Introducing Tro+ Mune

This article was originally posted on March 25, 2024 and updated on October 10, 2024.

Last October 2023, Troscriptions released Tro Zzz, our first product containing cordycepin. Tro Zzz contains 40 mg of cordycepin, a dose that enhances deep, slow-wave sleep (more on this later!) alongside several ingredients that modulate the GABA system.

On Pi Day, 2024 (3.14), we released Tro Mune, our health optimization ingestible troche for immune support which contains 75 mg of cordycepin for general sale.

This October 2024, we released Tro+ Mune for practitioners only, which contains 150 mg of cordycepin. Tro+ Mune’s higher cordycepin dose has many potential benefits which we will be discussing in this article, particularly its powerful effects on the immune system and as a profound neuroinflammatory downregulator. 

Before we get more into cordycepin, however, let’s first dive into a brief background on the Cordyceps mushroom.

Cordyceps

Cordyceps is a genus of fungus that contains approximately 600 described species. The name Cordyceps originates from the combination of Kordyle, meaning “club” in Greek, and -ceps, meaning “-headed” in Latin. These fungi have a worldwide distribution, though they are predominantly prevalent in Asia. The majority of the species are endoparasitoids, parasitic mainly on insects, arthropods, and even other fungi [1].

Once its spores infect the host, Cordyceps invades its organs, leading to its death. The fungus grows on the dead host, using it as a nutrient source until new spores are released to re-initiate the cycle on another host [2]. Some Cordyceps species even alter the host’s behavior (i.e., zombify) before killing it to maximize spore spreading [3]. But don’t worry, this is not The Last of Us, and Cordyceps will not infect humans! 

Many variants of Cordyceps have been used in Chinese medicine for more than a millennium, particularly Cordyceps sinensis, a highly regarded medicinal herb in Asia [2]. This fungus is thought to have been discovered 2000 years ago and its use was documented formally in the Qing dynasty in 1757 [4]. Most scientific research has been conducted on C. sinensis, which is included in the Chinese Pharmacopoeia [5]. However, due to complications in its endemic occurrence, growth, and life cycle, the long-term process of symbiosis is time-consuming, and the harvesting process of this species from its natural site in the high-altitude plateaus of the Himalayas results in a very difficult and costly endeavor [5].

As such, many have turned to Cordyceps militaris, which can be grown and obtained in vitro. In contrast to C. sinensis, C. militaris can be found in the tropical regions of the Northern Hemisphere. C. militaris is considered an alternative to C. sinensis because the qualitative and quantitative composition of bioactive substances from in vitro-cultivated C. militaris do not differ from those in C. sinensis fruiting bodies [5]. 

Notably, it was while investigating the antimicrobial activities of C. militaris for potential antibiotic development that scientists isolated cordycepin [6], an adenosine analog that has been found to have anti-inflammatory [7], anti-proliferative [8], and pro-apoptotic effects [9], among others (discussed below). Typically, there are only 300 to 800 micrograms of cordycepin per gram of C. militaris. C. sinensis, however, cannot synthesize or can only synthesize negligible amounts of cordycepin under in vitro culture conditions [10].

Cordycepin

Cordycepin, also known as 3’-deoxyadenosine, is a compound typically derived from the species C. militaris. It is a 3’-deoxyribonucleoside and a derivative of adenosine, differing by the replacement of the hydroxy group in the 3’ position with hydrogen. Though originally extracted from C. militaris, it can now be synthesized directly from adenosine in a multi-step process [11].

Adenosine is a naturally occurring nucleoside that plays a significant role in the brain as a modulator with a generally inhibitory effect on neuronal activity. This is achieved through tonic activation of adenosine receptors (A1 and A2A) found in the extracellular space of brain tissue, resulting in inhibitory effects that are crucial for a range of neural functions including sleep regulation, neuroprotection, seizure susceptibility, and even the modulation of effects of substances like ethanol and chronic drug use [12].

Due to the absence of oxygen in the 3’ position of cordycepin’s ribose moiety and its structural similarity to adenosine [13], some enzymes such as adenosine kinases, which typically phosphorylates adenosine to AMP, ADP, and ADP, cannot distinguish between cordycepin and adenosine, thus leading to the conversion of cordycepin into cordycepin mono, di, and tri-phosphate. It is this latter form, cordycepin tri-phosphate, that participates in several biochemical reactions discussed below [14,15]. In addition, cordycepin's structural difference from adenosine also greatly increases its potency due to its resistance to enzymatic degradation [16]. 

Cordycepin has received much attention due to its broad-spectrum biological activity and therapeutic potential, including anti-diabetic, anti-fungal, anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anticancer, and antiviral properties, among many others [17]. In the succeeding sections, we’ll detail some of cordycepin’s many benefits, particularly on the immune system, and the studies that support them. We will also discuss cordycepin dosing and give corresponding human dosing, when appropriate, in a summary at the end of the article. 

Cordycepin promotes deep sleep

Due to cordycepin’s similar chemical structure to adenosine and its resistance to enzymatic degradation, some studies have focused on its diverse effects on the central nervous system, such as sleep regulation. Studies have found that targeting adenosine receptors can aid in treating sleep disorders, including insomnia [18]. 

In an animal study to determine whether cordycepin increases natural sleep in rats, cordycepin was found to reduce sleep-wake cycles, increase non-rapid eye movement (NREM) sleep, decrease REM sleep, and decrease wakefulness [19]. 

Given its efficacy, cordycepin could be a potential therapeutic aid for sleep disorders, especially those where deep sleep is affected. Deep sleep is essential for glymphatic system function. It is also when our immune system does significant heavy lifting. So it can be easily argued that increasing deep sleep using cordycepin very likely has a direct effect on immune performance, in addition to the detailed mechanisms discussed later in this article. As mothers always say, sleep is the best medicine! 

Cordycepin protects the brain

Research has shown that cordycepin might provide long-term neuroprotective effects. For instance, in a traumatic brain injury (TBI) mouse model, cordycepin was intraperitoneally administered for a week, which ameliorated long-term neurological deficits and reduced neuronal tissue loss, as well as preserving the long-term integrity of white matter [20]. 

In Parkinson’s disease, a study with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model found that cordycepin significantly mitigated MPTP-induced behavior disorder and neuroapoptosis, diminished the loss of dopaminergic neurons in the striatum-substantia nigra pathway, elevated striatal monoamine levels and its metabolites, and inhibited the polarization of microglia and the expression of pro-inflammatory factors [21]. 

In Alzheimer’s disease (AD), a study investigated the neuro-promoting effects of cordycepin on amyloid-beta precursor protein synthesis in human neuroblastoma SH-SY5Y cells, and it was found that cordycepin boosted SH-SY5Y cell proliferation and decreased AD pathology [22].

Cordycepin’s anti-allergic and anti-inflammatory properties

Extracts of C. militaris and C. sinensis have both been found to have anti-allergic properties; the former in the management of allergic enteritis and modulating gut microbiota, and the latter in the alleviation of immune hypersensitivity reactions in allergic rhinitis and asthma [23,24]. Cordycepin has also been shown to exert anti-asthmatic activity in ovalbumin-induced asthma mice [25,26]; additionally, when co-administered with corticosteroids, cordycepin exhibited a synergistic effect on these animal models [27].

Cordycepin’s effects on inflammation and inflammatory diseases have also been extensively studied. Increasing evidence suggests that cordycepin ameliorates inflammatory disorders by reducing the levels of pro-inflammatory mediators and regulating various signaling pathways, including NF-κB, RIP2/Caspase-1, Akt/GSK-3β/p70S6K, TGF-β/Smads, TNF-alpha, Nrf2/HO-1 among others [28]. 

For example, in a murine macrophage RAW 264.7 cell study, cordycepin suppressed the production of pro-inflammatory mediators such as inducible nitric oxide and prostaglandin E2. Also, it inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha and interleukin (IL)-1-beta [29]. Similarly, in mice models of atopic dermatitis, oral administration of cordycepin induced fewer infiltrated immune cells and lower levels of cytokines, thus ameliorating symptoms [30]. 

Cordycepin’s anti-viral and anti-cancer properties

Cordycepin has been found to enhance immunity by inhibiting the proliferation of viral RNA and suppressing cytokine storms, thereby suggesting its potential in the treatment of viral infections [28]. Cordycepin also promotes anti-tumor functions in immune cells by upregulating immune responses and downregulating the tumor microenvironment. Additionally, it is also associated with cytokine production and stimulates phagocytosis in immune cells, highlighting its role in both enhancing and regulating the immune response [31].

Cordycepin’s structural similarity to adenosine allows it to potentially interfere with DNA and RNA synthesis, the inhibition of which is widely used in anti-viral and anti-cancer therapy as nucleic acids are essential macromolecules [32]. It is well-established that cordycepin can terminate RNA synthesis when incorporated into RNA polymerases and poly(A) polymerase, likely in its bioactive form cordycepin-triphosphate [33,34]. 

A study on the inhibitory activity of cordycepin on SARS-CoV-2 replication found that it was able to potently inhibit the multiplication of the new resistant strains of the virus with a very minute in vitro anti-SARS-CoV-2 EC50 (the half-maximal effective concentration), indicating the possibility of repurposing cordycepin against COVID-19 and other viral infections [35].

As cancer is caused by an imbalance between the progression of the cell cycle and programmed cell death or apoptosis [36], the majority of anti-cancer drugs and treatments exert anti-proliferative effects through cell cycle arrest and the induction of apoptosis [37,38]. In cancer studies, cordycepin has been found to exert antiangiogenic, anti-metastatic, and antiproliferative effects and induce apoptosis [39]. By activating receptors that typically respond to similar molecules such as adenosine or adenosine triphosphate, cordycepin can induce apoptosis. 

In addition, cordycepin may inhibit mTOR signaling, leading to a reduction in cell proliferation and growth. This effect is particularly relevant in the context of cancer, where hyperactivation of the mTOR pathway is common [40]. 

In a study investigating cordycepin’s anti-tumor effect on colon cancer both in vitro and in vivo, cordycepin was found to inhibit the growth, migration, and promoted apoptosis of CT26 cells in a dose-dependent manner [41]. In human gallbladder cancer cell lines NOZ and GBC-SD and lung cancer lines, there was a similar effect found [42,43]. 

Cordycepin’s mitigation of metabolic disorders 

In a type 2 diabetes mellitus (T2DM) mouse model study, C. militaris extracts, and cordycepin were found to downregulate glucose and lipid metabolism parameters, oxidative stress biomarkers, and inflammation cytokines, indicating that C. militaris extracts and cordycepin could alleviate T2DM [44]. 

Based on these findings, cordycepin may affect insulin resistance, blood sugar level, amino acid metabolism, fatty acid metabolism, anti-inflammatory capacity, and energy supply in T2DM through several metabolic pathways but primarily as an inflammatory downregulator.

In another study, diabetic mice were intraperitoneally administered different doses of cordycepin daily for 21 days; the results showed that cordycepin elicited hypoglycemic activity and contributed to the regulation of glucose metabolism in the liver, therefore it is possible cordycepin could alleviate some metabolic syndrome symptoms via the regulation of glucose absorption in vivo [45]. 

Additional studies show that cordycepin, through the activation of AMPK and the downregulation of inflammation, may also reduce total lipids, DL-C, VLDL-C as well as LDL-C/HDL-C and TC/HDL-C ratios [46].

Cordycepin Dosing 

Many human studies have used Cordyceps mushrooms, but few have used cordycepin alone. We do know, however, that in humans, 3.5-6.0 g/day of Cordyceps extract is considered therapeutically effective and shows no adverse effects [47,48], with cordycepin only taking up to 0.97% in the fruiting body and 0.36% in the corpus of C. militaris [49].

In addition, the maximum tolerance of cordycepin in mice with no adverse effects was found to be 3600 mg/kg [45], an extremely high dose. In comparison, the therapeutic dose is usually around 60 mg/kg in animal models [50]. Although the therapeutic dosages of cordycepin used in studies vary, the significant difference in the therapeutic range and the maximum dose, without the induction of any adverse effects, highlights cordycepin’s exceptional safety profile (see some precautions below).

For studies on cordycepin and sleep, the converted dosing of 2-4 mg/kg where mice had a deep sleep benefit is approximately equivalent to 12-24 mg for humans. For studies involving neuroprotection,10 mg/kg for mice converts to approximately 121 mg for humans. For cancer and diabetes studies, the converted dosing for cordycepin ranges from 145 to 150 mg in humans. 

We chose 150 mg for Tro+ Mune because it was the highest equivalent dosage of cordycepin used therapeutically in these clinical studies.

Precautions

As the Cordyceps mushroom is naturally occurring, it is considered pharmacologically safe for human consumption, and this extends to cordycepin, one of its natural extracts. However, in some cases, the Cordyceps mushroom has been reported to cause dry mouth, nausea, abdominal distension, throat discomfort, headache, diarrhea, and allergic reactions; as such, patients suffering from systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis may want to avoid consumption [51].

Concerning cordycepin, clinical evidence on the interactions with drugs or supplements is limited and is based on a theoretical understanding of its pharmacological actions rather than direct evidence. Caution is especially advised for patients on anticoagulants and antiplatelet drugs, diabetic drugs, hypertensive drugs, and chemotherapeutic agents. In addition, cordycepin will increase deep sleep so it should be taken in the evenings, before bed. 

Conclusion

In this article, we took a deep dive into cordycepin. Specifically, we discussed the fungi it originates from, its molecular mechanisms, and its wide range of beneficial properties, including deep sleep, neuroprotection, anti-allergy, anti-inflammatory, anti-viral, anti-cancer, and the regulation of metabolic disorders. We also discussed the potential dosing and precautions. 

Tro Zzz was created to enhance sleep induction, increase sleep time, enhance deep sleep, and make it easier to go back to bed, even if wake-ups still occur. In this product, we combined cordycepin with the power of the GABA system for a comprehensive sleep solution.

While sharing the sleep-enhancing effect thanks to cordycepin, Tro+ Mune was created for immune support. It helps fight off foreign invaders, decreases inflammation, protects the brain, enhances detoxification, and improves metabolic health.

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