Life Extension Magazine®

In a clinical trial two probiotic strains produced a 50% improvement in depression scores

How probiotics can reduce anxiety and depression

Researchers have discovered a link between poor gut health and depression. In a clinical trial two probiotic strains produced a 50% improvement in depression scores without side effects or medication.

Scientifically reviewed by: Amanda Martin, DC, in January 2024. Written by: Heather L. Makar.

Roughly 25% of adults in the U.S. suffer from anxiety, depression, or both.1

Many find that antidepressant drugs don't work for them, or they discontinue them as a result of side effects.

There's an alternative solution.

A link has been found between gut health and mood disorders.2-5

One trial in healthy human volunteers found that a blend of two probiotics improved median self-rated scores of feelings of depression and anxiety by 50% —without side effects or dependence.6

Another clinical trials showed how a plant extract enabled anti-depressive benefits without side effects.7

These ingredients may provide a safe way to improve mood.

Depression and Anxiety

Depression affects more than 21 million adults in the U.S.8 Rates of anxiety and depression skyrocketed during the pandemic.9

Medication and counseling can help. But two thirds of those taking antidepressants experience side effects,10 including sexual dysfunction, fatigue, weight gain, and insomnia.11

Only a small percentage of people taking antidepressants get a clinically significant response. Because of this, many stop taking them.12

Roughly 60% of those affected by mood disorders are not receiving treatment.13

The Gut-Brain Axis

Probiotics have been shown to provide some relief for symptoms of depression, and perhaps to a lesser extent symptoms of anxiety, in multiple clinical trials.14,15

The likely reason: the gut-brain axis.

Though we think of neurons primarily as brain cells, a network of 200-600 million neurons lines the gastrointestinal tract.16,20

The gut-brain axis is a two-way communication system between the digestive system and the brain.16-19

The gut microbiota is the name for the trillions of bacteria and other microorganisms that live in our digestive tract. The greatest amounts are in the large intestine.

Some of these bacteria produce substances that contribute to immune response. They also alter the synthesis and degradation of neurotransmitters that neurons in the gut use to transmit signals to regions of the brain responsible for mood regulation and learning.5,21,22

Stress and depression may alter gut bacteria and promote secretion of pro-inflammatory cytokines and neurotransmitters.23 These signaling molecules can promote inflammation in the brain, which can worsen symptoms of mood disorders23,24 and cognition.24,25 Some species may even encourage dysregulated eating.26

Probiotics Improve Mental Health

Probiotics are beneficial bacteria that support immune, digestive, and oral health. They also play a vital role in psychological wellbeing.6,16,17,27

The gut contains trillions of bacteria21 with the neural system of the intestine  composed of 200-600 million neurons, cells that receive, process, and transmit information.20 

The gut communicates with the brain through these neurons and the vagus nerve or by modulation of neuroactive compounds produced by the microbiome.21

  • Gut microorganisms can produce/modulate many kinds of neurotransmitters, chemicals that send signals from one neuron to another. They include dopamine, serotonin, and norepinephrine, which are important to regulating mood.21
  • Probiotics have been shown, in a study in healthy individuals, to reduce self-rated scores for depression, anxiety, and stress.28  Another study showed that treatment with Lactobacillus species resulted in lower levels of cortisol, an important stress hormone.27
  • Preclinical evidence has shown that certain intestinal bacteria increase brain levels of BDNF (brain-derived neurotrophic factor), a growth factor known to promote neuron development, survival, and function, and support synapse health.23
  • Stress is one of the factors that plays an integral role in intestinal barrier function, causing "leaky gut" which allows pro-inflammatory molecules to enter the blood, causing dysregulation of the immune system.26 Chronic stress can also change the composition of the microbiome and impact its barrier function.24 That, in turn, can negatively affect mood.26

What You Need To Know

Improve Mood Without Side Effects

  • Millions of Americans suffer from anxiety and depression, but many find prescription antidepressants ineffective, or they don’t like the side effects.
  • Two strains of probiotics, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, stimulate beneficial neuromodulators that travel from the gut to the brain. In a clinical study, they reduced depression and anxiety scores by 50% in healthy individuals.
  • The spice saffron interacts with neurotransmitters in the brain. In clinical studies, it was as effective as multiple antidepressant and anti-anxiety drugs, including Prozac® and Celexa®.
  • A combination of saffron and probiotics can work to relieve depression and anxiety and improve mood, without side effects.

Specific Probiotic Strains

Two strains of probiotic bacteria, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, have been shown in animal models to play a role in beneficially modulating the gut-brain axis6,27,29 by:

  • Maintaining a balance of the microbiome by competitive exclusion of bad gut bacteria (such as clostridium).27  Clostridium bacteria, for example  are known to produce propionic acid that has been associated in other animal studies with anxiety and aggression,30
  • Increasing levels of doublecortin (a protein that helps movement and differentiation of neurons) in the hippocampus (the brain’s memory-processing region). Doublecortin is also a marker for new brain-cell formation in an experimental model of chronic stress. This increase may indicate that the brain is regenerating healthy tissue that can lead to future resilience against stress,29
  • Supporting the hypothalamic-pituitary-adrenal axis balance,
  • Reducing levels of pro-inflammatory cytokines and improving production of anti-inflammatory cytokines,27 and
  • Tightening the “leaky gut” induced by stress.29,31

Success in Human Trials

Human trials of these probiotics have shown impressive results in reducing symptoms of depression and anxiety.

In one clinical trial, healthy participants took either three billion CFUs (colony forming units) of combined Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 or a placebo daily.

After one month, compared to placebo, those who took the probiotics had a:27
  • 50% improvement in depression scores,
  • 49% improvement in global severity index, a measure of overall psychological distress,
  • 60% improvement in anger-hostility scores, and a
  • 13% reduction in free urinary cortisol, a measure of chronic stress.

A follow-up analysis of this study found that the probiotic formula also worked well in improving self-rated anxiety and depression scores in patients who began the study with low stress levels as measured by urinary cortisol.6 As is the case with most probiotics, these were well tolerated with few, if any, side effects.

Anxiety and stress are associated with intestinal disturbances.2

In another trial, participants aged 18-60, with at least two self-reported symptoms of stress, were given either a placebo or the probiotic combination at the same dosage as in the other studies.32

After three weeks the probiotic-treated subjects experienced a complete elimination of stress-induced nausea and vomiting and compared to the placebo group, approximately 8.6 times the reduction in stress-induced abdominal pain, and nearly double the reduction in flatulence and gas.

Once again, the probiotics were found to be safe and did not cause unpleasant side effects.

Saffron Enhances Mood

Saffron has been used in Persian and Chinese medicine to treat depression for centuries.33-35

Preclinical research suggests it may help relieve depression and anxiety as a result of its potential influence on three neurotransmitter-signaling pathways involved in mood regulation in the brain:

  • Dopamine,36 which contributes to feelings of pleasure, learning, and motivation,37
  • Serotonin,38 responsible for a behavior pattern, mood, sleep pattern, anxiety, feelings of comfort, and well-being, and37
  • Norepinephrine,39  responsible for alertness, arousal, decision-making, focus, and attention.37

Effective in Clinical Trials

In a series of human studies, researchers tested 30 mg of saffron head-to-head against common antidepressant drugs, including:

  • Imipramine (Tofranil®),40
  • Fluoxetine (Prozac®),33,41 and
  • Citalopram (Celexa®).42

In each case, saffron was found to be as effective as the drug in treating depression.

Combining the probiotics Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 with an extract of saffron offers a multipronged attack on anxiety and depression and a way to boost mood without side effects.

Summary

The probiotics Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 work through the gut-brain axis to reduce feelings of depression and anxiety.

Saffron extract interacts with neurotransmitters to improve mood and has been shown to work as well as prescription drugs to treat depression.7,43

A combination of these ingredients is not associated with significant side effects and could help people struggling with anxiety and depression.

If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-866-864-3027.

References

  1. Available at: https://ct.counseling.org/2015/07/treating-depression-and-anxiety/. Accessed 04/09/2023,
  2. Available at: https://www.health.harvard.edu/diseases-and-conditions/the-gut-brain-connection. Accessed October 5, 2023.
  3. Available at: https://www.hopkinsmedicine.org/health/wellness-and-prevention/the-brain-gut-connection. Accessed October 9, 2023.
  4. Huang TT, Lai JB, Du YL, et al. Current Understanding of Gut Microbiota in Mood Disorders: An Update of Human Studies. Front Genet. 2019;10:98.
  5. Cox LM, Weiner HL. Microbiota Signaling Pathways that Influence Neurologic Disease. Neurotherapeutics. 2018 2018/01/01;15(1):135-45.
  6. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011 Jul-Aug;2(4):256-61.
  7. Shafiee M, Arekhi S, Omranzadeh A, et al. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-7.
  8. Available at: https://www.nimh.nih.gov/health/statistics/major-depression. Accessed 04/09/2023,
  9. Available at: https://www.who.int/news/item/02-03-2022-covid-19-pandemic-triggers-25-increase-in-prevalence-of-anxiety-and-depression-worldwide. Accessed 04/11/2023,
  10. Available at: https://www.consumerreports.org/cro/2013/09/best-treatments-for-depression/index.htm. Accessed 04/09/2023,
  11. Available at: https://www.health.harvard.edu/newsletter_article/what-are-the-real-risks-of-antidepressants. Accessed October 4, 2023.
  12. Taliaz D, Spinrad A, Barzilay R, et al. Optimizing prediction of response to antidepressant medications using machine learning and integrated genetic, clinical, and demographic data. Translational Psychiatry. 2021 2021/07/08;11(1):381.
  13. Available at: https://mhanational.org/issues/state-mental-health-america. Accessed October 4, 2023.
  14. Chao L, Liu C, Sutthawongwadee S, et al. Effects of Probiotics on Depressive or Anxiety Variables in Healthy Participants Under Stress Conditions or With a Depressive or Anxiety Diagnosis: A Meta-Analysis of Randomized Controlled Trials. Front Neurol. 2020 2020-May-22;11:421.
  15. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019 Jul;102:13-23.
  16. Liu L, Zhu G. Gut-Brain Axis and Mood Disorder. Front Psychiatry. 2018;9:223.
  17. Rieder R, Wisniewski PJ, Alderman BL, et al. Microbes and mental health: A review. Brain Behav Immun. 2017 Nov;66:9-17.
  18. Kelly JR, Minuto C, Cryan JF, et al. Cross Talk: The Microbiota and Neurodevelopmental Disorders. Front Neurosci. 2017;11:490.
  19. Clark A, Mach N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes. J Int Soc Sports Nutr. 2016;13:43.
  20. Furness JB, Callaghan BP, Rivera LR, et al. The enteric nervous system and gastrointestinal innervation:
  21. Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018 Aug 15;1693(Pt B):128-33.
  22. Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014 Aug;11(8):506-14.
  23. Clapp M, Aurora N, Herrera L, et al. Gut microbiota's effect on mental health: The gut-brain axis. Clin Pract. 2017 Sep 15;7(4):987.
  24. Yarandi SS, Peterson DA, Treisman GJ, et al. Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases. J Neurogastroenterol Motil. 2016 Apr 30;22(2):201-12.
  25. Ge L, Liu S, Li S, et al. Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut-brain communications. Front Immunol. 2022;13:1016578.
  26. Madison A, Kiecolt-Glaser JK. Stress, depression, diet, and the gut microbiota: human-bacteria interactions at the core of psychoneuroimmunology and nutrition. Curr Opin Behav Sci. 2019 Aug;28:105-10.
  27. Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011 Mar;105(5):755-64.
  28. Mohammadi AA, Jazayeri S, Khosravi-Darani K, et al. The effects of probiotics on mental health and hypothalamic-pituitary-adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers. Nutr Neurosci. 2016 Nov;19(9):387-95.
  29. Ait-Belgnaoui A, Colom A, Braniste V, et al. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol Motil. 2014 Apr;26(4):510-20.
  30. Rao AV, Bested AC, Beaulne TM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009 Mar 19;1(1):6.
  31. Arseneault-Breard J, Rondeau I, Gilbert K, et al. Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model. Br J Nutr. 2012 Jun;107(12):1793-9.
  32. Diop L, Guillou S, Durand H. Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res. 2008 Jan;28(1):1-5.
  33. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005 Feb 28;97(2):281-4.
  34. Cardone L, Castronuovo D, Perniola M, et al. Saffron (Crocus sativus L.), the king of spices: An overview. Scientia Horticulturae. 2020 2020/10/15/;272:109560.
  35. Wenger T. History of saffron. Longhua Chinese Medicine. 2022;5.
  36. Khazdair MR, Boskabady MH, Hosseini M, et al. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015Sep-Oct;5(5):376-91.
  37. Available at: https://my.clevelandclinic.org/health/articles/22513-neurotransmitters. Accessed October 5, 2023.
  38. Hausenblas HA, Heekin K, Mutchie HL, et al. A systematic review of randomized controlled trials examining the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes. J Integr Med. 2015 Jul;13(4):231-40.
  39. Jelodar G, Javid Z, Sahraian A, et al. Saffron improved depression and reduced homocysteine level in patients with major depression: A Randomized, double-blind study. Avicenna J Phytomed. 2018 Jan-Feb;8(1):43-50.
  40. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med. 2004 Sep 2;4:12.
  41. Sahraian A, Jelodar S, Javid Z, et al. Study the effects of saffron on depression and lipid profiles: A double blind comparative study. Asian J Psychiatr. 2016 Aug;22:174-6.
  42. Ghajar A, Neishabouri SM, Velayati N, et al. Crocus sativus L. versus Citalopram in the Treatment of Major Depressive Disorder with Anxious Distress: A Double-Blind, Controlled Clinical Trial. Pharmacopsychiatry. 2017 Jul;50(4):152-60.
  43. Ashktorab H, Soleimani A, Singh G, et al. Saffron: The Golden Spice with Therapeutic Properties on Digestive Diseases. Nutrients. 2019 Apr 26;11(5).