ABSTRACT: Is Saffron Effective for Depression?
Poster Presentation by: Gisoo Imani & Jacqueline Clark
BACKGROUND
Saffron (Crocus sativus) is a perennial flower cultivated in Turkey, Iran, China, India, Algeria, and parts of Europe,1,4 with 85% of the world’s saffron being produced by Iran.2 The part of the plant that has been used since ancient times as a spice, natural coloring agent, and medicine is the dried stigma from the flower. Each flower contains only three bright red-orange stigmas, which must be cultivated and harvested by hand. To produce just one pound of saffron, approximately 225,000 stigmas must be hand-picked from the flowers, which bloom only once per year in the fall.2,9 As one might imagine, this labor-intensive harvesting process justifies why saffron is the world’s most expensive spice. Traditionally, saffron has been used for a plethora of medical conditions, but its use as treatment for depression has the strongest scientific support thus far.14 Crocin, crocetin, and safranal are the primary chemical constituents isolated from saffron stigmas,4,6 with crocetin appearing to be most responsible for the pharmacological activities of saffron. 7,9 Orally, saffron is well-tolerated in reported doses of 30 mg daily to 100 mg daily for up to 12 weeks, but slightly higher doses of saffron extract used for at least 26 weeks have increased incidence of mild side effects such as dry mouth, anxiety, agitation, drowsiness, nausea, vomiting, constipation, change in appetite, flushing, and headache.9 Saffron is thought to interact with antidiabetic medications due to its combined effect on reducing fasting glucose levels and also with antihypertensive medications due to a potential additive effect of lowering blood pressure.9 Therefore, saffron should be used cautiously in patients taking medication for diabetes or hypertension. The mechanism of action for saffron in depression has yet to be fully elucidated. However, it may exert its antidepressant effect by modulating levels of serotonin, dopamine, and norepinephrine in the brain.9-12 The purpose of this review poster is to determine if there is scientific support for the use of saffron in treating patients with depression.
CLINICAL EVIDENCE
In a meta-analysis by Toth et al.,12 the antidepressant effect of saffron was evaluated. The purpose of this study was to compare the changes in depression severity in patients receiving saffron at pharmacological doses vs. placebo or conventional antidepressants. Nine randomized controlled trials were quantitatively synthesized. The effect size was calculated using Hedges’ g; risk of bias was assessed using the Cochrane Collaboration tool; and heterogeneity was determined using Cochran’s Q test and Higgin’s I^2. The results showed that saffron had significantly greater efficacy on reducing the severity of mild to moderate depression compared to placebo (g=0.891, 95% CI:0.369-1.412, p=0.001) and was non-inferior to fluoxetine and citalopram (g=-0.246; 95% CI: -0.495-0.004, p=0.053). The authors conclude that saffron is superior to placebo and noninferior to SSRIs in the treatment of mild to moderate depression. Further, they conclude that saffron reduces the severity of depression, although the optimal dose and treatment duration remains unknown.
Another meta-analysis by Hausenblas et al.3 examined the effects of saffron supplementation on symptoms of depression in adult patients with major depressive disorder (MDD). The comparators were placebo or conventional antidepressants. Five randomized, double-blinded controlled trials were included, and a random effects model was used to calculate the weighted mean effect sizes. The findings showed that saffron supplementation significantly decreased symptoms of depression compared to placebo (MES=1.62, p<0.001), and its effects were not significantly different from fluoxetine and imipramine (MES=-0.15, p=0.42). The authors conclude that short-term saffron supplementation may be helpful for treating depression symptoms in adults with MDD.
In a systematic review and meta-analysis by Khaksarian et al.,5 the effectiveness of saffron compared to placebo and fluoxetine in the treatment of depression was evaluated. Eight randomized controlled trials were included; effect sizes were calculated as standardized mean differences (SMD); and heterogeneity was determined using the I^2 test. The results showed that saffron is more effective in treating depression than placebo with a SMD of -0.86 (95% CI: -1.73 to 0.00) and was comparable to fluoxetine with a SMD of 0.11 (95% CI: -0.20 to 0.43). The authors concluded that saffron is more effective than placebo and has comparable efficacy to fluoxetine in improving symptoms of depression.
CONCLUSION
The findings of the clinical trials presented suggest that saffron may be beneficial as monotherapy and may have comparable effects to traditional antidepressants such as fluoxetine in improving symptoms of depression. Although some methodological limitations and non-negligible heterogeneity in the studies exist, the results were clinically significant. Future research should be conducted to study the long-term effects of saffron in treating depressive symptoms (>12 weeks), the mechanism of action for the antidepressant effects, and the optimal dosing for treatment of depression, since these crucial components for supporting the clinical use of saffron as treatment for depression remain unknown.
REFERENCES:
- American Botanical Council. Saffron. HerbClip Online, 2018. Accessed: 07/16/2021; Available from: herbalgram.org/resources/herbclip/herbclip-news/2018/saffron/.
- Fulton, A. The Secret History of the World’s Priciest Spice. National Geographic, 2017. Accessed: 07/14/2021; Available from: https://www.nationalgeographic.com/culture/article/history-origin-of-saffron-spice-iran.
- Hausenblas, H.A., et al., Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med, 2013. 11(6): p. 377-83
- Javadi, B., A. Sahebkar, and S.A. Emami, A survey on saffron in major islamic traditional medicine books. Iran J Basic Med Sci, 2013. 16(1): p. 1-11.
- Khaksarian, M., et al., The efficacy of Crocus sativus (Saffron) versus placebo and Fluoxetine in treating depression: a systematic review and meta-analysis. Psychol Res Behav Manag, 2019. 12: p. 297-305.
- Khan, I.A. and E.A. Abourashed, Natural Ingredients: Saffron, in Leung’s Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. 2010, John Wiley & Sons, Inc. p. 547-548.
- Leone, S., et al., Phytotherapic use of the Crocus sativus L. (Saffron) and its potential applications: A brief overview. Phytother Res, 2018. 32(12): p. 2364-2375.
- Marx, W., et al., Effect of saffron supplementation on symptoms of depression and anxiety: a systematic review and meta-analysis. Nutr Rev, 2019.
- Natural Medicines, Saffron [Professional Monograph]. 2021, Therapeutic Research Center. Accessed: 07/14/2021; Available from: https://naturalmedicines-therapeuticresearch-com.ezproxy.lib.utah.edu/databases/food,-herbs-supplements/professional.aspx?productid=844#background
- Sarris, J., Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res, 2018. 32(7): p. 1147-1162.
- Shafiee, M., et al., Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord, 2018. 227: p. 330-337.
- Toth, B., et al., The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-analysis. Planta Med, 2019. 85(1): p. 24-31.
- Wang, Y., et al., Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med, 2010. 64(1): p. 24-30.
- Woolven, L. and T. Snider Saffron: The Salubrious Spice. HerbalGram: The Journal of the American Botanical Council, 2016. 61-71. Available from: https://www.herbalgram.org/resources/herbalgram/issues/110/table-of-contents/hg110-feat-saffron/
Responses
Hello Gisoo and Jacqueline – what are the two main things you learned from preparing and developing this topic?
I was not familiar at all with saffron, so I learned a great deal in general, from its historical utility to its potential clinical utility in a variety of different medical conditions. For me, it was interesting to learn about the pharmacology and mechanism of action for this product because even though it has been used for thousands and thousands of years for mood-enhancing properties and antidepressant effects, the research has not confidently attributed a specific mechanism for such effects. Also, I enjoyed discovering the fun facts about this spice – I can’t believe it was used as an antidote for the bubonic plague!
Thank you for asking. I learned that saffron may be an effective alternative therapy for treating depressive symptoms in a short-term duration (6-12 weeks), however long-term effects have yet to be studied. Although the focus of our project was on the effectiveness of saffron in treating depression, I was also able to learn that this supplement tends to be safe at appropriate doses (<1.5 g/day per Toth B. et al) with fewer reported adverse effects (headache, constipation, dry mouth, sedation, urinary retention, etc.) compared to conventional antidepressants (Shafiee et al.).
Interesting topic!! In the cited studies were there any explanations of what the definitions of mild or moderate depression? Did the authors address percentages of response or remission? How expensive is saffron? Were the studies in the analyses of sufficient duration?
No specific definitions have been provided in Study 1; however, in studies 2 and 3 depression has been characterized by symptoms of excessive changes in weight, sleep disorders, difficulty concentrating, persistent feeling of grief, fatigue, anhedonia, and thoughts of suicide in severe cases. Study 2 specifies that for MDD the duration of these symptoms would have to be 2 weeks or longer. None of the studies unfortunately included any information regarding the response and remission rate of the subjects, therefore only an improvement in their symptoms or lack there of was noted. This would perhaps serve as a great primary outcome for future studies on this topic in order to gain a better understanding of the efficacy of saffron. Jacqueline will go into detail about the remaining 2 questions 🙂
Thank you for the great questions! A few of my classmates have asked similar questions about the cost of saffron, and toward the bottom of the comments section I linked a really interesting video that goes into depth about the production process and why it is so expensive – the amount of time and effort makes this harvesting process a very delicate process, and I imagine it is a prized flower for the people of Iran, who have passed the tradition of cultivating and harvesting saffron down from generation to generation. According to one article, real saffron can cost over $10,000 per kilogram!! I have to emphasize “real” because there has been a huge uptick in the amount of adulterated and even fake saffron products out there, some of which have been shown to be made of corn silks, coconut fibers, or even horsehair instead of the actual saffron stigma threads. The same source as the video link I posted below discusses a 2-year international investigation into a fake-saffron crime ring in the UK. It turns out Spain exported 190,000 kg of saffron, while the country’s total production amounted to only 1,500 kg; during this span of time, reportedly up to 90% of Spanish saffron exports were fraudulent! People are going to great lengths to capitalize on the value of this coveted spice.
To address your other question, for what the authors concluded from the studies, I would say the studies we analyzed were of sufficient duration. However, in most cases the authors concluded an improvement in symptoms after a duration of up to 12 weeks, which is a fair comparison to the medications they assessed, since typical SSRIs are expected to produce initial effects within a few weeks and continued improvement out to 4-6 weeks. It is important to make the distinction of symptomatic improvement rather than just saying it is effective for treating depression. If you are asking whether or not I think they were of sufficient duration to draw conclusions about long-term treatment of depression, I would say we wouldn’t extrapolate any findings to a timeframe past 12 weeks. This is a huge limitation of the studies on saffron so far, since major depressive disorder (MDD), for example, is known to be long-term if not lifelong for most patients. Something somewhat related to this question that I thought about during our project: It would be really interesting to evaluate saffron’s utility as a potential maintenance therapy for patients with MDD. Maintenance therapy is designed to prevent relapse in patients with recurrent depression who have achieved remission, and since a lot of the studies we looked at showed a more favorable side effect profile, saffron could potentially be an attractive option for patients who require long-term use of symptomatic control such as with maintenance therapy!
Great poster Jacqueline and Gisoo! I can tell you both put a lot of hard work into making this! What made both of you pick this topic and herbal supplement? Do you know anyone who has tried using saffron to treat depression?
Thanks for the great question Brittney! Personally, saffron is a spice that’s always been used in my household in black tea, Persian desserts (ice creams and pastries), and dishes (garnish rice, additive in stews and meat marinations) for its color, flavor, and aroma. Also, in the Persian culture it is known to improve mood and boost energy. I know of a few people who swear by its effects and continuously use it in their foods.
That’s awesome! Thank you for sharing!
Thank you Brittney! Honestly, Gisoo mentioned the topic to me, so she gets the credit for that. Once she mentioned it to me and I glanced over some of the supporting evidence obtained for its use in depression, I was excited to learn more about it. It has been fascinating to learn how this spice is produced. I don’t know anyone personally who has used it for depression. That said, I wouldn’t be opposed to sprinkling it on some of my own food here and there just based on centuries-old anecdotal evidence for enhancing mood and boosting energy in general. 🙂
Hi Jacqueline and Gisoo! Your poster is so organized and I like the bright colors! I can tell you went to a lot of work. As you mentioned, I’ve heard Saffron is extremely expensive due to how it is harvested. Do you have an estimate for how much it would cost a patient to take a Saffron supplement for the 12 weeks that the patients were watched in the studies?
I also had a question regarding the cost, do you think it would be feasible for patients to pay for saffron over the counter when antidepressant medications are usually well covered by insurance?
Hi Paige! Thanks for the question. I totally agree with your thoughts on feasibility of purchasing such an expensive product when antidepressant meds are typically well-covered by insurance. Something of note is that current research is assessing the utility of other components of the plant itself, which would subsequently lower cost if there are ways to attain larger-scale production of saffron without compromising the quality/beneficial effects (discussed more in-depth in response to Feng’s comment below).
Another thing I would like to mention is that while antidepressants are usually well-covered, a lot of times in today’s day and age patients are seeking out more natural ways to address medical conditions like depression, so it’s reasonable to believe that even if they pay a bit more, if the patient is more adamant about “natural” product over cost they may be willing to wager on insurance coverage. Personally I think it would be cool to be able to discuss with a patient that the supplement has been superior to placebo and noninferior to some antidepressants for up to 12 weeks, but as you know, 12 weeks is highly conservative estimate for the amount of time someone may need to treat depression, so utility passed that timeframe needs to be studied further. Also of note, the clinical studies have shown fewer side effects compared to antidepressants, which could further the appeal to patients who have experienced some of the negative side effects associated with those medications.
Hi Rilee! Thanks so much for your kind words about our poster.
The cost of real saffron is wildly high. There are some sources estimating its price per pound at $1,500 and up! For its use as a spice in foods etc it is sold by the gram. Even still, one particular article evaluated different costs of spices in particular at a renowned, quality store called Spice House in Chicago, and each gram of “superior grade” saffron is $6.79, and an even finer version called “coupé grade” saffron for $8.29 per gram. So when you look up saffron products on, for instance, Amazon or other wholesale vendors, it is important to invest in quality. The same article discusses another company, Vanilla Saffron Imports out of San Francisco, which does direct-import business pricing saffron for $1,162.24 per pound, or $72.95 per ounce, and even vets its saffron for compliance with ISO standards. Cheaper saffron products often leave in the tasteless yellow stamens, which add weight and diluting out the red stigmas that give the famous taste– or more oftentimes than not, you could be getting adulterated product with no saffron components whatsoever! (https://money.cnn.com/galleries/2008/fsb/0807/gallery.most_expensive_foods.fsb/4.html)
Specifically to address the cost of patients to take a Saffron supplement and what that cost would look like, I have found it difficult to find an exact price. In fact, something interesting I found when reading through a lot of these studies is that the In clinical trials, saffron stigma has been donated by or purchased from specific companies in Iran, including Novin Saffron Co., Green Plants of Life Co., and East Sorkhfam Saffron Co. Pharmactive Biotech Products SL Company in Spain has also donated saffron stigma for clinical trials. (Natural Medicines Monograph). Therefore, as donated products to support the studies, I imagine the cost to the patients was negligible upon enrollment into the studies. It does make you wonder about the potential for sponsorship bias though!
Jacqueline, that is super interesting about all of the saffron being donated for the studies! Thanks for looking into all of that!
Awesome poster guys! Would it be safe to take a saffron supplement in addition to other antidepressants?
I guess this would piggyback Laura’s question but is there documentation of additive effects with antidepressants? What depression scale was used to determine effectiveness of Saffron in your trials?
Thank you Katelin! Hopefully my response to Laura’s question answered yours about the additive effects of saffron with antidepressants. Regarding the depression scale in study 1, out of the 12 studies included 9 used Hamilton Depression Rating Scale (HAM-D) and 3 used Beck Depression Inventory II (BDI-II). Similarly, in study 2, HAM-D was used. Study 3, however, does not clearly state what depression scale was used in each of their included studies.
Hey Laura! Thank you for asking. In the 3 studies that we looked into, none of them included an intervention group of saffron + an antidepressant and rather it was listed as an exclusion criteria for these meta-analyses. Although, per Natural Medicines a small clinical study was able to show that 15 mg of crocin (a saffron constituent) twice daily for 4 weeks in addition to an SSRI can improve depressive symptoms by 14%-26% in comparison to SSRI with placebo.
Hi Gisoo and Jacqueline! I really enjoyed your poster a lot and I really loved the color scheme. What are your thoughts on the price of saffron and how that would affects its viability as a treatment option?
Thank you Feng! It’s a beautiful flower, so we had a great color scheme to work with:)
The cost is something that would be hugely impactful to saffron’s viability as a treatment option. In fact, most of the trials thus far will mention that aspect as a limitation of findings. With the harvest process being so time and labor-intensive, it is obvious that sources of the stigmas of C. sativus are scarce; if overexploitation of this plant for medicinal and commercial use continues with a low reproduction rate, it would not be a very viable option, at least not for very many people outside areas of harvest. Something notable though is that within the field there is research looking into other portions of the C. sativus plant to assess its potential utility and relative potency as well. One study has looked into the antidepressant properties of the corms (like flower bulbs) due to larger size and higher yield compared with stigmas.
One study by Wang et. al looked at bioactive fractions of the plant by fractionation of the extract of C. sativus corms and investigated the antidepressant-like properties of the fractions in behavioral models of
depression in mice. Their results were promising in that the extract of C. sativus corms was effective as an antidepressant medical plant material. If research continues to find utility to other portions of the plant, maybe there will be ways to have larger-scale production of saffron to address this limitation!
This isn’t really a question, just a comment. Feng and I are doing our website evaluation on Olly vitamins, which are super trendy right now. One of their most popular products is their “Hello Happy” gummy worms, which contain saffron and vitamin D. I was honestly pretty skeptical about this product, but looking at your studies, maybe it actually has more benefit than I thought. Super good job, you guys!
Thank you Emma! 🙂 Olly is a super popular brand- that will be a neat website to evaluate. Also, I am curious about this specific gummy worm product now! Definitely going to look into that one to see more about its sourcing for the saffron component and what amount they are using per gummy worm.
For those interested in the cost of this spice and what makes it so expensive, here is a link to a great video discussing the cultivation and harvesting process. 🙂
https://www.businessinsider.com/why-real-saffron-is-so-expensive-2020-6?amp
Hi guys, beautiful poster! One question I have is did you guys look at any specific types of depression it worked on, or just generalized depressive mood?
Thank you Jackie! That’s a great question. The first meta-analysis included studies with mild to moderate depression patient population although did not define it clearly. The second meta-analysis included studies with symptomatic MDD patient populations as defined by the DSM-IV. The third meta-analysis included studies with mild to severe depression patient population as defined by the DSM.
Hi Jacqueline! What an interesting topic!! The article showing that saff was as effective as prozac is rather curious! Did any of the authors try to elaborate on a mechanism of saffron for treating MDD? Also, when cooking with saffron, dough, for example, can turn a yellowish color; wonder if there were any derm effects for yellow/orange hues! Saff is super expensive in the cooking world. Wonder how that would price out if it were to be a tablet formulation! I liked the “color” formats of your poster!! Very creative!! Nice work! Thank you!
Hi Dr. Orlando- thank you for your interest in our poster and for the kind words! 🙂
The Khaksarian et al article comparing saffron to Prozac discusses potential MOA in their Discussion section. Mostly the authors discuss saffron’s effects on modulating neurotransmitters, including increasing serotonin levels and inhibiting serotonin reuptake in synapses, likely pointing this out due to fluoxetine’s MOA of being SSRI itself. The specific constituent isolated from the saffron stigma thought to give saffron its SSRI-like effects is safranal, the volatile oil component of the extract.
Per the Natural Medicines database, dermatologic reactions from oral saffron induced mild sweating and flushing type reactions in trials of patients taking 30-60 mg daily. To get to a point of dermatologic yellow/orange of the skin, oral intake doses would have to exceed a dose of 5 or more grams, which is the threshold to produce saffron poisoning. Yellowing of the skin is listed as a potential manifestation of saffron poisoning.
Thanks again for looking at our poster- we are glad you found the topic as interesting as we did! 🙂
Hi Can I please ask I have started to make a tea with saffron at night and I am also on Mirtazapin 45mg – will the saffron have adverse effects at all – although it it making me sleep a little better – but during the day I am feeling a bit spaced out – slightly disorientated – should I stop taking the Saffron – just need an answer – many thanks Penny
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