On Good Friday, 1962, 20 students from Andover-Newton Theological Seminary sat in a small prayer room in the basement of Boston University’s Marsh Chapel waiting for the drugs they’d just taken to kick in. Ten had been given an active placebo, ten had been given 30 milligrams of psilocybin, a drug they were otherwise told little about. Everyone was blind as to which. 

After perhaps 30 minutes, half of the students began to notice some odd bodily sensations: a prickle just under the skin, a continuous flushing in the face, dizziness. Some assumed that this was the onset of the psilocybin. It was in fact niacin, which in large doses triggers the dilation of capillaries close to the skin. Though uncomfortable, the niacin flush dissipated within an hour. By that time, it had become apparent which students were actually in the experimental group. Spread out across the chapel, they appeared to be experiencing a dilation of an entirely different kind. 

One student described hearing the scripture as read by a “chorus of angels in bass clef.” One wept, swept up “in a glow of holy light.” One became suddenly cognizant of his place in “one great cosmic drama.” One felt himself compelled to the organ, where he played a hymn which inspired in another — also in the psilocybin group — “a brief but violently intense feeling of joy.” Several described a collapse of the ordinary sense of division between self and other. One watched himself merge with the pews. 

The experiment lasted four hours, but for those in the experimental group it lacked a temporal quality entirely. “Matter and time seemed to be of no consequence,” said one. “I was living in the most beautiful reality I had ever known, and it was eternal.” And yet despite this departure from ordinary consciousness, the insights of those hours retained an intuitive level of truth. Even decades later, it remained for most a formative experience in their lives. ¹

The Good Friday experiment was the first controlled demonstration that psychedelics can occasion experiences equivalent to those described by religious mystics. This was Walter Pahnke’s goal in designing the study, which formed the basis of his thesis at Harvard Divinity School. Pahnke — “Wally” to his friends — had recently graduated from Harvard Medical School, but had wanted to augment that knowledge, and pursue his own interests in mysticism, through his divinity degree. 

“Some of the researchers who have experimented with synthesized mescaline, LSD, or psilocybin have remarked upon the similarity between drug-induced and mystical experience,” he wrote. But the research done to date had been done in noncontrolled settings, with participants subject to suggestion. “Our study was an attempt to explore this claim in a systematic and scientific way.” 

To do this, Pahnke needed a way to measure the experience. 

The result, a 129-item questionnaire, forms the basis for one of the instruments most widely used in today’s trials to characterize some of the subjective effects of psychedelics: the Mystical Experience Questionnaire. What this scale — and a few others like it — captures is at the heart of one of psychedelic science’s biggest questions. 

Today’s new wave of psychedelic trials, most notably of psilocybin, have shown profound potential to address a wide range of mental health issues. An incomplete list includes end-of-life anxiety, treatment-resistant depression, substance-use disorders, anorexia, and OCD. With the advent of new imaging technologies, scientists now hold a much better, if still crude, understanding of the neurobiological mechanisms that underpin the experience, as well as the structural changes in the brain that could explain their therapeutic effects. One of the leading theories is that psychedelics promote neural plasticity — the ability of the brain to restructure and adapt — and that this capacity is separate from the subjective effects. 

But it’s not clear whether the structural changes effected by psychedelics are sufficient to explain why they work. That’s because, apart from dose, the strongest and most consistent predictor of enduring positive outcomes appears to be the quality of subjective experience — and more specifically, the degree to which that experience can be classified as mystical.

Some researchers believe the quality of the subjective experience to be the critical determinant of therapeutic success. The empirical evidence for that depends largely on a few different scales. But others think the subjective experience may only be epiphenomenal, that the content of the psychedelic experience may not be required for therapeutic benefit at all. 

As the FDA inches closer to regulatory approval of psychedelics, this question gathers more weight. If projects to create equally effective nonsubjective psychedelics succeed, it is likely that at some point in the medium-term future, we will need to decide which is the first-line or default treatment. Where researchers fall may depend on the value they assign to experience.

The modern study of mysticism begins with William James. In The Varieties of Religious Experience, James drew on the historical and contemporary record of mystical states to characterize what he saw as four elements common across the experience: its ineffability, the transience of its effects, the passivity on the part of the witness, and what James described as the noetic quality of the content, the sense that the insights occasioned by the experience are true and are meaningful. 

Most scientists before James regarded mystical states as mental illness. James, a radical empiricist, held that experience is the foundation of knowledge. He believed that mystical states could provide “revelations of new depths of truth.” And he did not draw a hierarchy between the sources of mystical experience, whether spontaneously induced, achieved through prayer, solitude, or privation, or occasioned by any one of some of the psychoactive substances used in the West at the time — including peyote, chloroform, hashish, and nitrous oxide. ²  

Although The Varieties is now part of the canon in religious studies and psychology, it would be decades before other researchers built upon the foundation it laid. This changed in the 1950s when psychedelic drugs entered American culture. The psychiatrist Humphry Osmond, who coined the term psychedelic in 1956, began pioneering the use of LSD in therapy. Early initiates like Aldous Huxley described experiences on psychedelics that appeared to match those of historical mystics. And in the scientific study of mystical states, psychedelic drugs offered some advantages. They reliably produced an altered state of consciousness. They could be measured, dosed, and given blindly. ³ And — perhaps with the right questionnaire — the mystical experience itself could be measured. 

In designing the questionnaire for the Good Friday experiment, Pahnke drew heavily on the work of the Princeton philosopher W.T. Stace — who was heavily influenced by James. Stace, like Huxley, was a perennialist: he believed that spiritual traditions across culture and time shared a unifying core. His 1960 book Mysticism and Philosophy surveyed mystical experience across religions to identify its common elements. With Stace’s exposition as a guide, Pahnke identified nine: ineffability, transience, and noetic quality ⁴ were retained from James. To these, he added feelings of unity; ⁵ transcendence of time and space; deeply felt positive mood; sacredness; paradoxicality; and persisting positive changes in attitude and behavior. 

At first blush, the idea of putting these categories into a scale seems like its own paradox. How can timelessness or paradoxicality, for instance, be quantified? But Pahnke ignored the metaphysics. For each of the nine categories, Pahnke developed a list of questions and put them all in what was then called the “post-drug questionnaire.” His intuition was that each element existed on a continuum, where one’s experience, for example, of having known the universe in its wholeness, one’s sense of ultimate goodness as the basis of reality, or one’s judgment that the sense of the experience cannot be adequately described in words could simply be scored between 0 (did not experience at all) and 4 (experienced strongly). 

None of the subjects in the Good Friday experiment experienced what Pahnke then defined as “a complete” mystical experience (fours all the way down), but most of their experiences were profound. ⁶ And as may be laughably obvious to anyone who has taken 30 milligrams of psilocybin, there were statistically significant differences in the mystical experience between the groups on each element. Pahnke considered the experiment strong evidence that psychedelic and religious mystical experience were indistinguishable, and that “psilocybin, if not LSD and mescaline by analogy, [hold potential] as a tool for the study of the mystical states of consciousness.”

The Good Friday experiment arrived in the middle of two decades of scientific research on the therapeutic potential of psychedelics in everything from end-of-life anxiety to alcoholism to creative problem solving. ⁷ For a short time, Pahnke continued his research on psychedelics at the Maryland Psychiatric Research Center, frequently in collaboration with the psychologist and therapist William “Bill” Richards. (Richards, one of the most influential figures in modern psychedelic research, had been introduced to the field in 1963 without ever having heard the term; while a graduate student in Göttingen, he enrolled in a trial of “an experimental drug” — psilocybin — as a walk-in). 

Together, they revised Pahnke’s post-drug questionnaire, now called the Mystical Experience Questionnaire (MEQ). In addition to altering some of the wording (the original questionnaire was written for graduate students), Pahnke and Richards collapsed paradoxicality and ineffability (as describing roughly the same thing), removed transience (a holdover from James, who wanted to show mystical states weren’t permanently pathological), and removed persisting positive effects — which became, in various forms, an outcome of interest. 

But that first psychedelic era quickly faded. In 1963, just a year after Good Friday, Harvard fired Timothy Leary — Pahnke’s academic advisor — for turning on, tuning in, and (officially) dropping his teaching responsibilities. Recreational usage through the ’60s led to a number of highly publicized accidents, which led (arguably) to moral panic. ⁸ Public opinion turned. In 1970, the FDA classified psilocybin and LSD as Schedule 1 drugs, after which research effectively froze. 

The thaw was augured in 2006 by a study focused — somewhat surprisingly — not on any clinical benefit of psychedelics, but on the mystical experience. The pilot, loosely based on the Good Friday experiment, was titled “Psilocybin Can Occasion Mystical-Type Experiences Having Substantial and Sustained Personal Meaning and Spiritual Significance.” 

The study, led by Roland Griffiths at Johns Hopkins University, provided fresh and more rigorously controlled evidence that psilocybin can cause experiences with marked similarities to “classic” mystical experiences — experiences, as the title suggests, that also held high degrees of personal meaning and spiritual significance. Most of the participants rated the experience in the top five most meaningful of their lives; a few the single most. 

Bill Richards, the bridge between the two eras, had moved to Hopkins to work as the head guide in the trials. He brought with him the MEQ, though the study also used two other scales to measure the mystical experience: Hood’s Mysticism Scale and an early form of what would become the Altered States of Consciousness Scale, then called the APZ. ⁹ “The scientist in me laughs sometimes that, in a sense, we’re saying, ‘And what percentage of God did you experience?’” Richards said. “It’s like looking up at the Milky Way and wondering how many stars are out there tonight. There’s something ludicrous about science venturing into this realm.” 

But we do have good estimates for how many stars are in the Milky Way. ¹⁰ And there were early indications that the MEQ measured something useful. Specifically, that first study suggested that the degree of mystical experience predicted — possibly mediated — the outcomes of psychedelic experience. 

In a follow-up 14 months after the trial, researchers saw a moderately strong correlation between MEQ scores and how meaningful participants rated the experience. ¹¹ The association held even when controlling for self-reported intensity of the drug, suggesting there was something unique in the subjective effects leading to positive outcomes. (Perhaps just as importantly, the study demonstrated to the FDA and the broader public that psychedelics, in controlled environments, were safe.) 

More evidence continued to suggest the predictive and possibly explanatory power of the mystical experience. In 2011, Katherine MacLean, a newly minted research psychologist, arrived as a postdoc at Hopkins. Once there, “Roland handed me the data from the first two studies and basically said, ‘see if there's anything we missed,’” she said. One of the first things she noticed is that it wasn’t entirely clear what the MEQ was measuring: The scale had never been validated — a term of art in the psychometric field that roughly refers to the extensive process that assesses the degree to which a scale measures what it claims to measure consistently and accurately. 

“I had been trained in a rigorous psychology program,” MacLean said. “When I first looked at those items, I said to Roland, ‘This is meaningless. This mystical score that we’re getting doesn’t stand up at all.’” The scale required validation, MacLean said, if the Hopkins psychedelic research was to be accepted by the wider scientific community — nearly all the research up to that point had been published in pharmacology journals. It was also possible that only some of the categories included by Pahnke, perhaps even a few questions, were driving the predictive power of the scale. The scale needed validation in order to more empirically demonstrate that the subjective effects of psychedelics were driving their benefit.

MacLean, with statistician Jeannie-Marie Sheppard Leoutsakos, conducted a factor analysis of the questionnaire — a statistical technique that condenses the information contained in a number of original variables by identifying the pattern of correlations between them. ¹² Because factor analysis requires a large sample size, MacLean recruited respondents from corners of the internet where the answer to “Have you had a profound experience with psilocybin mushrooms?” was likely to be yes. ¹³ The analysis yielded just four factors. Questions from four of the original factors — on internal unity, external unity, noetic quality, and sacredness — loaded on just one factor, now renamed the “mystical” factor, suggesting that they all moved together. Positive mood, time and space, and ineffability were also retained, but these added less explanatory value. 

“It wasn't the same factors as Bill and Walter presumed,” MacLean said. “It’s mostly this one big factor. Did you experience God? That’s it.” In that way, “the MEQ is subversive because it forces scientists to grapple with something that they don't want to grapple with.”

Indeed, plenty of researchers have argued that mysticism isn’t something science should be grappling with at all, and that better theories, informed by a suite of new brain imaging technologies, explain the benefits of psychedelics independent of their subjective effects. 

The science here is still in its early stages, but a very brief and overwhelmingly incomplete explanation of what psychedelics do in the brain goes like this: Depression, anxiety, addiction, and PTSD share common neural circuitry and are visible in brain structure. ¹⁴ Usually, this takes the form of neuronal atrophy: depressed people, for instance, have smaller neurons and reduced neural density in some regions of the brain — notably in the prefrontal cortex. Depression is also linked to impairments in neural plasticity (the ability to form new dendritic spines and synapses) as well as dysregulation of brain-derived neurotrophic factor (BDNF), a protein involved in neuron growth, development, and survival. 

In the early 2010s, animal models demonstrated that ketamine could rapidly repair neuronal atrophy. In 2018, the lab of David Olson, a chemist and neuroscientist at the University of California, Davis, showed that classic psychedelics can do the same. Numerous studies (limited so far to animal models) have demonstrated that these drugs appear to work by triggering the release of BDNF, increasing synaptic growth, and increasing the number of connections between neurons, effectively fostering an adaptive “rewiring” in neural circuits. The effects, taken together, are an increase in neuroplasticity. ¹⁵  

And this increase in neuroplasticity can be separated from the subjective effects of psychedelic drugs. “There’s strong evidence that the serotonin 2A receptor mediates both the psychoplastogenic effects, or the effects on structural neuroplasticity, and the mystical-type experiences,” said Olson. “Pretty much every time you hit the threshold to produce a mystical-type experience, you’ve already hit the threshold to produce plasticity. It’s very hard to disentangle them.” 

Those who think that subjective effects are necessary for therapeutic outcomes “really emphasize this nice correlation between increases in therapeutic effects and mystical-type experiences,” Olson said. “But correlation does not imply causation. When I think about a good correlation, I’m thinking of an R squared of 0.98.” There is plenty of evidence, both qualitative and quantitative, that those who score low on mystical experience still receive therapeutic benefit. “While the subjective experience might have some therapeutic benefit,” Olson said, “I don’t think it’s essential.”

Olson’s work, most of it in mice models, has shown that minor modifications to the structure of psychedelic molecules can foster plasticity without inducing subjective effects. This points to the possibility that the subjective effects of psychedelics — mystical or otherwise — may not be necessary for enduring therapeutic change, could either be proxies for the physical changes which actually lead to the benefits, or simply could be epiphenomenal. The company he founded, Delix Therapeutics, is currently testing one of those compounds in a Phase 1 trial.

While the correlation between the mystical experience and outcomes of psychedelic therapy may not be 0.98, it is still relatively consistent across studies and — compared to a lot of psychological research — relatively strong. A 2022 meta-analysis of clinical trials found that 10 out of 12 showed a significant association between the degree of mystical experience and beneficial outcomes, with the amount of variance explained by scores on any of the mystical experience scales ranging between 40% and 70%. It “seems vital that appropriate consideration is paid to the importance of promoting a certain kind of experience,” concludes one of the studies, “as the quality of that experience may be the critical determinant of therapeutic success.” ¹⁶  

But what exactly about the quality of the experience leads to outcomes? The statistics are inconclusive, but there’s plenty of evidence that suggests that a purely neurobiological explanation is unsatisfying. “There is no doubt that some therapeutic effects occur through mechanisms unrelated to the acute subjective effects, but their magnitude and duration are currently unknown,” said David Yaden, who studies the measurement of altered states of consciousness at Hopkins. “To see persisting benefits that last many months from an experience lasting just a few hours, I suspect cognitive shifts related to the experience are required to perpetuate those effects.” 

In other words, independent of the role that structural brain changes play, the subjective experience (and the mystical experience is our best measure for this) may help to provide direction of some kind, revelation, as James had it, of new depths of truth, paths to travel as changes in plasticity take effect. This is most clearly illustrated in the qualitative descriptions in some of the psilocybin trials for addictive disorders. One patient enrolled in a smoking cessation trial described a sudden realization about her own-self conception: “I’m me, and there are no defining characteristics! . . . That made me realize I’m not a smoker.” Another felt as if she’d died as a smoker to be resurrected as a non-smoker: “I jumped up and I said ‘I’m not a smoker anymore. It’s all done.’” ¹⁷ It’s possible that structural brain changes made the temptation they faced in the weeks that followed easier to resist, but it seems likely that the insights they experienced helped determine the role those changes played. 

But results aren’t always so neat or linear, and that makes broader conclusions more difficult to draw. A 2020 systematic review of 15 qualitative studies struggled to find a clear-cut distinction between the different therapeutic mechanisms described by participants; mystical experience, insights, connectedness, and an expanded emotional spectrum ​​all seemed to overlap. It nevertheless concluded: “psychedelic treatments exhibit similar therapeutic processes and result in comparable outcomes.” In part, this is the challenge of making empirical sense out of experiences that are definitionally ineffable. 

Each of the researchers I spoke to who fall into the subjective camp seemed to have their own interpretations of this power. “I’ve never really been of the school that thinks that mystical experiences are important for clinical outcomes or like mental health,” MacLean told me. “I think that what they are important for is people who feel stuck in a particularly rigid reality.” Richards described the idea of the nonsubjective psychedelic experience as going through the art museum with a blindfold. What happens in a psychedelic experience is “not an undesirable side effect,” he said. “Psychiatry has lost its appreciation for the incredible beauty and intelligence of the human psyche.” 

And, of course, it’s probably easier to see the value of the experience if you’ve witnessed it firsthand. Yaden’s interest in mystical experience began with his own, an “infinite, 360-degree, horizonless, timeless place” and feeling of love that arrived spontaneously, not by any psychedelic trigger, in his dorm room. Richards got turned on in the ’60s. MacLean, in her book Midnight Water, described knowing from the time she was 19 that “psychedelics would be a defining feature of my life.” Griffiths came to psychedelics as a detour from his own profound experience in meditation, but only recently used LSD following a terminal cancer diagnosis. Olson, however, has never tried psychedelics. “I just try to follow the data wherever it leads me,” he said.

They all do. But they’re not all looking in the same places. 

In 2021, Yaden and Griffiths proposed an experiment, the only definitive study that could disprove the importance of subjective effects: the administration of psychedelics to individuals rendered fully unconscious via deep anesthesia, and who subsequently reported no memory of the psychedelic experience. If full and lasting therapeutic efficacy remains under these conditions, the subjective effects — importantly, not limited to the mystical experience — would be proven irrelevant. The RECAP study, currently underway at the University of Wisconsin, is investigating a variant of this: whether the coadministration of midazolam, an amnesiac sedative, can effectively wipe participant’s memories of the subjective effects. Results are still forthcoming.

So too are the results of clinical trials of what Olson calls neuroplastogens. Olson’s argument for why non-hallucinogenic psychoplastogens (his preferred term) ¹⁸ are necessary is threefold. First, administration of psychedelic drugs with support before, during, and after treatment is expensive. Second, many people may be reluctant to use them due to stigma or fear. And last, psychedelic-assisted therapy is contraindicated for those with a family history of psychotic disorders. ¹⁹ “I think we need to develop both types of medicines in order to have the best coverage across all patient populations,” Olson said. 

Yaden and Olson are now engaged in a further debate. If nonsubjective psychedelics (Yaden’s preferred term), or non-hallucinogenic psychoplastogens, are equally as effective as those that cause psychedelic experiences, with equivalent risk/benefit profile, which should be the standard of care? 

Yaden argues that nonsubjective substances should be reserved only for the special cases in which subjective effects are contraindicated. Classic psychedelics should be the default. “There are reasons to prioritize subjective psychedelics due to the high ratings of well-being and meaning associated with these experiences for many (not all),” Yaden said. ²⁰ About three-quarters of participants continue to report the experience to be among the most meaningful of their lives. Olson argues that nonsubjective compounds, if effective, will be faster, cheaper, and easier to access. To Yaden’s argument about personal meaning, Olson (with Delix’s chief scientific officer, Kurt Rasmussen) responded that “this argument appears to be outside the scope of medicine and is perhaps more relevant to a discussion about whether all individuals should be allowed to use psychedelics for personal growth and betterment.” But "in the end," Yaden said, "Olson and I agree on the principle of autonomy." If nonsubjective psychedelics prove effective, patients should be allowed to choose.

In the interest of subjectivity, I should be clear: I wanted to write about this in order to understand my own psychedelic experiences. My entry point into psychedelics was academic. In 2015, I was in grad school; I was also in therapy, and I stumbled upon a series of articles that suggested that psychedelics were more effective than what I was doing on the couch. More so: Many studies suggested that the mechanism was this thing called the mystical experience. 

The hallmark of the mystical experience is generally described as some form of realization about the nature of reality and consciousness, the experience that all is one, a glimpse into, as Terence McKenna has it, what it is all about. But I found myself, after several high-dose sessions, feeling as if I’d seen a different show. My experiences have been profound, provocative, and beautiful, the typical kaleidoscopic fantasia, but they never approached what I understood the literature to describe as mystical. But they have nevertheless been useful. 

Throughout the writing of this piece, I struggled to match my own experience to the criteria on the MEQ. The experience of unity with ultimate reality, the insight that “all is one,” the fusion of my self into a larger whole — each of these are components of the mystical factor of the MEQ, and I score low on all three, at least below the threshold of a “complete mystical experience.” But the gain of insightful knowledge at an intuitive level, what James originally described as the noetic quality — also on the mystical factor — has for me been profound. 

Sometimes that kind of insight has been clear. I first used psilocybin in the middle of a turbulent relationship, which for weeks I’d been considering leaving. Four hours later, the answer to do so seemed so laughably obvious as to feel like I was reflecting on it from years of distance. Two years later, on another trip, image of my current partner, and the comfort that brought, served as a guide.

But more curious and more confusing to me has been the way that, in the days after one trip, some of the various anxieties I once carried, corners of my psyche I spent years in therapy trying to understand, just became kind of boring, ceased to hold over me any psychic power, and subsequently, if gradually, dissipated. I can’t point to anything in my subjective experience during the trip that led to that. Was this what it felt like for increased plasticity to take effect? The best word I have for it is grace. 

There is something ludicrous about science venturing into this realm; I think it’s a challenge that any journalist or academic has to reckon with in considering their own experience objectively. “We play the science game as competently as we can,” Richards said. “But let’s not take it too seriously.” If there’s a consistent lesson in my own psychedelic use, it’s that my default tendency to analyze, to play the science game as competently as I can, works great for my day job, but holds much less traction when it comes to individual questions of how to exist in the world. 

Richards, even through a screen, is the sort of person who seems to genuinely embody what Carl Rogers called unconditional positive regard. And so all of this came fumbling out of me toward the end of our interview, which I’d tried to keep as empirically grounded as possible, but, I’ll be honest, had started to feel more like therapy. (My sense is that this may be a typical experience with Bill.) So I asked him about this challenge — of trying to understand my own experience through the scientific literature — and even as I did, I could feel it was the wrong direction, sensed what his answer might be. “You can’t have a happy marriage with your intellectual side,” he said. 

“People are arriving at the psychedelic experience, or some form of visionary or mystical consciousness, from different places at different places in their lives,” Richards said. “Some are more ready to integrate insights than others. Some are more ready to allow experiences to occur than others.” (Point taken.) “We have to be very cautious writing about it and not oversimplify it.” 

Though simplifying it is, in some sense, exactly what the measurement of the subjective psychedelic experience is doing — collapsing paradoxical and indescribable qualia into psychometrically validated scales which feed into some statistical model. The scales aren’t perfect. It seems quite clear that many of them remain strongly rooted in the perennialist tradition. Though that’s only a problem if you think perennial philosophy is wrong. 

Still, my varied experience seems equally interpretable in terms of subjective experience and of physical effects. That seems to be where the science is at as well — at least for now. And as many researchers note, it’s likely that there’s no single mediating factor that can explain such complex phenomena that, at least in clinical settings, hold promise across so many indications. But what both the project to empirically study the subjective effects of psychedelics and the push to identify the neurological mechanisms behind their therapeutic potential don’t point to, what I take to be the most mysterious point of all, is that it’s not strictly necessary to understand why psychedelics work to know that they do. Call it neurological. Call it pharmacological. Call it mystical. Call it grace.