SAFFRON
(Crocus Sativus L)
Saffron is a common spice, [predominately used in middle eastern and Mediterranean diet and has for a long time been used for its incredible odour and colour it can give food, especially on rice (when traditionally used in Iran as an example). Enough about its use in diet, lets delve deeper into its active constituents and the reasons that make it a therapeutic agent for various disorders in the modern age. It also goes without saying, that there's no doubt its long history was likely due to its medicinal benefits.
In the modern era, its been closely analysed for a wide range of ailments including anywhere such as cancer (only in vivo and in vitro experiments) and not yet in clinical studies, yet with some potential for selective anti-cancer effects.
Unlike such effects however, not only in vivo, but also clinical studies involving humans have shown promising antidepressant effects from using various herbal extractions, involving our understanding of its phytochemistry and psychopharmacology. (Schmidt et al., 2007).
It’s important to note however that there’s still much we don’t know about its exact pharmacology and even its active constituents. So far, its established that we’re dealing with at least 150 volatile and several non-volatile compounds and its estimated that only about 40-50% of its active constituents have been identified, at least it was so as of 2016.
At least two glycosides including Crocin with its distinctive yellow orange colour, picrocrocin (generally consisting at about 4% of total percent and contributing to its slight bitterness. In addition to these, there seems to be an abundance of volatile oils (between 0.4 to 1%), carotinoids, fatty oils and also starch.
Most of the pharmacological studies surrounding the spice revolved around its antidepressant, anxiolytic, anticonvulsant, memory improvement, treatment of tremor and morphine induced withdrawal symptoms, along with everything from anti-cancer to smooth muscle relaxation properties, anti-inflammatory, analgesic and even hepatic, renal and cognitive CNS protective characteristics. (Al-Snafi, 2016)
Of all these various mechanisms and effects however, only a select few have shown their significance when it comes to animal and especially human trials. For example, spice's anticonvulsant and anti-Alzheimer's effect have been shown in clinical trials involving both species. More importantly, its clinical efficacy in treating mild to moderate depression through its active constituents that appear to influence increased levels of glutamate and dopamine in the brain in a dose-dependent manner has clinically shown in human studies (albeit not high quality ones as of yet). Its interaction with the opioid receptor has also been clearly identified and shown to at least have an effect on morphine withdrawal via a yet to be known mechanism and relative potency.
The Saffron aroma is due to its constituent aglyconesafranal and accompany various other cartenoids and glycosides including alpha-crocetin (leading to its yellow color), at least two other cartenoids and even small amounts of vitamin B2. ( (Khazdair et al., 2015) In aqueous extracts of the stigmas, crocin but not safranol shown an effect on enhanced sexual activity when tested in rats. Interestingly, newer clinical studies have even shown that it can reverse SSRI-induced sexual dysfunction and loss of libido and anorgasmia when used in a combination therapy, so this effect has been established in more than just rats. This is in additional to both crocin as well as safranol being powerful oxygen radical scavengers. (Farahmand et al., 2013)
In traditional medicine, the spice and its extracts were used as both a herbal sedative, as well as a stimulant, a diaphoretic, in addition to an expectorant. Even its aphrodisiac effects and antispasmodic use was quite common throughout its old history (Nemati et al., 2008). In one experimental study, it was even shown to be effective in relieving symptoms of premenstrual syndrome (PMS), with a significant observation on the Total Daily Menstrual Daily Symptoms and Hamilton Depression Rating, especially in cycles 3 and 4. (Agha-Hosseini et al., 2008)
Earlier studies had shown that ethanolic extracts of the petals of the spice have shown to reduce blood pressure in both rats and guinea pigs (at a dose of 500 mg/kg). (Fatehi et al., 2003) Additionally, it was shown that certain crocin analogues isolated from saffron noticeably enhanced blood flow in the retina and even facilitated retinal recovery in guinea pigs. Some of these studies were partially confirmed in human participants who's normal white blood cell count (WBC) significantly increased following the administration of whole spectrum saffron extract, rather than crocin isolates or placebo, suggesting other mechanisms and/or compounds may be contribute to this effect. Its also important to note that these hematologic factors were unchanged for the duration of the 3 months throughout which this particular study was closely monitored. (Mousavi et al., 2015)
A potent stimulatory effect of saffron was linked to its safranal content and showed a downregulation on beta-2-adrenoreceptors. Moreover, safranal appeared to produce a blocking effect on muscarinic receptors and a mild inhibitory effect on histamine (H1) receptors, proposing a potential for being a competitive antagonist for this receptor. (Nemati et al., 2008) (Boskabady et al., 2010). In another experiment using a saffron extract, it was shown in mice that alcohol induced impairment of learning behaviour is reversed and prevented the inhibition of hippocampal potentiation produced by alcohol in the long run (ethanol) which is supposedly related to activity-dependent synaptic plasticity and hence involved with memory and learning, at least in mice. (Abe and Saito, 2000)
Moving now more toward the pharmacokinetics and practical use of saffron extracts at this time, there have been numerous human clinical studies done on its more exact metabolism and the digestion process involved with the orally ingesting extract tablets, with their standardized bio-active components. The extract used was called "Affron".
One study which was done by calculating blood samples of healthy individuals every 30 minutes during the first 3 hours, and once at the 24 hour mark. This was after the administration of two relatively low doses of an extract in doses 56 and 84 mg, in 13 individuals. In addition, HPLC-PAD/MS analysis was performed for the identification of its active components and their distribution throughout the body. Roughly 40% bioavailability was observed for crosin isomers, with safranal showing up to two-fold increase in its concentration after the digestion process. Crocetin itself reaches maximum plasma concentrations within 60 - 90 minutes after oral consumption, showing dose-dependent response kinetics, while demonstrating that many crocin isomers are rapidly transformed into crocetin and therefore appropriate for medicinal use of different kinds, primarily via standardizations based on crocetin. The fact that the formulation was in a galenic form is at least partially thought to be an influence in a similar in terms of Cmax, whilst having an improved bioavailability and a quicker onset of effects.
In summary, besides the general use of saffron as a spice in food and its use in diet, the medicinal role of safranal and crosin isomers which show bio-activity and therapeutic potential, especially when combined with other naturally-occurring antioxidants such kaempferol derivatives. It should also be highlighted that picrocrotin is very poorly absorbed in the gut. The psychoactivity of its aforementioned compounds are likely the result of the proposed antidepressant and anxiolytic effects due to its inhibition of monoamines including serotonin (with unknown exact potency and dose response), NMDA antagonism and GABA agonism. With the NMDA antagonism likely contributing to some of its application in treatment of ADHD, when compared in at least one double blind study with Ritalin (methylphenidate). Meanwhile, its anti-inflammatory, neuroprotective and antioxidant characteristics may contribute to its benefits on the eye. It was also established that with this particular formulation (Affron), even the consistency of up to 2-3 mg of crocin was enough to obtain a similar Cmax values compared to studies using higher doses of the purified compound, hence showing relatively good efficacy in terms of bioavailability and rapid absorption with this galenic formulation. (Almodovar et al., 2020). Saffron may also have a potential role in cancer, reducing cardiovascular disease and age-related macular degeneration.
The half life of full spectrum saffron with the main constituent where it is detected by crocetin tends to be 6-7 hours, with a blood peak level at the 4 hour mark, on average. In most clinical studies, doses ranging from 20 - 400 mg/day of pure saffron has been used. However, doses up to 1.5g a day appear to be considered likely safe, with toxic effects having been reported at doses 5g and above.
Doses 10 - 20 g may be fatal. An average dose for depression can be as little as 20 - 30 mg/day of either saffron extract or stimga/petal), while doses up to 400 mg/day have been used for hypertensive purposes. Caution is always advised when combining serotonergic compounds (natural or synthetic) with antidepressants, especially MAOIs.
