A Potentially Lethal Combination
By Chris D. Meletis, ND

Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants in the world. Often, however, individuals taking SSRIs for depression also suffer from one or more painful conditions, such as arthritis, sports injuries, back problems, and headaches. To alleviate pain, a person on an SSRI will commonly reach for a class of analgesic drugs known as NSAIDs (ibuprofen, naproxen, aspirin etc.). Research is beginning to indicate, however, that combining these two classes of drugs could prove to be a lethal mistake as the risk of gastrointestinal bleeding is now thought to be increased in SSRI users who also take NSAIDs. Furthermore, emerging science indicates that the combination of SSRIs and even low-dose aspirin also can elevate the risk of GI bleeding, sobering news for people taking both SSRIs and an aspirin a day to reduce the risk of heart attacks.

Eight analgesic preparations with approved indications for acute pain were among the top 200 drugs prescribed in the United States in 2006. Additionally, an estimated 36 million Americans use over-the-counter analgesics daily. Most people are aware that the over-the-counter analgesics known as NSAIDs can cause gastrointestinal bleeding when taken alone. But it’s less commonly known that when NSAIDs are combined with SSRIs, it increases the SSRI’s tendency to promote bleeding in the gut. Because aspirin is often promoted as a safer alternative to the rest of the NSAIDs family, many people taking SSRIs with aspirin probably don’t realize they are putting themselves at additional risk.

Gastrointestinal Bleeding

Gastrointestinal bleeding can originate in the gastrointestinal tract, anywhere from the mouth to the anus. Bleeding can be microscopic, where the amount of blood is so small that only lab testing can detect it, or it can be acute, massive, and life threatening. Prolonged microscopic bleeding can cause loss of iron and anemia. Acute, massive bleeding can result in diminished blood volume (hypovolemia), shock, and death.
Bleeding in this area in the body is referred to as either upper GI bleeding, which occurs in the upper gastrointestinal tract between the mouth and outflow tract of the stomach, or lower GI bleeding, which occurs in the lower GI tract from the outflow tract of the stomach to the small and large bowels to the anus.

Certain individuals are at higher risk of suffering from gastrointestinal bleeding, including the elderly and people who have hemorrhoids, duodenal and gastric ulcers, ulcerative colitis, Crohn’s disease, esophageal varices, esophagitis, intestinal polyps and tumors, celiac sprue, intestinal vasculitis, cow’s milk allergy, and anal fissures.
Gastrointestinal bleeding is a common clinical presentation increasing in an aging population, frequently requiring hospitalization, with significant morbidity, mortality, and costs.

Symptoms of GI Bleeding

GI bleeding is internal and doesn’t always manifest in an obvious manner, so people who experience GI bleeding can be pain free. Therefore, recognizing the symptoms is important. Depending on whether the source of the bleeding is in the upper or lower digestive tract, the symptoms vary. If the upper GI tract is affected, the symptoms can include vomiting bright red blood, vomiting dark clots or coffee ground-like material, or passing black, tar like stool. When bleeding occurs in the lower GI tract, symptoms can manifest as passing pure blood or bright red or maroon blood mixed in stool.
Microscopic bleeding often does not present with these obvious symptoms and therefore can go unnoticed, slowly eroding away ones foundation of health.

How SSRIs Disrupt the Digestive Tract

Normally, when serotonin from blood platelets is released it augments platelet aggregation, the process where blood cells clump together to prevent bleeding. Evidence suggests that SSRI antidepressants may inhibit uptake and storage of serotonin by platelets. When serotonin uptake is reduced in blood platelets, platelet aggregation also is reduced, which may predispose patients to bleeding.1
Other researchers have proposed that SSRIs may increase gastrointestinal bleeding due to an increase in capillary fragility after taking the drugs.2

SSRIs Plus NSAIDs = Double Disaster

Researchers have obtained mixed results when studying whether SSRIs alone increase the risk of gastrointestinal bleeding. However, compelling and consistent evidence exists to show that when SSRIs are combined with the analgesic pain relievers known as NSAIDs (ibuprofen, Naproxen, etc.) including low-dose aspirin, it substantially increases the risk of GI bleeding. In one of the most comprehensive studies on this subject, published earlier this year, researchers conducted an analysis of the medical literature to determine whether there is an interaction between SSRIs and NSAIDs. Four studies involving 153,000 patients met their criteria for inclusion in the review. After studying the medical literature, they concluded that the risk of developing upper gastrointestinal bleeding increased significantly in SSRI users who also took NSAIDs. In subjects more than 50 years old with no risk factors of upper gastrointestinal bleeding, the subjects needed to take 411 SSRIs per year to experience bleeding, but only 106 SSRIs per year were needed to experience GI bleeding when NSAIDs were used concomitantly with the SSRIs. Analysis of further reports showed that upper gastrointestinal bleeding occurred after a median of 25 weeks on SSRIs and that 67 percent of these patients experiencing bleeding also were on NSAIDs.3

A recent study on SSRIs and bleeding indicates the increased risk of gastrointestinal harm may expand beyond NSAIDs to other classes of drugs such as corticosteroids, which are commonly used by rheumatoid arthritis patients. Researchers studied 1,321 subjects with upper GI bleeding and compared them with 10,000 control patients with no GI bleeding.

The results indicated that 5.3 percent of the subjects who had GI bleeding were taking SSRIs, compared to only 3 percent of the controls, an increased risk of 60 percent. There was an almost fivefold increased risk of GI bleeding among users of SSRIs also using corticosteroids. Among those taking NSAIDs and SSRIs, there was a ninefold increased risk of gastrointestinal bleeding.4

Upper GI Tract Lower GI Tract Microscopic Bleeding
Vomiting bright read blood, vomitind dark clots or coffe fround-like material, or passing black, tar like stool. Passing pure blood or bright red or maroon blood mixed in stool Often has no symptoms, but can lower iron levels and destroy health over time.

Other studies have found that even low-dose aspirin, when combined with SSRIs, can increase the risk of bleeding, although the risk is slightly less than with other NSAIDs.5

Safe Pain Support

Individuals on SSRIs who want to manage pain without increasing risk of Gl bleeding can engage in a two-step approach that includes both 1) strengthening the gastrointestinal tract to repair the damage already done by antidepressants plus NSAIDs or corticosteroids and 2) using natural substances to alleviate pain.
First, to strengthen GI health, consuming GI Cell Support, which contains glutamine, deglycyrrhizinated licorice (DGL), N-acetyl glucosamine, marshmallow, berberine, cabbage, slippery elm, phosphatidylcholine, and gamma oryzanol can be critical in nourishing the GI tract.

Glutamine is essential for maintaining intestinal structure and serves as metabolic fuel for enterocytes that line the colon and affect cell proliferation.6-7 DGL licorice is of particular interest to those concerned about GI bleeding since most of the research on DGL has focused on upper GI health, including ulcer healing.8-9 Another nutrient relevant to GI health is N-acetyl glucosamine, important in inflammatory bowel disease (IBD) when N-acetylation of glucosamine is relatively deficient, possibly reducing the synthesis of the gastric and intestinal mucosa’s protective glycoprotein cover.10

Other nutrients that can protect the GI tract include 1) Marshmallow leaf and root, which supports colon health by soothing and protecting mucous membranes from local irritation,11 2) Berberine, which helps control inflammation by selectively inhibiting cyclooxygenase (COX)-2 expression and blocking proinflammatory cytokines,12 3) Cabbage, which has significantly reduced the healing time in peptic ulcer patients,13 4) Slippery elm, which stimulates mucous secretion that coats and protects the delicate lining of the intestines from ulcers and ingested irritants,14 5) Phosphatidylcholine, which has been shown to support the health of ulcerative colitis patients and reduce their dependence on corticosteroids,15 and 6) gamma oryzanol, which inhibits excess gastric acid secretion.16

After using GI Cell Support to strengthen GI health, the next step for SSRI users is to alleviate pain without increasing the risk of GI bleeding. One of the most effective natural approaches involves using a formula called EnFlex™ that contains the amino acid DL-phenylalanine, the botanicals turmeric and Boswellia serrata, and the proteolytic enzyme nattokinase, which work synergistically specifically to inhibit pain.

A number of compounds have been shown to inhibit the break down of enkephalins, which are the body’s natural opioid pain reducers. DL-Phenylalanine, one of these enkephalinase inhibitors, may be effective in a number of human “endorphin deficiency diseases” such as depression and arthritis. It has been used successfully for the management of chronic pain in humans.17-18 DL-Phenylalanine works synergistically with turmeric, a botanical with known anti-inflammatory activity.19 Turmeric has profoundly inhibited joint inflammation and joint destruction in a dose-dependent manner in animal models of rheumatoid arthritis.20

Two other substances used clinically to enhance the effects of DL-P henylalanine and turmeric are Boswellia serrata and nattokinase. Boswellia serrata is a traditional herb with reported anti-inflammatory and analgesic activity. In a randomized, double-blind, placebo-controlled crossover study in 30 patients with osteoarthritis of the knee, Boswellia serrata extract or placebo was given for 8 weeks. All the patients receiving Boswellia supplementation reported a decrease in knee pain and frequency of swelling, and an increase in knee flexion and walking distance.21
Nattokinase is a proteolytic (protein-dissolving) enzyme. Proteolytic enzymes have analgesic effects in addition to anti-inflammatory and anti-edemic properties, indicating they may have a role to play in pain management.22 Nattokinase leads to dissolution of fibrin that build inside vessel walls in response to injuries.23 This proteolytic enzyme is used to digest the fibrin and reduce inflammation, the likely mechanism by which nattokinase may help reduce pain.


Combining SSRIs with NSAIDs, aspirin or corticosteroids is the equivalent of playing a game of gastrointestinal Russian roulette. For anyone taking SSRIs, a combination of natural pain relievers that includes DL-phenylalanine, turmeric, Boswellia serrata, and nattokinase can prove to be a safe alternative. Furthermore, using a supplement that contains glutamine, deglycyrrhizinated licorice (DGL), N-acetyl glucosamine, marshmallow, berberine, cabbage, slippery elm, phosphatidylcholine, and gamma oryzanol is an effective way to strengthen the GI tract for individuals who continue with SSRI treatment. Individuals planning to stop SSRI treatment should always discuss their plans with their physician before doing so.

1. Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature. Rev Med Interne. 2000 Feb;21(2):152-60.
2. No authors listed. Do SSRIs cause gastrointestinal bleeding? Drug Ther Bull. 2004 Mar;42(3):17-8.
3. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2008 Jan 1;27(1):31-40.
4. de Abajo FJ, García-Rodríguez LA. Risk of Upper Gastrointestinal Tract Bleeding Associated With Selective Serotonin Reuptake Inhibitors and Venlafaxine Therapy. Interaction With Nonsteroidal Anti-inflammatory Drugs and Effect of Acid-Suppressing Agents. Arch Gen Psychiatry. 2008;65(7):795-803.
5. Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003 Jan 13;163(1):59-64.
6. Sacks GS. Glutamine supplementation in catabolic patients. Ann Pharmacother. 1999;33:348-54.
7. Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev. 1999;4:239-48.
8. van Marle J, Aarsen PN, Lind A, van Weeren-Kramer J. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol. 1981;72:219-25.
9. Tewari SN, Wilson AK. Deglycyrrhizinated liquorice in duodenal ulcer. Practitioner. 1973;210:820-3.
10. Burton AF, Anderson FH. Decreased incorporation of 14C-glucosamine relative to 3H-N-acetyl glucosamine in the intestinal mucosa of patients with inflammatory bowel disease. Am J Gastroenterol. 1983;78:19-22.
11. Newall CA, Anderson LA, Philpson JD. Herbal Medicine: A Guide for Healthcare Professionals. London, UK: The Pharmaceutical Press, 1996.
12. Fukuda K, Hibiya Y, Mutoh M, et al. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol. 1999;66:227-33.
13. Cheney G. Vitamin U Therapy of Peptic Ulcer. California Medicine. 1952;77(4): 248-252.
14. Gruenwald J, Brendler T, Jaenicke C. PDR for Herbal Medicines. 1st ed. Montvale, NJ: Medical Economics Company, Inc., 1998.
15. Stremmel W, Ehehalt R, Autschbach F, Karner M. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial. Ann Intern Med. 2007 Nov 6;147(9):603-10.
16. Cicero AFG, Gaddi A. Rice Bran and Gamma-Oryzanol in the treatment of hyperlipoproteinemias and other conditions. Phytotherapy Research. 15(4):277-289.
17. Ehrenpreis S. Pharmacology of enkephalinase inhibitors: animal and human studies. Acupunct Electrother Res. 1985;10(3):203-208.
18. Walsh NE, Ramamurthy S, Schoenfeld L, et al. Analgesic effectiveness of D-phenylalanine in chronic pain patients. Arch Phys Med Rehabil. 1986 Jul;67(7):436-439.
19. Hsu CH, Cheng AL. Clinical studies with curcumin. Adv Exp Med Biol. 2007;595:471-480.
20. Funk JL, Frye JB, Oyarzo JN, et al. Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis Rheum. 2006 Nov;54(11):3452-3464.
21. Kimmatkar N, Thawani V, Hingorani L, et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee–a randomized double blind placebo controlled trial. Phytomedicine. 2003 Jan;10(1):3-7.
22. Klein G, Kullich W. Reducing pain by oral enzyme therapy in rheumatic diseases. Wien Med Wochenschr. 1999;149(21–22):577–580.
23. Suzuki Y, Kondo K, Ichise H, et al. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition. 2003 Mar;19(3):261-264

Posted by DrMeletis