Lopresti AL, Smith SJ. An examination into the mental and physical effects of saffron extract (affron^®) in recreationally-active adults: A randomized, double-blind, placebo-controlled study. J Int Soc Sports Nutr. June 7, 2022;19(1):219-238. doi: 10.1080/15502783.2022.2083455.

Many people turn to dietary supplements to enhance physical and mental performance. Increasing evidence supports the efficacy of saffron (Crocus sativus, Iridaceae) for these purposes. However, more evidence is necessary to support the potential mood-enhancing and ergogenicity of saffron. As such, this randomized, double-blind, placebo-controlled, parallel-group trial aimed to investigate the mental and physical effects of saffron in healthy, recreationally active adults.

Participants were recruited using social media advertisements and email databases between June and August 2021. Healthy participants aged 18 to 65 years who engaged in aerobic exercise more than three times per week for at least 45 minutes and at least six months before the study were eligible for inclusion. Those with the following criteria were excluded: presence of a medical condition or serious psychiatric disorder; regular use of medications or recent change in medications; significant injuries that affected study participation; illicit drug use or alcohol use disorder; excessive caffeine intake; significant surgery within the last year; or reported planned lifestyle change during the study period.

Eligible participants were randomized to a treatment or placebo group. The treatment group received a tablet containing 14 mg of saffron extract (affron^®; Pharmactive Biotech Products SL; Madrid, Spain) standardized to contain > 3.5% lepticrosalides, a measure of the bioactive compounds in saffron, including safranal and crocin isomers. The placebo tablet contained microcrystalline cellulose and calcium hydrogen phosphate, the same excipients in the saffron extract. The participants were instructed to continue their routine exercise regimen and take one tablet of their assigned treatment — which were matched for color coating, shape, and size — twice daily for six weeks. Treatment adherence was assessed using a mobile phone pill monitoring application.

The primary outcome was a change in the enjoyment of exercise as assessed by the Physical Activity Enjoyment Scale (PAES). The other outcomes included changes in mood states as assessed by the Profile of Mood States, Abbreviated Version (POMS-A) questionnaire, health-related quality of life as assessed by the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) questionnaire, and changes in sleep time and efficiency as assessed by a sleep, activity, and heart rate tracker (WHOOP) worn on the wrist. Blood samples for plasma concentrations of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and oxytocin were collected at baseline and week 6 to assess changes related to stress, fatigue, and mood. The tolerability of the treatments was assessed every 14 days.

Sixty-two participants met the inclusion criteria and were equally randomized to receive saffron or a placebo. One participant from the saffron group withdrew for an unknown reason, and two participants from the placebo group withdrew for an unknown reason and a sports injury. There were no significant inter-group changes in physical activity, body mass index, or blood pressure over the study period. For the primary outcome, a statistically significant increase in PAES score was observed over time in the saffron group (P = 0.001) but not the placebo group. There were no significant inter-group differences. An analysis by sex revealed that changes in PAES scores over time were significantly greater for males but not females in the saffron group compared with placebo. There were no significant inter-group differences in changes in POMS-A total mood disturbance scores or the PROMIS mental health and physical health scores.

For the WHOOP measurements, no significant inter-group differences were observed for changes in heart rate variability (HRV), resting heart rate (RHR), total sleep time, or sleep efficiency. Analysis of changes by sex revealed that males in the saffron group experienced a significantly larger increase in HRV over time compared with placebo (P = 0.001) with no significant inter-group differences observed in any of the WHOOP measures over time for females. There were no significant inter-group differences for changes in BDNF, NPY, or oxytocin over time. A sub-analysis by sex also revealed no significant inter-group changes in these blood measures. Treatment compliance was > 90% for all participants except one, and 69% of participants were unable to correctly identify their allocated treatment. Adverse events were reported in 16% of the participants from the saffron group and in 6% of the placebo group. In the saffron group, self-reported adverse effects included vivid dreams, increased muscle pain, and increased thirst. In the placebo group, there were reports of headaches and sleep disturbances.

Based on their findings, the authors conclude that supplementation with 14 mg of a saffron extract twice daily for six weeks was associated with improvements in self-reported exercise enjoyment and mood in healthy, recreationally active adults. However, these improvements were not significantly different compared with participants taking a placebo. A greater improvement in exercise enjoyment and mood was found in males but not females taking saffron compared with placebo, which the authors attribute to hormonal differences. Hormonal differences may also explain in part why males but not females in the saffron group experienced a greater increase in HRV as measured by WHOOP. Finally, no significant inter-group differences were observed for changes in BDNF, NPY, or oxytocin concentrations. The authors cite limitations related to small sample size, particularly after sex-based sub-group analyses and the use of WHOOP instead of gold-standard measures of sleep and HRV, which utilizes an electroencephalogram or actigraphy measures. As such, the authors call for future trials that use larger sample sizes, vary treatment periods, and utilize gold-standard outcome measures. Changes in sex hormones related to saffron supplementation and further research investigating mechanisms of action should also be examined.

Examining the effects of saffron as an adjunct to various exercise interventions in people of varying age, fitness level, mood, and exercise motivation will also be helpful to understand the mental and physical effects of saffron.

This study received funding from Pharmactive Biotech Products SLP. The lead author (ALL) is the managing director of a contract research organization that has received funding from unspecified nutraceutical companies. ALL has also received presentation honoraria from nutraceutical companies.

—Gavin Van De Walle, MS, RDN