“Clinically proven” is a very malleable term. What exactly does it mean for an intervention to have been clinically proven to work? In the world of dietary supplements, the veracity of this phrase very much exists in the eye of the beholder.
Take saffron, for example, the most expensive spice in the world. Many parents will be relieved to know that they can buy capsules of saffron that have been clinically proven to help sustain a steady mood in teenagers. Could the red botanical marvel really be the answer to a mercurial adolescence?
While a quick glance online seems to confirm that saffron is good for mental health, a closer look at the clinical trials themselves leaves me skeptical.
The cure-all spice
Saffron is derived from the plant Crocus sativus, which is grown mainly in Iran. It comes from a very specific part of the plant, its stigma, which is the part of the female organs that receives the pollen during pollination. The Crocus stigma is a deep red in colour, like three ruby-coloured shoelaces hanging out of a purple flower, and it has to be handpicked at dawn and dried to preserve its aroma. Saffron’s exorbitant price is due to the manual labour involved, but also to the fact that only 7% of the plant is used in the making of the spice. A thousand flowers are used to yield 5 grams of saffron, and each gram of the real stuff may cost you 10$ or more.
Saffron originated in Greece, from where it spread to different countries and became part of local folk traditions. The red spice was said to work against smallpox and measles. It could help with fractured bones. Ancient Romans added Crocus sativus to their wine to avoid hangovers. It was heralded as an aphrodisiac and a treatment for impotence. Even in our modern scientific literature, saffron is painted as a cure-all said to be an anticonvulsant, antidepressant, anti-inflammatory, and anticancer agent. I’ve heard it said that cure-alls cure nothing at all, and there is a lot of truth to that, but it is possible for an old folk remedy once thought to be a comprehensive pharmacy to be revealed to have some potency in one area or another. Plants, after all, are full of chemicals and many of our pharmaceuticals are ultimately derived from them.
The Crocus plant contains hundreds of chemicals and a few of them play important roles in the saffron spice. Picrocrocin gives it bitterness. Safranal contributes to the aroma of the spice. Crocins deliver saffron’s distinctive colour. It is possible for any one of these chemicals to have a significant impact on human health, and indeed many studies done in the laboratory have reported a number of effects that these molecules seem to have on biological systems. But just because large enough doses of a plant chemical seem to trigger a response in the complicated pathways of biology does not mean that consuming the spice itself will heal diseases.
For that, we need clinical studies. If we limit ourselves to the claim that saffron can stabilize mood—and, by extension, have a positive impact on depression and anxiety—we face a problem all-too common to the world of alternative medicine: researchers clamour for large trials yet fail to raise the money to conduct them.
“A large-scale trial is justified”
Results from the first clinical trial of saffron for depression were published in 2004. The pilot study was conducted by Professor Akhondzadeh, now Vice Dean for Research at Tehran University of Medical Sciences in Iran. His team would go on to conduct the vast majority of trials of saffron for depression. Here, 30 milligrams (mg) of saffron were given daily to 15 participants with depression and compared to 15 other participants who received a tricyclic antidepressant. The two had comparable efficacy against depression and the entire trial lasted six weeks.
Two years and four trials later, Akhondzadeh and his co-authors would declare that “a large-scale trial is justified,” yet this trial, as best as I can see, failed to materialize. Instead, multiple small trials were conducted, often comparing two groups of roughly 20 participants for six to eight weeks. Saffron was compared to different antidepressants and to placebos. Eventually, this team and others would go on to repeat small trials in ever more specialized populations. Did saffron work in depression with anxious distress? Did it work in depression associated with menopausal hot flashes? In the depression that sometimes accompanies percutaneous coronary interventions or coronary artery bypass grafting? How about in patients with type 2 diabetes or in women with overweight?
Some of these studies would fail to recruit the necessary number of participants to detect the effect they hypothesized would be there, yet the positive results were published nonetheless. What comes out of this underwhelming literature is that saffron seems to be more effective than placebo, no more effective than pharmaceuticals, and does not seem to increase the benefit of these pharmaceuticals when used in combination with them.
While these results seem encouraging, they come from very small, short-lived studies, and not all of these studies paint saffron in a positive light. That trial done in patients with type 2 diabetes led to the result that saffron was better than placebo at treating anxiety, anxiety and depression… but not depression alone. That same year, saffron did no better than placebo at treating depression in patients undergoing coronary artery bypass grafting, leading the authors to speculate that their depressive symptoms were somehow different than those of other populations in which saffron had seemingly been beneficial in other small trials.
An Australian study in adults with depression showed saffron worked when depression was objectively measured by a clinician but not when it was assessed by the people with the depression. Given that the trial only lasted eight weeks and that fewer than 70 people completed it in each group, I have to wonder if these results are just meaningless noise.
Anxiety and depression, of course, are not quite the same as being moody, but there have been so few published studies on the impact of saffron on moodiness. An Australian study reported that 28 mg of saffron (but not 22 mg) was better than placebo at improving low mood in healthy adults, but each group had only about 40 participants. A similarly limited study looked at youth anxiety and depressive symptoms, and while the teenagers reported an improvement, their parents did not. Both studies were funded by a saffron manufacturer. A study too small to be worth exploring looked at the effect of saffron on happiness levels during resistance training, while another industry-funded study came up negative until the data was tortured to confess.
There is also the issue of publication bias. A 2019 review of studies on saffron’s potential at treating depression and anxiety reported evidence of publication bias in this literature, which is when studies that yield negative results don’t see the light of day because they are seen as unimportant or unpublishable. In the case of saffron, there is another potential bias worth considering. Acupuncture was given cultural weight during China’s revolution under Mao Zedong, and nearly every clinical trial of this intervention reports a benefit… if the trial is conducted in China. Elsewhere, the results are a lot more mixed. I was reminded of this acupuncture effect when reviewing the evidence for saffron. Of the 23 studies examined in that 2019 review article, 21 were done in Iran, with 13 having been specifically conducted by the same research group. Iran is one of the world’s largest producers of saffron and many trials of saffron were funded by saffron manufacturers who, we are told, were not involved in the data analysis. The authors of an Australian study of saffron on youth anxiety and depression, itself financed by a saffron manufacturer, remarked that the benefits they found in their study was nowhere near as big as the one found in comparable Iranian studies.
And this sizable benefit reported by Iranian teams is puzzling. As the 2019 review remarks, the trials pitting saffron against a placebo suggest that saffron would be considerably more beneficial than standard pharmacotherapy for depression and anxiety based on our knowledge of the effectiveness of these drugs… but when saffron is directly compared to these medications, there is no difference in benefit. Something doesn’t add up.
The good news is that, compared to other alternative remedies such as miracle mineral supplement or colonic irrigation, the consumption of saffron appears to be quite safe in reasonable quantities. Toxicity is thought to occur at doses of 5 grams or more, which would be quite expensive. This high cost, though, has led to adulteration with cheaper lookalikes, like the stigmas of calendula and safflower or powdered curcuma. Iranian researchers have tested to see if the tepals of Crocus sativus (the technical term for the external part of a flower that cannot be said to be either a petal or a sepal) are as effective as the prized stigma. The tepals are larger and are not used to make the expensive spice, so this could be a way to save money. Unfortunately, while an early pilot trial seemed to show the tepals were as good as the stigma, tepals were quickly abandoned in future studies for reasons that are not clear to me.
Some manufacturers have released standardized extracts of saffron, which is a step in the right direction in ensuring consistency, but their testing suffers from the same problems described above: too few study participants and too little follow-up to properly put the extract through its paces.
I read many scientific papers whose introductions claimed that saffron “has been shown” to be more effective than placebo against depression, but when “has been shown” stands in for tiny pilot studies, I feel like motivated researchers are covering massive potholes with black paper and hoping no one notices.
It’s possible that saffron will conclusively be clinically proven to help stabilize one’s mood in the future. For now, given the state of the evidence, I remain skeptical.
Take-home message:
- Saffron, the most expensive spice in the world, is claimed to help stabilize a teenager’s mood and to help control anxiety and depression
- The evidence for this comes from very small clinical trials that lasted at most two months
- The vast majority of these trials were conducted in Iran, one of the leading producers of saffron, and there is reason to believe that trials that do not show a benefit to saffron do not always get published
