Cordyceps and Cordycepin: The Zombie Fungus with Massive Therapeutic Potential

The depiction of zombies in fantasy and science fiction has evolved over the decades. Initially, it was black magic or evil spells that raised the dead from their graves. However, in recent years, movies and video games have found more sophisticated ways of bringing the undead to life: radiation, biological weapons, genetic modification, and viruses, transforming them into what we now know as the ”infected.”

Earlier this year, HBO aired “The Last of Us,” a TV series based on a blockbuster zombie video game. The plot is simple: a pair of individuals trying to survive in a post-apocalyptical world overrun by the undead. Interestingly, this time, the cause of the pandemic was not a virus, but a fungus named Cordyceps. In a very clever introductory scene, epidemiologists talk about pandemics in a TV studio. One of them brings up the possibility of a global pandemic triggered by a fungus that takes control of human behavior, much as Cordyceps does with insects. Scary, huh?

But fear not, it is just a TV series.

Cordyceps does infect insects and, in some cases, alters their behavior to serve their own needs, but we humans are far from being turned into walking, hypertrophied mushrooms with cannibalistic instincts. On the contrary, Cordyceps has been used for centuries in traditional Chinese medicine due to its numerous benefits.

We briefly discussed Cordyceps in a previous article about therapeutic mushrooms, but in this article, we will go into more depth with an overview of the mushroom, its active component cordycepin, how it works, and reveal its promising therapeutic applications for a whole host of conditions.

What is Cordyceps?

Cordyceps is a genus of fungus that includes more than 500 described species. The name Cordyceps originates from the combination of two words: Kordyle, meaning “club” in Greek; and the stem ceps, meaning “head” in Latin. These fungi have a worldwide distribution and are prevalent in humid temperate and tropical forests, acting as endoparasites that infect insects, other arthropods, and even other fungi [1].

Once the spores infect the host, the mycelium invades the organs of the host, leading to its death. The fungus then grows on the dead host, using it as a nutrient source until new spores are released to initiate the cycle anew [2]. Some species of the same family even alter the host’s behavior before killing it to maximize spore spreading [3], which has inspired the popular “zombie-ant” term and served as inspiration for post-apocalyptical dramas.

Cordyceps species typically exhibit a high degree of host specificity, infecting only one or a few closely related species at most. This specific parasite-host interaction stems from the highly specialized mechanisms that evolved to elude the host’s immune system [4]. Remarkably, the evolution of these mechanisms resulted in the production of unique metabolites that may have beneficial effects on human health [5].

For centuries, traditional Chinese medicine has used Cordyceps as food and medicine [6]. The two most commonly employed species are Cordyceps sinensis and Cordyceps militaris. While C. sinensis is mainly found in high-altitude plateaus of the Himalayas, C. militaris is present in humid and tropical forests in Asia, Europe, and North America. However, obtaining high quantities of Cordyceps from the wild is challenging and expensive as they naturally grow on subterranean caterpillar larvae. Consequently, this led to the advancement of artificial cultivation and production techniques, particularly for C. militaris, which demonstrates greater feasibility for laboratory cultivation [7-9].

In 1950, while investigating the antimicrobial activities of Cordyceps for potential antibiotic development, scientists isolated a compound they named cordycepin [10]. In a typical Cordyceps militaris, there is between 300 to 800mcg (micrograms) per gram of Cordyceps. This adenosine derivative has been found to have anti-inflammatory [11], anti-proliferative [12], and pro-apoptotic effects [13]. However, the precise mechanisms through which cordycepin exerts these effects remain intriguing. Let’s delve into the underlying molecular mechanisms and explore their impact on human health.

Molecular mechanisms of cordycepin

Cordycepin (also known as 3’-deoxyadenosine) is considered an adenosine analogue [14]. In other words, they have similar molecular structures. Adenosine belongs to a group of molecules called nucleosides, which are vital components of nucleic acids (DNA and RNA). In addition, nucleosides play fundamental roles in many biological processes such as energy transfer and cell signaling. They consist of a nitrogenous base and a ribose, a 5-carbon sugar. If they are bound to one, two, or three phosphate groups, they are called nucleotides. In particular, adenosine is formed by an adenine bound to a ribose, which can be mono-, bi-, or tri-phosphorylated (AMP, ADP, and ATP, respectively). Adenosine also exhibits anticoagulant properties and can induce vasodilation, bradycardia, and regulate the sympathetic nervous system [15].

Due to its structural similarities with adenosine, cordycepin exerts diverse effects on physiological and pathophysiological processes. It is converted into 3’-deoxyinosine and cordycepin-triphosphate, their bioavailable and bioactive forms, respectively, by the same enzymes involved in adenosine metabolism [15].

The potential therapeutic applications of cordycepin have attracted significant research attention [5], leading to numerous efficacy studies that have been conducted in various animal species. These studies report efficacy in animal models of sleep disorders [16], cancer [17,18], asthma and lung inflammation [19], viral infection [20], and more.

Role of cordycepin in inflammation

Cordycepin’s effects on inflammatory diseases have been extensively studied. Increasing evidence suggests that cordycepin ameliorates inflammatory disorders by reducing the levels of pro-inflammatory mediators [19]. For instance, by modulating MAPK and NF-κB signaling pathways, cordycepin reduces NO, PGE2, TNF-α, IL-1β levels, and the production of cytokines TNF-α and IL-6 [21,22]. These anti-inflammatory properties make cordycepin a potential therapeutic candidate for conditions like allergic asthma or atopic dermatitis.

Cordycepin is effective in animal models of allergic asthma, which is caused by lymphocyte, eosinophil, and neutrophil infiltration into the lungs [23]. Cordycepin treatment led to reduced IgE levels and fewer infiltrated T helper type 2 (TH2) cells, along with their associated cytokines (IL-4, IL-5, and IL-13). The anti-inflammatory effects on allergic asthma models are thought to be driven by the alteration of MAPK and NF-κB pathways [24]. Additionally, when co-administered with corticosteroids, cordycepin exhibited a synergistic effect on animal models of allergic asthma [25].

Atopic dermatitis is a common, chronic, and highly pruritic inflammatory disease of the skin. It is associated with infiltrated mast cells, eosinophils, and leucocytes, as well as increased levels of TH2-associated cytokines [26]. In mice models of atopic dermatitis, cordycepin treatment induced fewer infiltrated immune cells and lower levels of cytokines, which significantly ameliorated the condition of the animals [27].

The immuno-modulatory effects of cordycepin might open other therapeutic opportunities beyond inflammatory disorders. Cordycepin treatment ameliorated long-term neurological deficits and reduced neuronal tissue loss in a mouse model of traumatic brain injury (TBI). This long-term neuroprotection was achieved by suppressing the infiltration of neutrophils after TBI, thus preserving the blood-brain barrier [28].

Anti-viral and anti-cancer properties of cordycepin

DNA and RNA synthesis inhibition is widely used in anti-viral and anti-cancer therapy, as nucleic acids are essential macromolecules for every living cell [29]. Cordycepin’s structural similarity to adenosine allows it to potentially interfere with DNA and RNA synthesis. Interestingly, cordycepin exhibited promising in vitro results as an anti-viral agent against dengue [30], Epstein-Barr [31], and hepatitis C viruses [32]. Recent research demonstrated that cordycepin inhibited SARS-CoV-2 replication of cultured animal cells in a time-dependent manner, without observable cytotoxicity [33]. The active form of cordycepin, cordycepin-triphosphate, likely acts as a substrate of the viral RNA-dependent RNA polymerase, halting viral RNA synthesis.

Beyond viral infections, cordycepin’s interference with DNA and RNA synthesis may also impair cancer cell proliferation. In addition to its effects on nucleic acid synthesis, cordycepin may also disrupt nucleotide biosynthesis by inhibiting enzymes involved in this process [34]. These effects on DNA synthesis can lead to DNA damage and eventual cell death [35]. Notably, cordycepin treatment increased DNA damage in a mouse model of a Leydig cell tumor [36].

Cordycepin is believed to induce programmed cell death (apoptosis) by activating receptors that typically respond to similar molecules such as adenosine or ATP. Adenosine receptors (ADORAs), death receptors (DRs), and the epidermal growth factor receptor (EGFR) are some cell receptors that might be involved in cordycepin-driven apoptosis [34].

The AMPK pathway is known to be activated by cordycepin and adenosine, and this modulation of cell signaling pathways could be another way through which cordycepin exerts its anti-cancer effect. The nucleoside activates the AMPK-mTOR pathway as well as autophagy and apoptosis in ovarian cancer cells [17]. Cordycepin-mediated activation of AMPK increased the sensitivity of lung cancer cells to cisplatin treatment [37]. AMPK pathway activation by cordycepin has other interesting, potential therapeutic applications apart from treating cancer, such as preventing radiation ulcers [38] or improving non-alcoholic steatohepatitis by protecting the liver from steatosis, fibrosis, and injury [39].

Wound healing with cordycepin

Research has shown that cordycepin actively improves the wound healing process, emphasizing its potential benefits. Activation of adenosine receptors by a combination of adenosine and cordycepin enhances cell migration rate in cultured human dermal fibroblasts, suggesting that the dual treatment enhanced the wound healing process through activation of mTOR, GSK3b, and Wnt/β-catenin pathways [40].

Cordycepin mitigates insomnia

Insomnia symptoms are a common health issue, with an estimated worldwide prevalence of 30% [41]. Studies suggest that adenosine receptors can be targeted to treat sleep disorders. In a study carried out in rats, cordycepin reduced sleep-wake cycles, increased non-rapid eye movement (NREM) sleep, decreased rapid eye movement (REM) sleep, prolonged total sleep time, and decreased wakefulness [16]. Adenosine also regulates circadian rhythm through adenosine receptor binding, which activates Ca²⁺-ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2 [42]. These findings indicate that cordycepin and its derivatives hold promise as potential treatments for sleep disorders.

Adverse effects

Cordycepin is naturally occurring and generally considered safe, with rare adverse effects reported. The compound exhibits toxicity against healthy erythrocytes in mice when combined with chemotherapy [19]. Other adverse effects such as nausea, dry mouth, abdominal distention, diarrhea, throat discomfort, headache, and allergic reactions have been noted in humans [5].

The highest dose of cordycepin tolerated by mice with no adverse effects is 3600 mg/kg [43], while the therapeutic dose falls to 60-70 mg/kg [38]. Cordycepin showed no toxic effects in dogs when administered at a dose of 20 mg/kg for 3 days [44]. This notable difference between the therapeutic and maximum doses with no adverse effects underscores cordycepin’s exceptional safety profile.

Rats tolerate doses of 4000 mg/kg of Cordyceps mycelium extract with no observed adverse effects [45]. In the case of humans, 3.5-6.0 g/day of Cordyceps mycelium extract is considered therapeutically effective and shows no adverse effects [7,8]. Although the therapeutic doses are safe, it is advisable for individuals with specific medical conditions to seek medical counseling before using cordycepin.

Conclusion

As we have seen, Cordyceps won’t turn us into mushroom zombies; instead, it offers potential health benefits. But not only that! Clinical trials with molecules created by modifying cordycepin’s structure are currently underway to evaluate its efficacy against cancer [46].

Although the molecular mechanisms underlying cordycepin’s pharmacological activity are not yet fully understood, ongoing research aims to unravel its molecular interactions and validate its potential as a therapeutic agent for various conditions and as an immune modulator. These efforts may lead to new avenues for drug development and personalized medicine, offering hope for improved treatments and better patient outcomes in the future.

Interested in trying out cordycepin? Then check out Tro Zzz, our troche formulated for sleep, and Tro Mune, our health optimization troche for immune support! Both of these buccal troches have cordycepin as either their main ingredient or one of their main ingredients.

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