Nikhil Teja, MD

 is rapidly expanding, fueled in part by patients seeking natural remedies over conventional pharmaceuticals. A 2010 

demonstrates that the majority of integrative medicine visits involve a mental health condition, of which depression is the most common.

 As psychiatrists trained in Western medicine, we are disconnected from such therapeutic modalities and their evidence basis, often struggling to provide appropriate psychoeducation to our patients. Here, we adopted an “open-minded” approach and examined the evidence behind the use of saffron in patients with depressive disorders.

 plant and has been used in Eastern medicine for centuries for various ailments including mood.

 Cultivation of the stigmas, which contain the components believed to have therapeutic properties, is extremely labor intensive. Stigmas contain 4 bioactive compounds: crocins and crocetins, which are responsible for the characteristic deep yellow color of saffron; picrocrocin, responsible for the characteristic bitter taste; and safranin, responsible for the hay-like aroma.

 These compounds exert antioxidant, anti-inflammatory, serotonergic, neuroendocrine, and neuroprotective effects. 

of 6 double-blind RCTs, all conducted in Iran, encompassing 230 adults with major depressive disorder (MDD) brought forward compelling evidence for the efficacy of saffron as an antidepressant.

 All studies compared saffron dosed 30 mg per day against conventional antidepressants, or placebo. Two studies compared saffron with placebo treatment; 3 compared it with fluoxetine 20 mg daily; and 1 with imipramine 100 mg daily. Overall, there was a significant reduction in the 

, without statistical significance between groups.

Since then, additional studies have emerged. A randomized controlled trial (RCT) comparing citalopram to saffron, showed improvements in both depression and anxiety over 6 weeks as measured by the HAMD and the Hamilton Anxiety Rating Scale (HAMA) in patients with mild to moderate symptoms.

 Another double-blind RCT used a slightly higher dose of saffron at 50 mg daily against placebo in mild to moderate MDD patients over 12 weeks. A statistically significant reduction in depression was found, as measured by the Beck Depression Inventory (BDI).

 looked specifically at the stigma component crocin dosed at 15 mg twice daily as an adjunct to SSRI treatment in 40 patients and found significant score improvement on the BDI after 4 weeks when compared with placebo. More recently, Kashani and colleagues

 compared saffron dosed at 15 mg twice daily against fluoxetine 20 mg daily in the treatment of mild to moderate postpartum depression over 6 weeks and found equal efficacy among the 2 treatments. Remission and partial response rates were almost identical between the groups. A 2019 study restricted to a patient population aged 60 years and older compared reduction in HAMD with daily treatment of saffron 60 mg against sertraline 100 mg for 6 weeks.

 In line with previous studies of wider patient populations, the researchers concluded that both agents were equally effective at reducing depressive symptoms.

 analyzed 23 studies and demonstrated saffron had a large positive effect size over placebo for depressive symptoms (g = 0.99) and anxiety symptoms (g = 0.95) and when used as an adjunct (g = 1.23) to traditional antidepressant medications. The authors went as far to conclude saffron appeared superior to placebo, both interdependently and as an adjunct, but a potential publication bias was noted. Two more recent meta-analyses have found similar results. In a 2018 meta-analysis of 7 RCTs, saffron was of comparable efficacy to traditional antidepressants and without any reports of serious adverse events reported.

 Most recently, Khaksarian and colleagues concluded that saffron was as effective as fluoxetine in the treatment of MDD upon review of 8 RCTs.

Importantly, no serious adverse effects were reported in any of these saffron studies. In fact, one study even evaluated its cardio protective effects in patients with comorbid depression and prior histories of post-percutaneous coronary interventions.

 The underlying mechanism for this was hypothesized to be attributed to crocin scavenging free radicals, exerting antioxidant effects, and inducing hypotensive effects.

Thus far, in several small studies, saffron dosed at 15 mg twice daily has shown similar efficacy to conventional antidepressants. This finding, however, was only demonstrated in patients with mild to moderate severity of unipolar depression. The exact adverse effects, long-term outcomes, as well as feasibility for use in populations with comorbidities or on complex regimens have not been explored. It is important to note that in all studies, 4 to 6 weeks were required for any demonstrable improvement. It is also relevant to note that studies of cognitive behavioral therapy (CBT) in mild to moderate depression have shown results on par with conventional antidepressants, and with the studies of saffron.

 are selling it for $120 per ounce, equating to 280 doses and about 86 cents per day or $26 per month—

Current evidence is intriguing regarding the potential antidepressant effects of saffron. We certainly do not consider this to be ready for clinical implementation and do not advocate for its endorsement by physicians in replacement of the current standard of care. However, it is likely that in our practices, we will encounter patients who have questions concerning integrative therapeutic modalities, and it is important to know the existing evidence as well as limitations of recent studies. Potentially, if saffron is to undergo rigorous large trials for safety and efficacy and obtain FDA approval, it could serve as an option for patients with unipolar mild-moderate depression who are resistant to conventional antidepressants or CBT.

is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is the Addiction Section Editor for 

is an upcoming PGY-5 Addiction Psychiatry Fellow at Dartmouth’s Geisel School of Medicine, Hanover, NH. The authors report no conflicts of interest concerning the subject matter of this article.

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Articles

Patients often have questions concerning integrative therapeutic modalities, and it is important to know the existing evidence as well as limitations of current research. 

Is There a Role for Saffron Phytotherapy in Treating Depression?

Affective disorders are among the most debilitating psychiatric conditions and afflict 20% of the population while contributing to significant morbidity and mortality.

 The association between cannabis use and unipolar depression has been well documented, as individuals with cannabis dependence are almost three times more likely to suffer from depressive disorders than the general population.

 Those with depressive conditions are in turn twice as likely to use cannabis than the general population.

 In patients with bipolar depression, much of the same is 

 cannabis use at baseline predicted an increased risk of manic symptoms at the three-year follow-up. There is now also evidence from longitudinal population-based 

 that suggest long-term cannabis use is associated with increased risk of suicidal ideation, suicide attempt, and death by suicide in a dose-dependent manner.

According to the National Academy of Sciences, Engineering, and Medicine 

 which summarizes the most comprehensive state of evidence regarding the health impacts of cannabis, there is a moderate level of evidence to support that cannabis use is associated with increased risk of developing depressive disorders; increased incidence of suicidal ideation and behavior (attempts as well as completion, particularly in heavy users); and increased symptoms of mania and hypomania in users with bipolar disorder. Limited 

 from statistical association raises concern that cannabis use increases the likelihood of developing bipolar disorder.

The role of the endocannabinoid system has been of interest since the 1990s when it was first discovered. A reduction in serum levels of 2-arachidonoylglycerol, one of the endocannabinoids, has been 

 in females diagnosed with major depressive disorder.

 Postmortem studies have also demonstrated 

 in cannabinoid receptor type 1 density and mRNA levels in the dorsolateral prefrontal cortex of those with depression who died by suicide.

 There is abundant further evidence to support that deficiency and overall dysregulation in endocannabinoid signaling is implicated in the pathophysiology of affective disorders.

The only randomized controlled trials of cannabinoids in humans for affective disorders are rather limited and date back to the 1970s.

 Here the investigators attempted to use oral tetrahydrocannabinol (THC) only in the treatment of unipolar and bipolar depressive disorders. Not only was there a complete failure of an antidepressant response, but also poor tolerability was demonstrated in the form of dysphoric, psychotic, and anxiety reactions.

 eight psychotropic-free hospitalized patients (four with bipolar depression and four with unipolar major depression) received under double blind conditions a seven-day course of placebo, followed by a seven-day course of twice daily oral THC 0.3 mg/kg, and then seven days of placebo. There was a 50% dropout during the THC treatment phase due to adverse effects such as severe anxiety attacks and depersonalization presenting as early as the first dose.

 13 hospitalized patients (five with bipolar depression and eight with unipolar major depression) were observed for 3 weeks and subsequently received, under double blind conditions, either oral THC titrated from 5 mg daily up to 20 mg twice daily or placebo. Seven participants experienced dysphoric reactions and six had to drop out due to panic reactions or psychotic disturbances, which occurred as early as the first dose.

There is much to be learned about the exact implication of the endocannabinoid system in mental health symptoms and overall clinical conditions. However, the current body of available knowledge certainly suggests involvement. Although the majority of data provide mere association, if one accepts the implied bidirectional relationship, there is significant concern of harm in individuals with affective disorders and cannabis use should be discouraged.

Although a better understanding of the endocannabinoid system may unveil pharmacotherapeutic targets, this is likely years away. To expedite this, pharmaceutical-grade cannabinoids are now available and should be utilized in furthering such research.

At this point, all organizations for mental health have issued warnings discouraging endorsement of cannabis use in general, as well as for attempts at management of any mental health clinical conditions. As clinicians, we need to be well versed with the above data in order to have meaningful conversations with our patients who are cannabis users or contemplate use.

is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. 

is a PGY-4 General Psychiatry Resident at Dartmouth’s Geisel School of Medicine, Hanover, NH. The authors report no conflicts of interest concerning the subject matter of this article.

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The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies

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Unpregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims

Î9-tetrahydrocannabinol in depressed patients

High frequency of dysphoric reactions to tetrahydrocannabinol among depressed patients

This research update underscores the need to be well versed in the data in order to have meaningful conversations with our patients who are cannabis users or contemplate use.

Nikhil Teja, MD

Articles

Is There a Role for Saffron Phytotherapy in Treating Depression?

An Overview of Cannabis Use in Individuals With Affective Disorders