In the opaque silence of the forest floor, fungi are hard at work. As the forest’s digestive system, they excrete acids and enzymes that orchestrate the slow churn of organic matter with the help of symbiotic bacteria. Mushrooms—the fruiting bodies of fungi—are just the tips of the vast underground mycelial network, the wood wide web. Mycelial hyphae form carpets that stretch up to thousands of acres in elaborately branching webs of tube-like cells whose growth patterns resemble those of neurons.
If someone were to suffer a physical trauma, lose blood, and go into a hypoxic state, endogenous hallucinogens would help neurons survive while that individual did something to relieve the trauma. Going into a dissociative state may help people survive such circumstances.—Steven Barker, Louisiana State University
In fact, fungal mycelia are also the forest’s nervous system. They act as environmental sensors, constantly navigating their surroundings through their subterranean interactions with trees, plants, and soil microorganisms. They negotiate nutrients and resources, communicate environmental threats like drought and insect infestation, and integrate a deluge of sensory information to solve problems and make decisions.1 They achieve this using electrical activity and neurotransmitters that are startlingly similar to those in the human brain and gut, which some scientists describe as intelligent communication.2-6
Among the millions of identified fungal species, approximately two hundred produce psychedelics. Psilocybin, the psychoactive component of magic mushrooms, is a common example. Psychedelic compounds are widespread in nature. Some plants produce N,N-dimethyltryptamine (DMT), which is considered an archetype hallucinogen because its basic chemical structure is repeated across other common psychedelics, including psilocybin.7,8
Humans and other animals also produce endogenous psychedelics, some of which are identical or closely related to those produced by fungi and plants.9 This is not entirely surprising given that the mind-altering effects of psychedelic drugs depend on the ability of human cells to bind and metabolize them using existing receptors and metabolic pathways. Researchers have found endogenous psychedelic production in the human brain and gut, the latter of which occurs with the help of symbiotic gut microbes.
The similarities between exogenous and endogenous psychedelics and the reasons humans synthesize psychoactive compounds are taking scientists on a mind-bending trip across millions of years of evolution. In doing so, they are discovering connections that span interkingdom and interspecies boundaries.
Trippy state of mind
Psilocybin and DMT belong to the ubiquitous group of signaling compounds known as indolamines—a class of neurotransmitters derived from the amino acid tryptophan that have far-reaching biological and physiological roles.10 For example, serotonin (5-hydroxytryptamine or 5-HT) is a well-known indolamine that signals between the gut and brain to coordinate digestion, gastrointestinal motility, appetite, mood, learning, memory, cognition, blood vessel constriction, and sleep.11 The human gut produces more than 90 percent of the body’s serotonin with the help of resident microbes. Fungi, plants, insects, and other animals also produce serotonin.12
Steven Barker, a professor emeritus at Louisiana State University, who studied the roles of endogenous psychedelics in human physiology and experience for almost five decades, said, “The tryptophan related compounds like serotonin and melatonin found in fungi, plants, animals, and humans are all basically the same. The genes for creating the enzymes that are responsible for producing these compounds are nearly identical. The conservation of structure and function is carried over, and they serve very similar, if not identical purposes in the brain, gut, and other organs.”
An increasing body of scientific evidence suggests that endogenous psychedelics are neurotransmitters and that they play a role in growing, maintaining, repairing, and protecting neurons in the brain.1 In one of his seminal works in the field, Barker showed the presence of DMT in the pineal gland and visual cortex of the rat brain. Barker and his colleagues also found indirect evidence of its presence in humans; the enzyme and other factors required for DMT biosynthesis, storage, and release are present in the human brain.13 “There is a lot of evidence, but it takes a while to get these compounds accepted as neurotransmitters, especially given the history and myths surrounding hallucinogens,” Barker said.
Barker’s team also performed seminal studies to determine the relationship between physiological hypoxia and endogenous hallucinogens. They induced cardiac arrest in rats to create a state of extended hypoxia and near death.9 They found that DMT rose significantly in the brain, and while there is no definite proof, Barker believes that this may help explain hallucinations during near death experiences. “The natural function of endogenous hallucinogens might be to protect neurons from hypoxia. If someone were to suffer a physical trauma, lose blood, and go into a hypoxic state, endogenous hallucinogens would help neurons survive while that individual did something to relieve the trauma. Going into a dissociative state may help people survive such circumstances,” Barker said. Indeed, other researchers have corroborated the role of DMT in protecting against hypoxic damage.14,15
WHAT A TRIP
Humans have consumed hallucinogenic fungi and plants for thousands of years. Many of these compounds share a common chemical structure with one another and with neurotransmitters widely produced by the human body, such as serotonin. Classic examples are psilocybin, which is synthesized by certain species of fungi, and N,N-Dimethyltryptamine (DMT), which is produced by some plants. The basic chemical structure of DMT is embedded in other psychedelics, including psilocybin.
The human body also produces DMT. Endogenous psychedelics may perform the following physiological roles:
Fungi serve as the digestive and nervous systems
Far out healing
Indigenous cultures consumed hallucinogenic indolamines long before they were discovered by modern humans. “They were used for ritualistic and medicinal purposes. We can now understand on a more current scientific basis how they work as therapeutics,” Barker said.
John Kelly, a psychiatrist and clinical senior lecturer at Trinity College Dublin, recently collaborated with his colleagues on the largest clinical trial of psilocybin in combination with psychotherapy for treatment-resistant depression.16,17 Kelly and his colleagues found that a single dose of psilocybin improved depression symptoms. “The most exciting thing is that psilocybin could potentially be harnessed across the different stages of therapy to improve patient outcomes,” Kelly said.
Some of the beneficial effects of psychedelic-assisted psychotherapy are mediated through the microbiota-gut-brain axis, the two-way communication avenue between the gut’s nervous system, also known as the enteric nervous system, and the brain. Various signaling molecules, including neurotransmitters, hormones, and immunomodulatory factors form the basis of this information exchange highway. The gut microbiota plays a central role in mental health by contributing to the production and integration of various metabolites, neurotransmitters, and neuromodulators, including serotonin and tryptamine, which relay chemical messages.18,19
The most exciting thing is that psilocybin could potentially be harnessed across the different stages of therapy to improve patient outcomes.—John Kelly, Trinity College Dublin
Psychedelic therapy may augment some of these key pathways along the microbiota-gut-brain axis to influence behavior. In fact, much like the endogenous opioid system against pain, the human body may be wired with an endogenous psychedelic system against depression.20 Here too, gut microbes play a key role in producing tryptamine from dietary sources of tryptophan, which is not all that surprising given that humans are a rich composite of diverse microbial communities that interact with human physiology at a fundamental level. Researchers continue to unravel the mechanisms by which gut microbes and the central nervous system interact and the roles that endogenous hallucinogens play in communicating between microorganisms, the gut, the brain, and downstream physiological processes.1
“Everything is connected in some way through patterns of information encoded by chemical messages. Everything we experience involves some kind of neurochemical interaction. That’s what all plants do. That’s what all fungi do. That’s what all animals do. We exchange chemical information,” Barker said.
Evolutionary conserved mechanisms between fungi and humans—particularly the signaling molecules they produce8—provide researchers with a colorful tapestry from which to gather deeper insight into the roles of endogenous hallucinogens in human health and disease. Whether the sprawling subterranean web of mycelial networks possess a kind of conscious intelligence of their own and how this may help researchers glean a deeper understanding of human consciousness is another matter entirely. Barker mused about a unique way to approach this question. “Well, I’d go out and collect myself a good bag of psilocybin mushrooms, eat them, and let them tell me. I haven’t done that in quite some time. It’s a bad scientist who doesn’t know their subject.”
- Kelly JR, et al. Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis. Int J Clin Health Psychol. 2023;23(2):100349.
- Adamatzky A. Language of fungi derived from their electrical spking activity. R Soc Open Sci. 2022;9(4):211926.
- Adamatzky A, Gandia A. Living mycelium composites discern weights via patterns of electrical activity. J Bioresour Bioprod. 2022;7(1):26-32.
- Gandia A, Adamatzky A. Electrical spiking of psilocybin fungi. Commun Integr Biol. 2022;15(1):226-231.
- Olsson S, Hansson B. Action potential-like activity found in fungal mycelia is sensitive to stimulation. Naturwissenschaften. 1995;82(1):30–31.
- Adamatzky A. On spiking behaviour of oyster fungi pleurotus djamor. Sci Rep. 2018;8(1):1–7.
- Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126(Pt 1):74-88.
- Cameron LP, Olson DE. Dark classics in chemical neuroscience: N, N-Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9(10):2344-2357.
- Dean JG, et al. Biosynthesis and extracellular concentrations of N,N-dimethyltryptamine (DMT) in mammalian brain. Sci Rep. 2019;9(1):9333.
- Lee JH, et al. Roles of indole as an interspecies and interkingdom signaling molecule. Trends Microbiol. 2015;23(11):707-718.
- Zifa E, Fillion G. 5-Hydroxytryptamine receptors. Pharmacol Rev. 1992;44(3):401-458.
- Negri S, et al. The case of tryptamine and serotonin in plants: a mysterious precursor for an illustrious metabolite. J Exp Bot. 2021;72(15):5336-5355.
- Barker SA. N, N-Dimethyltryptamine (DMT), an endogenous hallucinogen: past, present, and future research to determine its role and function. Front Neurosci. 2018;12:536.
- Szabo A, et al. The endogenous hallucinogen and trace amine N, N-dimethyltryptamine (DMT) displays potent protective effects against hypoxia via sigma-1 receptor activation in human primary iPSC-derived cortical neurons and microglia-like immune cells. Front Neurosci. 2016;10:423.
- Szabo A, Frecska E. Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection? Neural Regen Res. 2016;11(3):396-397.
- Goodwin GM, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648.
- Goodwin GM, et al. Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. J Affect Disord. 2023;327:120-127.
- Williams BB, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16(4):495-503.
- Strandwitz, P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018; 1693(Pt B):128-133.
- Sfera A, et al. Microbiota-derived psychedelics: Lessons from COVID-19. Adv Clin Exp Med. 2023;32(4):395-399.