“It does not seem to be an exaggeration to say that psychedelics, used responsibly and with proper caution, may become for psychiatry what the microscope is for biology or the telescope is for astronomy.” ~ Stanislav Grof
In Hesiod’s poem “Theogony,” which describes the lineage of the Greek titans and gods, Chaos is depicted as the primordial canvas of creation that births all subsequent beings, illustrating a phase transition from nothingness to somethingness. In physics, chaos refers to the behavior of highly unpredictable systems that are extremely sensitive to minute perturbations. A classic example of a chaotic system is the motion of pendulums attached end-to-end, where even the tiniest variation in initial conditions will permeate ensuing dynamics. Notably, mathematical quantities that measure certain properties of chaos provide valuable insights into brain states. In fact, these measurements have found a niche in the emerging field of psychedelic neuroscience.
The term “psychedelic,” coined by psychiatrist Humphry Osmond in 1956, originates from the Greek words psyche (mind) and deloun (manifest). Osmond, an early proponent of psychedelic treatment for mental illness, exchanged notes with novelist Aldous Huxley, to whom he had introduced the psychoactive drug mescaline. Seeking an alternative to “hallucinogen,” Huxley proposed “phanerothyme” from the Greek phanein (to show) and thymos (spirit). His suggestion read, “To make this mundane world sublime, Take half a gram of phanerothyme,” to which Osmond replied, “To fathom Hell or soar angelic, Just take a pinch of psychedelic.” Huxley recounted his experience with mescaline in “The Doors of Perception,” describing it as an eye-opening encounter where he tapped into “Mind at Large,” bringing him as close as one can get to “perceiving everything that is happening everywhere in the universe.” Between 1954 and 1960, Osmond and colleague Abraham Hoffer treated approximately 2,000 patients with alcoholism using lysergic acid diethylamide (LSD) at the Weyburn Mental Hospital in Saskatchewan, Canada, reporting notable one-year abstinence rates of up to 45%. By the early 1960s, over 1,000 scientific articles on LSD had been published worldwide, marking a prolific era of psychedelic research that would soon come to an end.
This period was also marred by the Thalidomide scandal, considered the biggest man-made medical disaster in history. Thalidomide, a sedative distributed in 46 countries, was prescribed to pregnant women to treat morning sickness, resulting in over 10,000 birth defects between 1957 and 1962. This disaster led to increased pharmaceutical oversight by Western government agencies. The American counterculture revolution of the 1960s, which figured the polarizing poster child of LSD, Timothy Leary, exacerbated growing wariness of authorities regarding drug use. By 1966, public and government outcry against psychedelics led Sandoz, a major supplier of LSD for medical research in the US, to cease shipments, significantly hindering scientific experiments. These events culminated in the 1970 Controlled Substances Act, ratified by Richard Nixon, marking the beginning of the so-called “war on drugs.” The legislation introduced a classification scheme categorizing substances by potential for abuse, medical use, and safety/addiction profile. Hallucinogens, despite their therapeutic potential, were designated as Schedule I substances, ushering in a period of stifled psychedelic research.
While recreational use of psychoactive drugs persisted, public interest in these compounds lay dormant until the 1990s, when tightly regulated small-scale research experiments were reintroduced. This shift was partly fueled by the works of ethnobotanist Terence McKenna, who drew inspiration from Aldous Huxley’s writings on hallucinogens. With the advent of advanced neuroimaging technologies, psychedelic research witnessed a renaissance in the late 2000s. A search on PubMed reveals that nearly 80% of all scientific articles on “psychedelics” or “hallucinogens” published since 1970 have appeared in the last 15 years.
Current research on hallucinogenic compounds focuses on “classic” or “classical” psychedelics, including LSD, psilocybin/psilocin, DMT/5-MeO-DMT, and mescaline. These chemical agents interact with serotonin receptors, particularly the 2A subtype, which are widely expressed throughout the brain, hence the alternative designation of “serotonergic” psychedelics. The serotonin system plays a crucial role in various processes, including emotional regulation, memory modulation, pain perception, and appetite. Although each classic psychedelic has a unique receptor affinity profile, it is believed that the docking of serotonin sites by these compounds triggers a cascade of cellular events that transiently alters the brain’s dynamic properties. This process, which begins with the binding of microscopic molecules to individual neurons, ultimately changes how entire populations of nerve cells communicate across the cortex. The scientific literature describes this phenomenon as the disintegration and desegregation of neocortical networks, which comprise specialized communities of neurons with distinctive information processing features. The seven “canonical” networks include the default mode, somatomotor, visual, dorsal attention, ventral attention, frontoparietal, and limbic. Disintegration involves a loss of unique properties within each network, while desegregation implies a gain of common attributes across networks. A useful heuristic is that parts of the brain that typically communicate become less chatty, while those that do not become chattier. This is where chaos enters the chat!
The entropic brain hypothesis, a leading model of chaotic neural dynamics, proposes that the brain operates within a specific range of entropy, outside of which consciousness may be lost. Entropy, measured using the Lempel-Ziv complexity metric, describes the uncertainty or unpredictability of brain behavior over time. An increase in neural entropy corresponds to a rise in potential brain configurations at any given moment. Notably, entropy levels have been shown to distinguish between varying degrees of consciousness. The perturbational-complexity index, a Lempel-Ziv derivative, has been used to differentiate between vegetative, minimally conscious, and locked-in syndrome states in clinical populations, as well as anesthesia, sleep, and wakefulness in healthy controls. Recent studies have challenged the notion that normal waking consciousness represents the peak of neural entropy, demonstrating that psychedelics increase dynamic complexity in the brain well above its already high baseline. Growing evidence supports the role of entropy measurements in assessing the information richness of subjective experiences. Thus, the complexification of whole-brain network dynamics appears to underlie the expanded states of mind reported during the psychedelic experience.
Beyond entropy, criticality is another valuable concept that has been increasingly applied to the study of chaotic brain properties. Criticality refers to the state of dynamic systems poised at the boundary between two phases, such as the transition from liquid water to steam, the emergence of magnetization in iron, or the reconfiguration of carbon atoms from graphite to diamond. Research suggests that the healthy human brain operates within a critical zone between order and disorder, with a tendency towards order or sub-criticality. Neural networks within this range exhibit optimized data processing characteristics, including enhanced information transmission and storage. It has been argued that evolution may have favored neural phenotypes that exhibit criticality for the survival advantage it confers. Measurements of criticality, such as power-law estimation and long-range temporal correlation, have been used in clinical research to identify fluctuating states of consciousness, predict epileptic seizure onset and location, detect neurodegenerative conditions, and characterize atypical neurodevelopment. Under the influence of psychedelics, resting neural dynamics may shift towards the super-critical limit, where randomness prevails. This upsurge is consistent with the entropic brain hypothesis, which proposes that increasing entropy in the brain makes it more critical and susceptible to perturbations.
It is essential to acknowledge that the neural mechanisms underlying the modulation of brain activity by hallucinogens are not yet fully understood. A recent meta-analysis of three classic psychedelics (DMT, LSD, and psilocybin) provided partial support for the desegregation of brain networks but failed to confirm their disintegration. Instead, the results showed increased internal coupling for the dorsal attention and frontoparietal networks, indicating greater self-integration within each system. Notable variations in functional connectivity were also observed between the three compounds. For example, only LSD increased the integration of the limbic network with the rest of the brain, while only DMT reduced coupling between the visual and dorsal attention networks. Furthermore, the relationship between entropy and criticality remains unclear, and the use of multiple indices to quantify these parameters in the context of non-overlapping brain data modalities limits generalizability. The field of psychedelic neuroscience is still in its early stages, hindered by ongoing prohibitions, and consequently, relatively unexplored. This inertia results in a limited number of available original neuroimaging datasets, restricting the scope of unbiased systematic reviews and meta-analyses due to sample overlap.
Nonetheless, one uncontroversial aspect is that psychedelic-assisted psychotherapy (PAP) may revolutionize the treatment of mental illness, given the growing evidence supporting its potential. PAP involves three phases: preparation sessions to discuss treatment procedures and goals, an experiential session where a predetermined dosage of a psychedelic compound is administered, and integration sessions to process experiences and emotions. This procedure is repeated once or twice over several weeks or months to maximize health outcomes. With an estimated 350 million people suffering from psychiatric disorders worldwide, PAP offers significant potential for reducing this global health burden. Depression, affecting approximately 280 million people, is a primary target, with 66% of cases failing to respond to conventional treatments. Recent studies have demonstrated that psilocybin therapy can provide rapid and sustained relief from depressive symptoms. Small-scale clinical studies have also shown positive preliminary results in treating obsessive-compulsive disorder, end-of-life distress, and substance abuse. Notably, a pilot study on smoking cessation using psilocybin and cognitive behavioral therapy achieved an 80% success rate at 6-month follow-up, far exceeding the 35% benchmark set by traditional therapies. In a secondary study with the same participants, 67% reported smoking cessation at 12-month follow-up with nearly 90% of them rating their psychedelic experiences among the 5 most personally and/or spiritually meaningful episodes of their lives. Ongoing clinical trials are investigating the efficacy of PAP for treatment-resistant depression, cancer-related anxiety, alcohol use disorder, and other conditions.
Proposed therapeutic neural mechanisms of psychedelics highlight the crucial role of transient alterations in dynamic brain properties in promoting psychological benefits. The downregulation of the default mode network (DMN) has garnered attention among neuroscientists. The DMN is a functionally diverse brain network that sits at the apex of a neural hierarchy between primary cortical regions involved in sensation and motor function, and “transmodal” areas associated with abstract forms of cognition. A new study published in Nature Neuroscience by Paquola et al. (2025), to which I contributed as a co-author, identified the DMN’s multifaceted cellular architecture as playing a crucial role in its functional versatility. The DMN is primarily involved in self-reflective processes, such as contemplating past autobiographical episodes or simulating future scenarios via mental time travel. Psychedelics, particularly at high doses, can induce ego death/dissolution by reducing within-network coupling of the DMN—specifically between ventromedial prefrontal, posterior cingulate, parahippocampal, and retrosplenial cortices—leading to a sense of selflessness and a profoundly meaningful experience of oneness or interconnectedness. This “unitive experience”—reminiscent of Huxley’s integration with “Mind at Large”—is strongly correlated with positive mental health outcomes. Another proposed mechanism, REBUS (RElaxed Beliefs Under pSychedelics), suggests that psychedelics attenuate negative assumptions about oneself by increasing global connectivity and reducing network modularity. This process, termed “neural annealing”—analogous to the metallurgic procedure of heating a metal and letting it cool down to make it more malleable—may dissolve consolidated neural patterns related to depressive moods, enabling the adoption of novel brain dynamics and healthier states of mind.
A discussion on psychedelics would be incomplete without exploring their phenomenology. The “mind-manifesting” potency of these compounds can precipitate transformative subjective experiences capable of informing the human condition. For over three millennia, hallucinogens have been a staple of Mesoamerican shamanic cultures, potentiating contemplative states of mind in ritualists. The psychedelic experience is utterly humbling, ineffable, otherworldly—dare I say divine? When it ends, it leaves a lasting impression that waking consciousness is like staying afloat in a seemingly bottomless ocean, the depths of which are only meant for the truly intrepid who submit to high doses of psychedelics. So-called “trips” typically last 4-6 hours for psilocybin (or magic) mushrooms and up to 12 hours for LSD, with initial effects occurring within 1 hour. DMT, however, acts extremely rapidly, with effects appearing sometimes within seconds of inhalation but only lasting approximately 20 minutes. Common phenomenological features of classic psychedelics include synesthesia, time distortion, visual alterations, ego dissolution, and a sense of oneness with one’s surroundings. While there are overlapping themes and archetypes, each psychedelic presents with its idiosyncrasies. For example, the results of a systematic review showed that LSD is associated with more intense visual hallucinations compared to psilocybin, while DMT is characterized by experiences of crossing into new realms and interacting with sentient meta-beings. Terence McKenna described these DMT entities as “self-transforming machine elves.” Some individuals have even reported episodes resembling near-death experiences with DMT.
While classic psychedelics hold great promise for understanding mental health and consciousness, it is essential to acknowledge the possibility of adverse events associated with them. Although lethal doses have not been reported in the medical literature, common physiological side effects include tachycardia and hypertension, which resolve after the trip. Therefore, individuals with pre-existing heart conditions should ideally consult medical professionals before experimenting with these substances. Those with psychosis and paranoia may also be poor candidates, as their symptoms may worsen under their influence. Additionally, some individuals have reported distressing experiences, or “bad trips.” However, negative effects can be mitigated by adequately accounting for the set and setting of the trip. A conducive set might include an optimistic mindset, while an optimal setting could involve a comfortable and reassuring environment with soothing music. Even challenging phases of a trip can be therapeutic if approached with humility and allowed to unfold, as they may represent uncomfortable truths that must be confronted and overcome for healing to occur.
At the time of writing this article, psychedelics are still federally banned in the United States. At the state level, efforts to decriminalize them have yielded mixed results. Oregon and Colorado are the only two states to have granted legal status to psilocybin for therapeutic use. Robert F. Kennedy Jr., the newly confirmed Secretary of the U.S. Department of Health and Human Services, has expressed strong interest in decriminalizing psychedelics under federal law, allowing each state to regulate them as it sees fit. If these substances were to receive sweeping nationwide approval, desirable changes in the social atmosphere would likely ensue, accelerating basic and applied research in the field, a prospect that holds great promise for humanity. Forerunners like Terence McKenna and Stanislav Grof praised the potential of psychedelics to drive positive self-change and foster human discovery. McKenna touted the consciousness-expanding effects of consuming a “heroic” dose of dried magic mushrooms on an empty stomach with eyes closed in silent darkness. Grof lauded the merits of using hallucinogens responsibly in his own field of psychiatry, comparing them to a magnifying lens capable of illuminating the deepest layers of the psyche. Understanding the mind is an ongoing endeavour that continues to inform the human experience and its place within the cosmos. In times gone by, Hesiod depicted a cosmos born of chaos. Today, psychedelics reveal that chaos is the manifesto of the mind, the cosmos within.
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Note: The highlighted co-author “Tavakol S” is Shahin Zagros (myself).