By Ellen Feldman, MD

Altru Health System, Grand Forks, ND

Dr. Feldman reports no financial relationships relevant to this field of study.

SUMMARY POINTS Saffron, from the stigma of the Crocus sativa plant, has been used medicinally in the Eastern world for centuries.

plant, has been used medicinally in the Eastern world for centuries. Researchers are investigating the use of saffron in mild-moderate depression.

A meta-analysis from 2015 and several subsequent studies show promising findings, with saffron (15 mg twice daily) demonstrating efficacy similar to conventional antidepressants in treatment of mild-moderate depression.

Side effects, long-term effects, and use in special populations remain under investigation.

SYNOPSIS: Saffron studies, while still preliminary, show potential for use of this ancient spice in combatting mild-moderate depression.

Phytotherapy, using scientific methods to determine appropriate and effective medicinal use of plant-derived medications, is of particular interest to integrative providers.1 With recent studies showing promising results, saffron, from the dried stigma of a delicate crocus flower, has the potential to attract interest not only from phytotherapists, but also from the medical community in general.

Even with controlled studies, is Western medicine ready to integrate into the arsenal of medical treatment a spice that has been known for medicinal use in the Eastern world for thousands of years? More specifically, can one of the most expensive spices in the world be useful in the fight against depression, one of the costliest and debilitating conditions known to humanity? These are questions posed by researchers interested in the mode of action, side effects, and efficacy of saffron in the treatment of depression. Current research certainly is promising, but conclusive, long-term studies still are necessary before firm recommendations regarding age, dosing requirements, and other specifics are available. However, knowledge regarding the background and origins of saffron, its historic role in Eastern medicine, the spread of its use to the Western world, and an up-to-date view of the most current studies regarding saffron is useful for providers when discussing this treatment option with patients.

Antidepressants and Depression

In 2013, the most recent year statistics are available, 12% of U.S. adults reported use of antidepressants. Notably, antidepressants are used to treat many disorders, including not only depression, but also anxiety, post-traumatic stress disorder, chronic pain, and mood disorders.2 The estimates for a diagnosis of adult depressive disorders number close to 16 million adults per year, or 6.7% of all U.S. adults.3 The global burden of depression is even more worrisome — according to the World Health Organization, 350 million people worldwide are affected by this disorder, making depression the leading cause of disability. Despite the widespread use of antidepressants, mortality remains a concern; severe depression remains associated with an increased risk of suicide, and depression after a myocardial infarction confers an increased risk of death.2,3

The categories of depression include major depressive disorder, premenstrual dysphoric disorder, dysthymic disorder, and unspecified depressive disorder. Although each diagnosis has distinguishing symptoms, all share the presence of a significant sad or irritable mood that impairs functioning and generally is associated with somatic or cognitive changes. The diagnostic criteria distinguish severity of symptoms on a scale from mild to severe.4 Understanding that “depression” encompasses a wide range of disorders and that even major depressive disorder symptoms occur on a scale or gradation of severity is useful in devising appropriate treatment plans and strategies.

There are more than 24 FDA-approved antidepressants. All have the potential for side effects that may limit use, including weight gain, loss of libido, fatigue, and/or insomnia. Most take four to six weeks to demonstrate an effect.5 A 2016 Canadian meta-analysis found about 50% of patients treated with a standard selective serotonin reuptake inhibitor (SSRI) failed or only partially responded to a first trial of antidepressants, and that the literature lacks guidelines regarding second-line treatment. Often, when faced with a response failure, providers recommend a switch to another agent or augmentation with another medication — a slippery slope that can result in more side effects and complications from polypharmacy.6

The side effects from antidepressants, the need to wait at least a month before symptom relief, as well as the uncertainty of response and the possibility of needing to change agents to find the “one that works” lead many to look toward integrative health interventions.7

Background and Origins

Saffron, from the dried stigma of the delicate Crocus sativus plant, holds a special place in Greek mythology, attesting to the importance of this spice even in ancient times. According to the early Greeks, the young Spartan Krokus fell in love with a nymph, Smilax. Impressing the gods with his love and devotion, he was granted immortality by transforming into a plant bearing his name and symbol of his love — a blood red stigma. In another version, Krokus, distracted by his love while playing discus with Hermes (son of Zeus), is killed accidentally. The flower is again a symbol of his immortality, with the red symbolizing the spill of his blood.8

Although the myths of origin are subject to interpretation, the importance and use of saffron over time is more clearly documented. Between 3500-5000 B.C., the Sumerians used saffron gathered from the wild as a remedy and potion for a variety of ailments. It was in or near ancient Persia that cultivation of this prized plant began, most likely selecting flowers with longer stigma to increase yield of the saffron spice. Persian history reveals saffron was mixed into hot tea to cure “melancholia,” and later Alexander the Great used saffron baths for generalized healing of wounds.9

Relics from the ancient Greek island of Santorini depict saffron production and application as a healing tool in pictorial form as early as 1700 B.C.10 Although the ancient Greeks and Romans valued saffron for a variety of uses, including as a coloring agent, food additive, and perfume, Cleopatra of Egypt apparently thought saffron contributed to “more pleasurable lovemaking” and Pliny the elder recommended saffron in gastrointestinal disorders. As the uses of saffron broadened, so did its value, and trade of this precious spice across the Mediterranean boomed.9

Saffron found its way via trade routes into India and China by the early centuries A.D., and the plant began being cultivated in Kashmir. Uses in this region included medicinal applications for “melancholia” and inflammation, as well as numerous non-medicinal uses.9

In the first century A.D., Greek medical practitioner Pedanius Dioscorides compiled the Materia Medica, a reference book regarding botanicals in medical practice that documented the use of saffron for healing wounds and inflammation. Over subsequent years, use, demand, and production waxed and waned. The difficulty of cultivating and the painstaking manner of collection (still a factor today) affected use. The Black Death in the 1300s led to an escalation in demand and use of saffron in Europe to treat the victims. Ultimately, the 14-week long “saffron war” was fought after the theft of a shipment of saffron was hijacked by nobles intent on market domination and was followed by a period of high demand for the crop accompanied by piracy and diversion of the shipments.11

The use and value of saffron again varied over the next several centuries as it was first cultivated in western Europe but then attacked by fungus and disease. German settlers known as the Pennsylvania Dutch carried corms of the Crocus sativus plant to their new land and cultivated this crop in eastern Pennsylvania, where it remains grown today. However, the bulk of saffron worldwide continues to come from Iran (where it bears the nickname “red gold”) and Greece.9,11

Production and Chemistry

Currently, saffron retails at up to $11,000 per kilogram. This high cost is primarily because of the labor-intensive production, which requires 450,000 handpicked stigmas (from approximately 150,000 crocus blossoms) to produce one kilogram of saffron. These valuable stigmas contain four bioactive compounds of medicinal relevance and are rich in carotenoids, containing both lycopene and beta-carotenes.11,12

The major bioactive components of saffron are crocins and crocetins, responsible for the characteristic deep yellow color of safranin; picrocrocin, responsible for the characteristic bitter taste; and safranin responsible for the hay-like aroma. It is believed these compounds provide antidepressant benefits via several mechanisms, most of which primarily have been tested in vitro or in animals. The need for human testing remains a priority.11,12

Antioxidant effect.11,12 Crocin, crocetin, and safranin are all strong antioxidants and may fight depression via protecting against and/or ameliorating oxidative stress (known to be increased in depression). Studies have shown that there is a synergistic effect when all three are present, enhancing potency under these conditions.

Anti-inflammatory actions.11,12 Depression is associated with increased C-reactive protein, and inflammation is suspected to be a factor in this disorder. Saffron has been shown to have strong anti-inflammatory properties in the lab, most likely from crocin and crocetin, although further studies are necessary to elicit a mechanism of action.

Serotoninergic effect.11,12 SSRIs, such as fluoxetine, are a conventional treatment for depression. Crocins may have a similar effect with antagonistic action at serotonin receptor sites. Studies are ongoing regarding the use of saffron in premenstrual dysphoric disorder with this action as a postulated mechanism.

Hypothalamus-pituitary-adrenal (HPA) modification.11,12 HPA dysregulation also has been investigated extensively in depressive disorders and is thought to affect neurotransmitter availability, oxidative stress, and inflammation. Saffron may lower the HPA response to stressful situations, but investigations are still in preliminary stages.

Neuroprotection.12 Preliminary studies have looked at the neuroprotective effect of crocin and safranin in stressed rats. It is known that many of the conventional antidepressants increase brain-derived neurotropic factor (BDNF), a brain protein thought to play a role in depression. Some researchers who have studied saffron and crocin have found similar effect on BDNF in rats exposed to stressful conditions.

Clinical Studies of Saffron in Depression

Two recent meta-analyses (2014 and 2015) included six high-quality, randomized, clinical trials regarding saffron and depression. Two hundred thirty adult patients participated in these studies. All were Iranian studies, all used the Hamilton Depression Rating Scale to measure outcome, and all were time-limited with a maximum of eight weeks until study conclusion. The intervention was a dose of 15 mg of standardized extract of saffron twice daily. Two studies were placebo-controlled, and four studies compared efficacy to antidepressants (fluoxetine 20 mg or imipramine 100 mg daily.)12,13

All the studies included non-hospitalized subjects who met criteria for mild to moderate major depressive disorder with limited comorbidities. Extract sources were both from the petal of the flower and the stigmata, but interestingly showed no variation in efficacy. Large treatment effects were recorded for saffron compared to placebo, and no significant difference in improvement was noted in the studies looking at saffron vs. antidepressants; both interventions looked equally effective. (See Table 1.)

Table 1: Compilation of Clinical Trials on the Use of Saffron in Depression Author and Year Type of Study and Number of Subjects Dose of intervention Scale Used to Measure Outcome Study Arms Result Summary Hausenblaus et al. 201513 Six studies randomized, double-blind regarding depression 230 adult participants with major depressive disorder Saffron capsule

30 mg/day HDRS Two studies: saffron vs. placebo Three studies: saffron vs. fluoxetine One study: saffron vs. imipramine Statistically significant reduction in HDRS with saffron Significant reduction in HDRS for all groups without statistically significant difference between groups Talaei et al. 201515 Randomized, double-blind, placebo-controlled 40 adult patients with major depressive disorder Crocin tablet 15 mg BID as adjunct to SSRI BDI Crocin plus SSRI vs. placebo plus SSRI 4 weeks Significant improvement

on BDI scores for crocin group

(P < 0.0001) Mazidi et al. 201614 Randomized, double-blind, placebo-controlled 60 adult patients with major depressive disorder Saffron capsule 50 mg daily BDI Saffron vs. placebo 12 weeks Significant improvement

in BDI scores for saffron group

(P < 0.001) Kashani et al. 201716 Randomized, double-blind 64 adult women with mild-moderate postpartum depression Saffron capsule

30 mg HDRS Saffron 15 mg BID vs. fluoxetine 20 mg Remission and partial response rates almost identical between the two groups (P = 1.00) SSRI: selective serotonin reuptake inhibitors; HDRS: Hamilton Depression Rating Scale; BDI: Beck's Depression Inventory

In even more recent studies, this trend of efficacy of saffron in treatment of depression continues. A 2016 12-week, placebo-controlled study by Mazidi et al included 60 adult patients and used a slightly higher dose of saffron at 50 mg daily. Significant lowering of depression as measured by the Beck Depression Inventory (BDI) was noted.14 Talaie et al looked specifically at crocin (15 mg twice daily) as an adjunctive treatment to an SSRI in 40 patients and found statistically significant score improvement on the BDI after four weeks when compared with placebo.15 A 2017 study by Kashani et al compared saffron (15 mg twice daily) to fluoxetine in the treatment of postpartum depression over six weeks; although the number of participants was low, the results suggested equal efficacy of the two agents.16

Safety

Safety and side effects of saffron clearly are an area for further study and methodical investigation. In all reviewed studies, saffron demonstrated side effects, including increased anxiety, increased appetite, nausea, and headache, although to varying degrees. In general, side effects from conventional antidepressants were less tolerated than side effects from the saffron or crocin groups; however, there was no clear statistical difference in adverse effects reported by any one group (including placebo).12,13 In addition, there may be changes in serotonin levels in the brain, such that extreme caution is advised with co-use with pharmaceutical antidepressants that may have the same, or similar, mechanisms of action, especially due to the risk of serotonin syndrome.13

Toxicology reports are inconsistent, but some studies of saffron have shown mild prolongation of blood coagulation and platelet aggregation, leading to a cautionary note to those on anticoagulant medications or with a bleeding disorder.11,12,13

Safe doses are up to 1.5 g daily, while doses in excess of 5 grams daily may be toxic. Notably, doses for treatment of depression range from 30-50 mg daily, leaving a wide margin of error. However, it is useful to understand the potential of toxicity or even fatality (20 grams) when treating depression because of the potential for suicidal thinking.12,13 As no published study of saffron has lasted longer than 12 weeks, it is difficult to document any long-term safety concerns.

Further Discussion

A 2010 survey reported that close to half of all U.S. visits to integrative medicine providers involved a psychiatric problem; another survey reported that half of all U.S. adults with self-reported depression acknowledged using integrative therapies.7 If only for these reasons alone, it is useful for the integrative provider to be prepared to discuss the use of saffron in treatment of depression.

It is also relevant to note that studies of cognitive behavioral therapy in mild to moderate depression have shown results on par with conventional antidepressants and with the studies of saffron.17,18 The American Psychiatric Association guidelines on treatment of depression encourage the use of psychotherapy as a first-line treatment in mild to moderate depression, while acknowledging that appropriate providers and patient preference is important to this decision and may sway the pendulum toward psychopharmacology, psychotherapy, or perhaps (optimally) a combination of the two modalities.19

It is equally important to understand the distinction between types of depression prior to making recommendations; patients with mild-moderate major depressive episodes have few symptoms in excess of those needed to qualify for a diagnosis and functional impairment is limited. The saffron studies excluded patients with more severe types of depression, hospitalized patients, and most comorbidities. For now, it is best to treat patients with severe depression, repeated episodes, and significant comorbidities with conventional antidepressants and appropriate psychotherapy.19

The scientific literature says little about the price of saffron supplements. Although bulk quantities are expensive, treatment doses are small enough that affordability may be within the reach of most. A 2013 review study noted an unwanted side effect of the rise in popularity of saffron may be an increase in attempts to adulterate saffron products.20 Checking labels carefully and obtaining products from established and reliable sources remains a good rule for most supplements and certainly for saffron.

Remembering these caveats, the saffron studies in depression overall are compelling and persuasive. Clearly, we need studies with more subjects over a longer time and with standardized procedures and extracts. Such studies can answer questions such as the length of time needed to solidify treatment, the risks of long-term side effects, and processes to determine quality of a saffron capsule. It seems appropriate and potentially exciting to tell patients that early studies of 15 mg saffron capsules twice daily appear promising in adults and as effective (but not more effective) than antidepressants alone. Reviewing the safety information and the limited information regarding long-term use is necessary as well. As with all herbal medicines, caution is advised regarding quality of individual preparations.

Conclusion

There is no doubt that current research points to the efficacy of saffron in treatment of adults with mild to moderate major depression and perhaps in other forms of depression as well, such as postpartum depression. There is potential for use of saffron as an adjunct to antidepressant treatment, or as first-line therapy, and potential to isolate bioactive components (such as crocin) to use for antidepressant effect. Unfortunately, what we do not know about saffron — including specific mechanisms of action, optimal length of treatment, long-term side effects, relative efficacy of type of extracts, and use in pediatric and geriatric populations — remains significant and a barrier to common use. In the postpartum, breastfeeding population, studies regarding safety for infants must be established before recommendation for use.

When treating adult patients with mild to moderate major depression, the integrative provider is on solid ground exploring saffron as an alternative to conventional antidepressants. Understanding that the research is in early stages and that many questions remain unanswered is an essential part of this discussion. Informing patients that nonpharmacologic interventions, such as cognitive behavioral therapy, have demonstrated similar benefits can help a patient both put the saffron results into perspective and make an informed decision regarding treatment options.

Addressing depression aggressively and promptly is helpful in preventing the debilitating and deteriorating course of untreated depression. The knowledge that alternative interventions exist can help lift the web of negative thinking and despair that so often accompanies a person in the midst of a depressive episode. Reminding patients that there are different avenues to symptom relief introduces hope and optimism — two important factors in the treatment of most disease states and certainly of particular relevance in the treatment of depression. Whether saffron will live up to its past reputation in healthcare remains uncertain, but the potential for use of this exotic spice in the treatment of depression is clear.

REFERENCES