-theanine is generally safe and well-tolerated, with no serious adverse events reported.
11. L-tryptophan
A systematic review, meta-analysis, and meta-regression from 2022 test the impact of tryptophan supplementation on sleep quality. Results from the study suggested that L-tryptophan supplementation can shorten wake after sleep onset.
A systematic review of the effect of L-tryptophan supplementation on mood and emotional functioning showed the effects of tryptophan intake on negative feelings and happy feelings in healthy individuals, with significant differences between the treatment and the control groups. This suggests that TRP intake may be an effective approach to decrease anxiety and increase positive mood in healthy individuals. Reviewing these 11 RCTs, we concluded that taking 0.14-3 g of TRP per day in addition to the usual meal can be expected to improve the mood of healthy individuals.
A meta-analysis of the kynurenine pathway aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs.
Safety: Regarding toxicity, L-tryptophan is generally safe and well-tolerated, with no serious adverse events reported.
12. Magnesium
L-Magnesium is a mineral that plays a crucial role in the human body, including the regulation of mood, sleep, and anxiety. A systematic review and meta-analysis (2017) of randomized controlled trials examined the effects of magnesium supplementation on subjective anxiety and stress. The review found that magnesium supplementation may assist in the reduction of stress and anxiety in people exposed to stressful conditions.
A systematic review and meta-analysis of randomized clinical trials (2023) test the effects of Magnesium supplementation on adults with depressive disorder. The findings from the meta-analysis showed a significant decline in depression scores due to intervention with magnesium supplements.
A Systematic Review from 2017 checks The Effects of Magnesium Supplementation on Subjective Anxiety and Stress. Conclusions: Existing evidence is suggestive of a beneficial effect of Mg on subjective anxiety in anxiety vulnerable samples.
Safety: magnesium is generally safe and well-tolerated, with no serious adverse events reported. However, taking high doses of magnesium supplements can lead to adverse effects such as diarrhea, nausea, and abdominal cramping.
13. Omega-3
A 2023 systematic review and meta-analysis of randomized controlled trials checked the Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults. Random-effects meta-analysis of ten RCTs comprising 1426 participants revealed statistically significant reduction in depression severity with EPA-enriched interventions at proportions ≥ 60% of total EPA + DHA and EPA.
A meta- analysis of randomized controlled trials (2017) that compared omega-3 fatty acids to placebo for short-course treatment of depression in pregnant women. The results showed that the omega-3 fatty acids as monotherapy produced better efficacy than placebo with standardized difference.
A recent study (2023) tests the effect of omega-3 fatty acids among those who experienced frequent social stress. Among those who were overweight or obese, both doses of omega-3 reduced depressive symptoms only in the context of frequent hostile interactions and social tension, and 2.5 g/d of omega-3 lowered depressive symptoms among those with less social recognition or more performance pressure.
Safety: omega-3 PUFAs are generally safe and well-tolerated, with no serious adverse events reported. However, taking high doses of omega-3 supplements can lead to adverse effects such as diarrhea, nausea, and abdominal cramping.
14. Passion Flower
A systematic review included nine clinical trials (2020) describing the effects of Passiflora incarnata in neuropsychiatric disorders. The majority of studies reported reduced anxiety levels following the administration of Passiflora incarnata preparations, with the effect less evident in people with mild anxiety symptoms. No adverse effects, including memory loss or collapse of psychometric functions, were observed. Conclusion: Passiflora incarnata may be helpful in treating some symptoms in neuropsychiatric patients.
One more systematic review from 2013 checks the Passiflora incarnata L.: Ethnopharmacology, clinical application, safety, and evaluation of clinical trials. This medicinal plant has shown a wide spectrum of pharmacological activities in preclinical experiments, including anxiolytic, sedative, antitussive, anti-asthmatic, and antidiabetic activities.
A study (2017) tests the improvement of Stress Resistance and Quality of Life of adults with Nervous Restlessness after Treatment with a Passionflower Dry Extract. After 12 weeks of treatment the passionflower extract appears to be effective in improving resilience and QoL in patient’s suffering from nervous restlessness and is well tolerated.
Safety: The plant has a good safety profile. Passionflower is well-tolerated and safe, but it can cause some side effects, such as nausea, vomiting, constipation, headache, and skin irritation.
15. Quercetin
A Comprehensive Review and Update (2022) of antidepressant Potential of Quercetin and its glycoside derivatives have been demonstrated by a large number of studies, and the related mechanisms have been continuously explored. After improving the studies regarding relevant mechanisms and safety, drugs based on quercetin and its glycoside derivatives can become the main components during depression treatment.
A Literature-Based Review from 2022 on Neuropharmacological Effects of Quercetin . To conclude, QUR serves as an effective therapeutic agent against various neurological disorders by reducing stress, inflammatory response and fostering brain growth. The overall analysis highlights the various neuroprotection aspects of QUR. Therefore, QUR can be considered as a strong dietary supplement with minimal toxicity as part of plant matrices.
Safety: regarding toxicity, Quercetin is generally safe and well-tolerated, with no serious adverse events reported. However, taking high doses of Quercetin supplements can lead to adverse effects such as gastrointestinal problems, liver damage, and drug interactions.
16. Valerian
Valerian (Valeriana officinalis L.) is a popular herbal medicine used as a sleep aid.
A systematic review and meta-analysis of randomized clinical trials found that valerian significantly improved mean anxiety and depression scores compared with the placebo, without serious side effects
A Randomized, Double-Blind, Placebo-Controlled, Clinical Study from October 2023 prove that valerian supplementation significantly improved various subjective and objective parameters of sleep-in young subjects with mild insomnia symptoms, such as overall sleep quality, sleep latency, sleep efficiency, and total sleep time. We also observed decreased anxiety and daytime sleepiness, and improved feeling of being refreshed after waking up with VE supplementation. VE was found to be safe and well tolerated throughout the study.
A Randomized, Double-blind, Crossover Clinical Trial (2021) sought to determine the effects of valerian on sleep quality,depression, and state anxiety in hemodialysis (HD) patients. The results showed that Valerian significantly improved sleep quality, the symptoms of state anxiety, and depression in HD patients.
Safety: valerian is well-tolerated and safe, but it can cause some side effects, such as headache, dizziness, gastrointestinal discomfort, and skin reactions. Valerian can also interact with some medications, such as sedatives, antidepressants, and anticoagulants.
17. Ziziphus Jujuba
Ziziphus Jujuba, also known as Chinese date, is a fruit that has been used in traditional medicine for its anxiolytic and hypnotic properties. A recent meta-analysis of 11 randomized controlled trials found that Ziziphus Jujuba supplementation significantly improved anxiety symptoms in adults.
Another systematic review of 12 studies concluded that Ziziphus Jujube supplementation could improve sleep quality and reduce anxiety.
A Review of Dietary Ziziphus jujuba Fruit (Jujube) from 2017 found that Jujube possesses neuroprotective activities, including protecting neuronal cells against neurotoxin stress, stimulating neuronal differentiation, increasing expression of neurotrophic factors, and promoting memory and learning. Flavonoid, cAMP, and jujuboside could be the potential bioactive ingredients to account for the aforesaid biological activities. These findings imply that jujube is a potential candidate for development of health supplements for prevention and/or treatment of neurological diseases.
A System Biology Study from 2020 that checks the Regulation of GABAA and 5-HT Receptors Involved in Anxiolytic Mechanisms of Jujube Seed. The findings suggest that anxiolytic mechanisms of SZJ mostly involve the regulation of GABAergic and serotonergic synapse pathways. The current results provide potential direction for future investigation of SZJ as an anxiolytic agent.
Safety: Ziziphus Jujubea is generally considered safe for consumption. However, some studies have reported mild side effects such as diarrhea, nausea, and abdominal pain.