Research on Unwind+ ingredients
Magnolia bark (Magnolia officinalis)
Magnolia Bark has been used in traditional Chinese medicine for over 1000 years to treat conditions such as acute pain, depression, stress, anxiety and nervous disorders. It is native to the mountains and valleys of China.
Whilst there have been more than 250 compounds isolated from Magnolia Bark, the most significant active constituents appear to be honokiol, magnolol and related compounds.
Stress, anxiety and sleep
Honokiol and magnolol have many complex actions, however both seem to act in part via GABAA (gamma-aminobutyric acid) receptor modulation (1). Honokiol also appears to stimulate increased production of GABA via glutamic acid decarboxylase (GAD) enzyme upregulation (2). The GABA system is critical component for mind relaxationa and sleep. Both magnolol (3) and honokiol (4) have been shown to induce non-REM sleep in animal models.
In two double blinded, placebo controlled human studies of a proprietary formula of Magnolia Officinalis and Phellodendron amurense, there were reduced levels of transient anxiety (5) and night time cortisol (6) with the Magnolia Bark product. Interestingly, dihydrohonokiol from Magnolia Bark had significant anti-anxiety effects but did not exhibit withdrawal effects when compared with diazepam in an animal study (7). Honokiol in Magnolia Bark appears to inhibit catecholamine release (e.g. adrenaline/epinephrine) from adrenal glands in a bovine model and this effect increased with higher doses (8).
The mixture of magnolol and honokiol from Magnolia Bark reduced stress induced changes in rat brains, showing potent antidepressant-like effects (9). This was shown again in another trial with mice, demonstrating significant increases in serotonin (10).
Pain and inflammation
4′-O-methylhonokiol in Magnolia Bark has demonstrated the ability to activate the cannabinoid analgesic system via the CB2 receptor and additionally inhibit the COX2 system, both of which create a degree of analgesia (11). A combination of magnolol and honokiol alleviated inflammatory pain in a mice model (12) and in a separate third degree burns trial honokiol demonstrated reductions in various inflammatory cytokines therefore promoting analgesia (13). There are numerous other trials investigating different compounds from Magnolia Bark in inflammation that are beyond this page.
Honokiol is the subject of a large number of animal and now human trials in cancer patients with potentially promising results. This is outside the scope of this page and we make no claims whatsoever about the ability to treat or manage cancer. For those interested, here is a 2020 review with hundreds of references (14).
For Unwind+, we chose a potent 400mg of 10:1 concentrated extract (derived from 4000mg of Magnolia Officinalis) per two capsule dose supplying all the naturally occurring active ingredients such as magnolol, honokiol and 4′-O-methylhonokiol rather than just standardizing for a single ingredient.
Lemon balm (Melissa officinalis)
Lemon balm is a perennial herb of the mint family that has been used for centuries in traditional medicine to remedy anxiety and insomnia, digestive issues, headaches, infections such as herpes, and in skin care regimes.
Lemon balm contains a number of interesting active ingredients, most notably ursolic acid, oleanolic acid and rosmarinic acid (known to inhibit GABA transaminase (15)), and antioxidant/anti-inflammatory flavonoids such as apigenin and luteolin (16).
Anxiety, stress and sleep
A proprietary lemon balm extract given twice a day to humans for 15 days showed reductions in anxiety and insomnia (17). Similar results of anxiolysis were found in two mice studies (18,19). These effects are likely related to the ability of lemon balm to inhibit GABA transaminase (normally this enzyme breaks down GABA), promoting more of the inhibitory neurotransmitter GABA in nerve synapses. A systematic review of 10 randomised controlled trials published in 2021 showed a statistically significant improvement in anxiety and depressive symptoms with the use of lemon balm (20).
A randomised, double blind, placebo controlled trial of 98 people investigated the combination of valerian and lemon balm. There was a statistically significant improvement in the quality of sleep in the valerian/lemon balm group with no difference in serious adverse effects versus placebo (21).
Nootropic and neuroprotective properties
Lemon balm has also been investigated for its potential interactions with the acetylcholine/muscarinic/nicotinic system. In a trial of 20 healthy people there were notable improvements after one ingestion in the speed of memory tasks and visual information processing at higher doses (22). Neuroprotective effects have been demonstrated in a hypoxia induced neuronal death model (23) as well as a MDMA (‘Ecstasy’) induced neuronal death model (24).
Unwind+ has 60mg of a very potent 40:1 extract (derived from 2400mg of melissa officinalis) per standard two capsule dose. Lemon balm can become stimulating at very high doses in some people owing to its rosmarinic acid content, so it was important for us to understand where this inflection point may be. Our goal was to supply as much as we could of active ingredients without causing stimulation.
Passionflower (Passiflora incarnata)
Passionflower was originally native to the Americas, where it has been used traditionally to remedy anxiety, insomnia, gastrointestinal issues and seizures. It is complex and contains a number of active ingredients including flavonoids such as isovitexin, vitexin, apigenin, luteolin and quercetin, as well as alkaloids such as harmine, harmaline and harmalol. It also contains a benzoflavone moiety which some believe contributes to its central nervous system effects.
Anxiety, stress and sleep
Passionflower has been shown to modulate the GABA system in various ways including acting as a re-uptake inhibitor (25) - keeping more ‘relaxing/inhibitory’ GABA available in nerve synapses. Due in part to these effects, Passionflower has been demonstrated via a systematic review of nine clinical trials in humans to have anti-anxiety effects “comparable to drugs such as oxazepam or midazolam” without any significant adverse effects like memory loss (26). These trials stretched across a number of contexts including using passionflower as a pre-medication before surgery. A direct comparison to oxazepam for those with generalised anxiety disorder was studied and found that Passionflower had similar efficacy but had less adverse effects. In particular oxazepam impaired work performance more than Passionflower (27).
Passionflower has also been trialed in those with insomnia. In a double-blind randomized placebo-controlled study, 110 participants consumed a passionflower extract at night for 2 weeks whilst various objective measurements were taken including polysomnography (a type of ‘sleep study’). Total sleep time was significantly increased versus placebo with passionflower (28). Whilst less scientifically dosed, a passionflower tea has also been studied for sleep and demonstrated subjective sleep benefits (29). A combination of herbs including passionflower was directly compared to zolpidem (a prescription drug for insomnia) and was found to be safe and of comparable efficacy (30).
Like Lemon Balm, we have sourced a highly potent 20:1 extract of passionflower (derived from 2400mg of Passionflower Incarnata per two capsule dose). This provides a higher dose than in studies and most products available to promote the desired effect, given we did not discover any significant safety concerns. We also believe that Passionflower’s mechanisms work synergistically with the other ingredients in Unwind+.
Ziziphus spinosa (Zizyphus jujuba var. spinosa, semen ziziphi spinosae, chinese date, jujube)
Ziziphus seeds have been used in traditional Chinese medicine for centuries to calm the mind and spirit and specifically have been used as part of a concoction called Suan Zao Ren to treat insomnia.
Ziziphus (referring to the seeds, not the fruit) contains many active ingredients but the saponins such as jujubosides and flavonoids such as spinosin appear to be responsible for its main effects.
Anxiety, stress and sleep
The jujubosides have been shown to increase the expression and activation of the GABAA receptor (31, 32). Ziziphus has also been shown to modulate the 5-HT (serotonin) receptors involved in anxiolysis (33). Sanjoinine A, another saponin in Ziziphus, was found to upregulate the glutamic acid decarboxylase (GAD) enzyme and to augment pentobarbital-induced sleeping behaviour (34). GAD is the enzyme that catalyses the production of GABA from glutamate. Spinosin, another key ingredient of Ziziphus, has been shown to increase slow wave sleep (deep sleep), total sleep time and sleep latency. The study proposed this was due to modulation of 5-HT1A receptors (35).
In a randomised, placebo-controlled, cross-over trial of people with insomnia, there was a significant increase in both quality and quantity of sleep with Ziziphus (36).
Cognitive enhancement and neuroprotection
In the animal domain, there have been numerous trials suggesting positive brain effects including on memory, hippocampal plasticity and neuroprotection (37, 38, 39). Antioxidant, anti-inflammatory and potentially enhanced cholinergic transmission have been implicated for these effects. Specific discussion of these trials is outside the scope of this page. Hopefully in the future there will be further studies in humans examining these effects.
Since Ziziphus effects are mostly demonstrated at high doses by weight which cannot practically fit into a small number of capsules, we sourced a 30:1 concentrated extract. There are multiple active ingredients contributing to the desired effects so we didn’t look for the extract to be standardised to any single ingredient. Standard two capsule dosing of Unwind+ is derived from approximately 7.2g of dry seed, ensuring sufficient potency. As Ziziphus promotes REM sleep we felt much higher doses along with the other ingredients could cause excessively vivid dreams in some people.
Taurine (L-taurine, 2-aminoethanesulfonic acid)
Taurine is a critically important amino sulfonic acid compound with neural inhibitory (relaxing) effects as well as antioxidant effects. Taurine is found in many organs of the body but particularly in tissues containing ‘excitable’ cells such as the heart and brain, as well as the retinas. Some Taurine can be produced by the human body in health but this may be impaired in illness, stressful states and ageing. For optimal levels it can be obtained in a diet high in certain seafoods and meats and/or in supplemental form. As Taurine is only found in animal derived products (41), vegans will consume no Taurine in their diet and have been shown to have lower plasma and urine levels (42). The average meat containing diet is thought to supply around 40-90mg of Taurine per day (43,44).
Taurine is often misinterpreted to be a compound that provides an energy boost like guarana and caffeine because it is included in many energy drinks. In fact, Taurine is used in this context to provide a gentle relaxation effect to offset the jitteriness from excessive caffeine.
Optimal central nervous system function
Taurine sits alongside GABA and glycine as a major ‘inhibitory’ neurotransmitter with widespread effects including weak agonism at GABAA and GABAB receptors (45,46), anti-anxiety effects in animals by activating glycine receptors (47) and increased glutamic acid decarboxylase (GAD) expression in taurine fed mice (48) leading to higher GABA levels and increased seizure threshold. Taurine administration in mice, who like humans can synthesize Taurine, is thought to reduce age-related changes in the GABAergic system (49).
Whilst a long way from humans, an interesting study in fruit flies demonstrated reductions in sleep with caffeine and inversely enhancement of sleep time with Taurine (50).
Taurine has also been suggested as a novel agent to consider in those with depression after promising animal studies, particularly in diabetics (51,52,53).
In a human randomized, double-blinded, placebo controlled trial, Taurine administration was shown to reduce blood pressure in pre-hypertensive individuals (54) due to improvement in vascular function. In animal studies Taurine has shown to have free radical scavenging and cardiac protective effects (55) as well as limitation of atherosclerosis (56).
In humans there are small trials suggestive of improvements in cardiac function with Taurine administration (57,58). Further large scale research is required to clarify.
Taurine has also been trialed for its antioxidant effects in liver disease in both animals and humans. Evidence is mounting regarding liver protective effects in a number of liver disease states such as chronic hepatitis, alcoholism, non-alcoholic fatty liver disease and iron overload (59,60,61,62).
We have included 500mg of vegan Taurine in a standard dose of Unwind+. This is significantly more than most people consume per day whilst still being safe support for the brain’s relaxation pathways in combination with the potent herbal extracts present in Unwind+.
Unwind+ is a calming, science-based formula designed by We Know Health™ expert Steven Musca to:
Promote mind relaxation, reduce time to fall asleep*, enhance sleep quality* and promote refreshing sleep* by optimising your brain's GABA levels and more.
In this modern world, it is very challenging to unwind at the end of the day, reduce racing thoughts and drift off to sleep peacefully. Many of us are tense, worn out, 'wired but tired' and troubled by sleep deprivation. Unwind+ is expertly formulated for this situation.
Nothing to mess with your circadian rhythm hormones or make you drowsy in the morning... or herbs that smell like stinky feet here! We focused on a formula that would leave you feeling more refreshed and less hungover.
Oh and not to mention we are pioneering clean, transparent medicine labelling in Australia!
* As traditionally used in Chinese medicine.
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