Here are two articles that look at the use of psychedelics in psychotherapy. The first was posted last week at Salon, a reprint from the original post at Scientific American. The second one comes from Utne Reader back in 2013, and it was reprinted from Spirituality and Health.

Before these drugs became were banned as Schedule I narcotics (which is technically stupid, as narcotics are opiate-based pain killers, not entheogens), there was primitive but highly promising research into the use of these chemicals to treat everything from alcoholism to end-of-life anxiety (LSD), from PTSD to agoraphobia (MDMA).

 

Finally, due primarily to the efforts of MAPS (Multidisciplinary Association for Psychedelic Studies), these chemicals are once again being researched, and the research is demonstrating effectiveness in a lot of domains:

• LSD reduces end-of-life anxiety and here 
• LSD helps in the treatment of alcoholism
• LSD therapy can help treat various addictions
• MDMA helps heal PTSD and anxiety (CNN reporter Amber Lyons), and here, and here
• MDMA can support healing from serious childhood trauma
• Ibogaine, in a single dose, can eliminate opiate withdrawal
• Ayahuasca users show significantly lower levels of  depression, anxiety, hostility, paranoid ideation, and phobias
• Nearly every Ayahuasca study (through 2012)
• Psilocybin, induces neurogenesis and potentially cures some forms of mental illness
• Psilocybin enhances recall of autobiographical memory and helps reverse negative cognitive biases
• Psilocybin and LSD can reduce frequency and pain of cluster headaches (and migraines)
• Psilocybin has potential in treating depression, anxiety, and possibly cluster headaches
• Psilocybin can ease anxiety in terminal illness
• Psilocybin supports good mental health, with zero neurotoxicity

Here are the two main articles.

How psychedelic drugs could revolutionize American medicine

A DEA ban is dramatically hindering vital research into possible new treatments of mental disorders

Roni Jacobson, Scientific American
Thursday, Aug 28, 2014 

(Credit: agsandrew via Shutterstock)

This article was originally published by Scientific American.

Almost immediately after Albert Hofmann discovered the hallucinogenic properties of LSD in the 1940s, research on psychedelic drugs took off. These consciousness-altering drugs showed promise for treating anxiety, depression, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) and addiction, but increasing government conservatism caused a research blackout that lasted decades. Lately, however, there has been a resurgence of interest in psychedelics as possible therapeutic agents. This past spring Swiss researchers published results from the first drug trial involving LSD in more than 40 years.

slightly larger image

Time for a Psychedelic Spring?

Although the freeze on psychedelic research is thawing, scientists say that restrictive drug policies are continuing to hinder their progress. In the U.S., LSD, psilocybin, MDMA, DMT, peyote, cannabis and ibogaine (a hallucinogen derived from an African shrub) are all classified as Schedule I illegal drugs, which the U.S. Drug Enforcement Administration defines as having a high potential for abuse and no currently accepted medical applications—despite extensive scientific evidence to the contrary. In a joint report released in June, the Drug Policy Alliance and the Multidisciplinary Association for Psychedelic Studies catalogue several ways in which they say that the DEA has unfairly obstructed research on psychedelics, including by overruling an internal recommendation in 1986 that MDMA be placed on a less restrictive schedule.

The DEA and the U.S. Food and Drug Administration maintain that there is insufficient research to justify recategorization. This stance creates a catch-22 by basing the decision on the need for more research while limiting the ability of scientists to conduct that research. The June report recommends transferring responsibility for drug scheduling from the DEA to another agency or nongovernmental organization without a history of antidrug bias, such as the U.S. National Academy of Sciences. No matter how it happens, until the drugs are reclassified, bringing psychedelics from research into clinical practice will be an uphill battle.

* * * * *

Medicinal Uses for Psychedelic Drugs

After a 40-plus year hiatus, research into medicinal uses for psychedelic drugs from ayahuasca to MDMA could reveal treatment for depression, anxiety, and PTSD.

May/June 2013
By Don Lattin, from Spirituality and Health

You get out of your body and look back and see what is wrong with you. I saw the shell of the person I didn’t want to be and stepped out of it. Photo By Bruno Borges

Ric Godfrey had the shakes. At night, his body temperature would drop and he’d start to tremble. During the day, he was jumpy. He was always looking around, always on edge. His vibe scared the people around him. He couldn’t hang on to a job.

He started drinking and drugging, anything to numb out.

Years passed before a Department of Veterans Affairs counselor told him he had severe post-traumatic stress disorder, or PTSD. The former Marine had spent the early 1990s interrogating prisoners in Kuwait. Years later, he was still playing out the Persian Gulf War.

Counseling helped a little, but the symptoms continued. He went to rehab for his substance abuse, then tried Alcoholics Anonymous. “That went on for 10 years,” he said. “I don’t know how many times I hit rock bottom.”

Then one of his Seattle neighbors—a woman who also suffered from PTSD—told him about a group of veterans who were going down to Peru to try a psychedelic drug called ayahuasca, a jungle vine that is brewed into a tea. Indigenous Peruvians called it “sacred medicine.” A wealthy veteran had started a healing center in South America and would pay all his expenses.

The next thing Ric knew, he was crawling into a tent on a platform out in the middle of the Amazon jungle. The sun went down. The shaman gave him the tea, a blessing, and a pail in which to vomit.

“Your body will not keep it in you,” Ric recalled. “At first, it’s the worst thing you’ve ever done in your life. Then all of a sudden you blink your eyes and you are not there anymore. You get out of your body and look back and see what is wrong with you. I saw the shell of the person I didn’t want to be and stepped out of it. It was the most amazing thing. I’ve taken lots of drugs before, but I never remembered. I think this is the key. You actually gain knowledge from this. I don’t even consider it a drug. It’s an eye-opener. It makes you think about stuff. Your deepest, darkest secrets, stuff you have been holding on to since you were eight years old—it washes out of you, and you feel like a totally different person. People look at you differently. Your whole world changes before your eyes.”

Three years later, Ric Godfrey says he hasn’t had a single symptom of the shakes or night terror since he came back from the jungle. He’s relaxed and holding down a great job.

“I’ve always been afraid that someone was out to get me, but I don’t have that fear anymore,” he says. “I still like to sit with my back to the wall. I still have certain military idiosyncrasies, but I’m not afraid anymore.”

Psychedelic drugs are back. Not that they ever really went away. You could always find them on the street, in the psychedelic underground, and along the more enlightened edges of the drug culture. What’s new is that these powerful mind-altering substances are coming out of the drug counterculture and back into the mainstream laboratories of some of the world’s leading universities and medical centers. Research projects and pilot studies at Johns Hopkins, Harvard, Purdue University, and the University of California, Los Angeles, are probing their mind-altering mysteries and healing powers. Psychedelic drugs like psilocybin and Ecstasy are still illegal for street use and cannot be legally prescribed by doctors, but university administrators, government regulatory agencies, and private donors are once again giving the stamp of approval—and the money needed—for research into beneficial uses for this “sacred medicine.”

“This field of research is finally coming of age,” said David Nichols, a veteran researcher and recently retired professor from the Purdue University College of Pharmacy and the Indiana University School of Medicine. “As Crosby, Stills, and Nash said, it’s been a long time coming.”

Leading the campaign in the new wave of government-sanctioned research is the Multidisciplinary Association for Psychedelic Studies (MAPS), an independent nonprofit that has raised millions of dollars to fund an ongoing study into the use of MDMA, also known as Ecstasy, to treat returning war veterans and rape survivors suffering from PTSD.

In the first phase of that study, MAPS researcher Michael Mithoefer, a psychiatrist from South Carolina, treated 21 patients. Some participants were given MDMA with psychotherapy, while some got a placebo along with their therapy. Researchers hoped to show that MDMA’s ability to enhance trust, empathy, and openness would make it easier for patients to recount a traumatic event. It did. Over 80 percent of those who received MDMA had no PTSD symptoms two months later, compared with around 25 percent of those who got the placebo. Patients with MDMA-assisted therapy did better than those treated with traditional prescription drugs, such as Zoloft or Paxil.

In November 2012, Mithoefer and his colleagues released more results in a paper published in the Journal of Psychopharmacology. It showed that the benefits of MDMA-assisted psychotherapy were sustained over an average of three and a half years from the time the drug had been last ingested, an exceptionally lengthy period for a follow-up study. Furthermore, there were no reports of lasting harmful effects from exposure to the drug.

Rick Doblin, the executive director of MAPS, envisions his organization as a self-supporting nonprofit that will train therapists, run its own clinics, and distribute Ecstasy to doctors and psychologists.

MAPS now controls 960 grams of Ecstasy that was legally manufactured in 1985 by Nichols, the Purdue University chemist. That’s enough for between 4,000 and 5,000 doses, and it has not lost its potency. “It’s still the world’s purest MDMA,” Doblin said.

The use of psychedelic drugs for therapeutic purposes is not without controversy, however. In the 1950s, writer Aldous Huxley warned that psychedelics can take users to “heaven or hell”—for some, a path to enlightenment; for others, the spark for psychosis.

Huston Smith, a scholar of world religions who was another early explorer, noted the drugs can mimic “authentic religious experience” but questioned whether altered states of consciousness actually change the way people live their lives.

Smith also issued early warnings that today’s “ayahuasca tourists” might consider. While “sacred medicine” may be helpful for someone who was raised in a Native American religious culture, it may prove disastrous for an outsider unprepared for a mind-blowing trip. “History shows that minority faiths are viable, but only when they are cradled in communities that are solid and structured enough to constitute what are in effect churches,” Huston writes in an essay titled “Psychedelic Theophanies and the Religious Life.” More recently, the dangers of using psychedelics without medical supervision were illustrated when a man died after ingesting ayahuasca at the same Peruvian retreat center where Ric Godfrey had his life-changing experience.

Doblin and other advocates of psychedelic-assisted therapy acknowledge that these powerful substances—while not as addictive as drugs like alcohol, heroin, or cocaine—can be abused by recreational users. They propose a system in which they can be prescribed by doctors and administered by trained therapists.

Nevertheless, researchers and advocates contend that psychedelic drugs, used under close supervision, hold great promise for a deeper understanding of the connection between the brain and human consciousness.

“Where does our capacity for consciousness come from?” asked David Presti, who teaches graduate and undergraduate courses in neuroscience at the University of California, Berkeley. “It’s still a huge mystery. It’s the biggest mystery of all in science, and psychedelics are the most powerful probe to study that connection.”

In an interview in his office in the Life Sciences Building on the Berkeley campus, Presti held up a large piece of dried ayahuasca vine. He said brain scientists are confirming what shamanic cultures around the world have known for millennia. “These substances have a profound capacity when used under appropriate conditions to be catalysts for real transformation in people, for real healing.”

A Johns Hopkins study of psilocybin and mystical experience is a good example. Follow-up surveys of 36 “hallucinogen-naive adults” who took psilocybin under the supervision of Roland Griffiths, a professor in the departments of psychiatry and neuroscience at Johns Hopkins, found that two-thirds of them rated the sessions as being “among the five most spiritually significant experiences of their lives.”

Griffiths’ work on the behavioral and subjective effects of mood-altering drugs has been largely supported by grants from the National Institutes of Health. Along with Charles Grob, a professor of psychiatry and pediatrics at UCLA, he has studied the effects of psilocybin to treat anxiety in cancer patients—their research found that low doses of psilocybin improved the patients’ mood and reduced their need for narcotic pain relievers. Another Johns Hopkins researcher, Matthew Johnson, has begun a new pilot study to see if the active ingredient in psilocybin mushrooms, commonly called “magic mushrooms,” can help people overcome their addiction to tobacco.

Griffiths’ personal interest in meditation inspired his study of psilocybin-occasioned mystical experience in healthy volunteers. One research subject, Brian, who asked that his last name not be used, recalled, “I was unified with everything. I still had enough awareness to get up and walk to the bathroom, but everything was so incredibly beautiful that I laughed and cried at the same time. I was one with it. It was just incredible—one of the top five experiences I have ever had in my life.”

The experience was so spiritually profound that Brian recommitted himself to his study of meditation and Buddhism and in late 2012 was scheduled to be ordained as a monk in the Soto Zen tradition.

For Presti, outcomes like Brian’s are not surprising.

“One of the ways psychedelics work is by reducing our psychological defenses. They allow the person to become aware of uncomfortable feelings and thoughts so they can come to the surface and be therapeutically processed,” he said. “Nobody knows exactly how these things work, but there may be some kind of hard rewiring that goes on in the brain. They may increase neuroplasticity—make the neurons more susceptible to forming new connections.”

He believes the substances should also be studied as a possible treatment for depression.

“But there is a lot of resistance to this from the pharmaceutical industry. The last thing it wants to see is a substance people only use once or twice. They want us to use something every day for the rest of our life. That’s how they make money.”

Other researchers are troubled that the new wave of psychedelic research is blurring the lines between spiritual experience and the hard science of medicine.

“We are not purveyors of spirituality. Having an epiphany is not a part of medicine,” said John Mendelson, a senior scientist at the California Pacific Medical Research Center in San Francisco. “Most of medicine is not predicated on making you better than you are. It’s getting you back to where you were. There are lots of people and things out there can make us feel better, but our job is to diagnose and treat and fix diseases.”

That view is no longer going unchallenged.

A new generation of dedicated psychedelic drug researchers has emerged on university campuses across the nation. Many of them gathered last September at a “Psychedemia” conference at the University of Pennsylvania in Philadelphia. They see their mission as “integrating psychedelics into academia.”

“Psychedelic studies are entering the mainstream,” said Neşe Devenot, a young graduate student at Penn and a lead organizer of the multidisciplinary conference. “You can talk about this now at the dinner table without coming across as some kind of fanatic.”

During a lunch break at the weekend conference, one of the wise elders in the field of psychedelic drug research, Johns Hopkins psychologist William A. Richards, sat in the cafeteria in the basement of Houston Hall, surveying the buzz of intergenerational excitement. Richards has been exploring these realms since the early 1960s with such luminaries as Stanislav Grof, Abraham Maslow, Walter Pahnke, and, yes, Timothy Leary.

Richards knows there could be another backlash against psychedelic drug research, not just by those who are still fighting the “war on drugs” but also by academics who resist the idea that scholars should seriously study something as slippery as spirituality.

“But if mysticism is to emerge from silent monastic cells into the bright light of scientific discourse, I see no alternative,” Richards says. “We have arrived at that frontier where the growing edge of true science meets the mystery of the unknown. Here faith takes over, either belief in something or belief in nothing. These experiences are not in any drug. They are in us.”

Don Lattin’s latest book is a memoir titled Distilled Spirits: Getting High, Then Sober, With a Famous Writer, a Forgotten Philosopher, and a Hopeless Drunk. Reprinted from Spirituality & Health, (January/February 2013), a bimonthly magazine that reports on the current spiritual renaissance.

 

I've been binge watching a new series called Black Box, kind of like House, MD, but specific to neuroscience diagnostic mysteries (oh, and the main character is bipolar rather than narcissistic).

In the 5th episode (there's only 7 so far), one of the recurring characters has a brain tumor metastasize to his liver, which leaves him less than 6 months to live. He freaks out because the glioblastoma (one of the most common forms of brain tumor) had responded to treatment and he had finally reconnected with his estranged son.

The main character, a neuroscientist, suggests that maybe psilocybin will help ease his death anxiety. She repeats statistics of a study by her friend that showed 72% of terminal subjects in the study who received psilocybin had profound spiritual experiences that eased their anxiety.

And that was on ABC, not HBO or some other cable network.

A 2011 study out of UCLA showed that 11 of 12 subjects in the psilocybin study experienced reductions in Profile of Mood States (POMS) scores following administration of psilocybin. At 5 and 6 months post trial, the scores remained lower (this despite a rebound in the scores during the 2nd, 3rd, and 4th months).

You can read the study (Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer) in JAMA Psychiatry. I posted back in 2012 on some of the research into psilocybin for cancer patients.

There are studies underway in the use of psilocybin in treating:

• addiction in treatment-resistant nicotine addicts
• anxiety in terminal cancer patients
• recall of remote autobiographical memories

All of this is background to a new study in Frontiers in Human Neuroscience that looks at both psilocybin and MDMA and how they generate changes in resting-state functional connectivity (RSFC). Between-network RSFC increased under psilocybin, suggesting reduced differentiation between networks in the altered state of consciousness. There was also decreased RSFC between visual and sensorimotor resting state networks (RSN). MDMA had a much smaller effect on between-network RSFC. The suggestion is that classic psychedelics are more likely to produce profound effects on perception.

Full Citation: 
Roseman, L, Leech, R, Feilding, A, Nutt, DJ, and Carhart-Harris, RL. (2014, May 27). The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience; 8:204. doi: 10.3389/fnhum.2014.00204

The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

Leor Roseman [1,2], Robert Leech [2], Amanda Feilding [3], David J. Nutt [1], and Robin L. Carhart-Harris [1]

1. Centre for Neuropsychopharmacology, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
2. Computational, Cognitive and Clinical Neuroscience Laboratory, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
3. The Beckley Foundation, Oxford, UK

Abstract

Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.

Introduction

Psychedelic drugs have been used throughout history by different cultures as a means of altering consciousness. They are powerful tools for understanding the neurobiology of consciousness yet they have been underutilized by modern science, arguably due to political rather than scientific circumstances (Nutt et al., 2013). The majority of consciousness research has focused on states of reduced consciousness such as coma and sleep (Laureys, 2005). Indeed, consciousness has been defined as that which is lost during dreamless sleep (Tononi, 2004) but consciousness can also be studied in terms of changes in the mode or style of waking consciousness, such as is seen in the psychedelic state. Another popular model of consciousness describes it using two parameters: (1) wakefulness or arousal and (2) awareness (Laureys et al., 2009). It is recognized that these parameters have a mostly linear relationship; however, REM sleep and the vegetative state are considered anomalies, since the former involves greater awareness than would be predicted by wakefulness and the latter displays less (Laureys et al., 2009). The position of the psychedelic state in this model has never been considered before and it presents another interesting anomaly. There is no evidence of reduced wakefulness in the psychedelic state and although awareness is altered, it would be misleading to say that it is reduced. Indeed, the psychedelic state has been referred to as an “expansive” state of consciousness (Huxley, 1959). Thus, it is important to investigate what the neurobiological basis of this putative broadening of consciousness is.

One of the most popular theories of consciousness is the “information integration” theory of Tononi (2012). This proposes that consciousness depends on the presence of two key parameters: (1) information and (2) integration. Information is derived from information theory (Shannon and Weaver, 1949) and in the context of consciousness, refers to the potential size of the repertoire of different metastable states (Tognoli and Kelso, 2014) (or “sub-states”) the mind/brain can enter over time. Integration refers to the capacity of the mind/brain to integrate processes into a collective whole. The parameter of awareness is likely to be related to the property of information, since the greater the repertoire of sub-states the mind can enter, and the easier it can move between these, the broader consciousness will be.

In recent years, there has been an increasing interest in human fMRI measures of resting state functional connectivity (RSFC) (Damoiseaux and Greicius, 2009). Resting state networks (RSN) can be identified using seed-based approaches (Biswal et al., 1995) and independent component analysis (ICA) (Beckmann et al., 2005). These RSNs resemble stimulus-evoked networks (Smith et al., 2009) and may be thought of as metastable sub-states making-up a particular (macro) state of consciousness (Carhart-Harris et al., 2014a). Thus, one way to describe the quality of a macro-state of consciousness may be to investigate the integrity and dynamics of its sub-states and how they interact with each other. One way this can be done is by looking at the internal stability (integrity) of an RSN, i.e., reflected in the strength of the coupling between its constituent nodes. For example, we have found decreased intra-RSN connectivity post-psilocybin with both fMRI (Carhart-Harris et al., 2012a) and magnetoencephalography (MEG) (Muthukumaraswamy et al., 2013), implying a general breakdown of the integrity or internal stability of RSNs under psilocybin.

Another way to address the behavior of a system's sub-states is to look at their relationship with each other, e.g., by measuring between-RSN functional connectivity or coupling. A frequently investigated RSN is the default mode network (DMN) (Raichle et al., 2001). The DMN is known to be more active during rest than during goal-directed cognition and its activity has been found to be “anti-correlated” or at least uncorrelated or orthogonal with activity in networks that are engaged during goal-directed cognition - referred to generically as “task positive networks” or TPNs. This anticorrelation is preserved under task free conditions (Fox et al., 2005), implying that it is an important feature of normal consciousness, perhaps accounting for the distinction between externally focused cognition and introspection (Carhart-Harris et al., 2012b). We recently found that the classic psychedelic drug psilocybin reduces the anticorrelation between DMN and a number of TPNs during resting conditions, and this was interpreted as a decrease in the natural distinction between externally-focused attention and introspection (Carhart-Harris et al., 2012b), which is relevant to the notion of “ego-boundaries,” i.e., an agent's sense of being apart from or separate to its environment. It would be a natural extension of the above analysis to address the full gamut of between-RSN FC identified by ICA rather than just focusing on just the DMN-RSN RSFC. This was the aim of the present study.

The primary focus of the present paper is the classic psychedelic state and determining its underlying neurodynamics as measured with fMRI. However, in order to understand the psychedelic state, it is useful to compare it with other states of consciousness to see how it relates to these. Thus, the present analysis focuses on the brain effects of a classic psychedelic drug, psilocybin (the active component of magic mushrooms) and compares this with the effects of the pro-serotonergic stimulant, 3–4 methylenedioxymethamphetanine, MDMA. MDMA is a potent monoamine releaser that produces an acute euphoria in most individuals but it is not considered a classic psychedelic, as psilocybin is. Direct 5-HT2AR stimulation is the defining pharmacological property of classic serotonergic psychedelics, but relative to classic psychedelics, MDMA has a far weaker affinity for the 5-HT2A receptor (Green et al., 2003). Instead, MDMA produces a more generalized, non-selective activation of monoamine receptors by increasing the concentration of their endogenous ligands in the synapse via transporter-mediated release (Green et al., 2003). The primary subjective effects of MDMA include increased positive mood, heightened sensations and prosocial sentiments and although it can produce mild visual hallucinatory phenomena, it does not alter consciousness in the same fundamental manner as classic psychedelics (Gouzoulis-Mayfrank et al., 1996).

Thus, comparing changes in RSFC under psilocybin and MDMA can enable us to isolate and identify effects that are unique to the psychedelic-induced altered state of consciousness produced by classic psychedelics such as psilocybin. Considering the previous findings of decreased intra-RSN FC and DMN-TPN anti-correlation under psilocybin (Carhart-Harris et al., 2012a,b; Muthukumaraswamy et al., 2013), we hypothesized that the normal differentiation between RSNs would be affected by psilocybin such that RSNs whose activity is usually highly correlated would show reduced RSFC under psilocybin (but not MDMA) and that networks that are normally anti-correlated would show reduced anti-correlation under psilocybin (but not MDMA). If the hypothesized effects are present under psilocybin but absent under MDMA, this will strengthen the inference that they are specifically related to psilocybin more profound effects on consciousness.

Materials and Methods

Design

Psilocybin

This is an entirely new analysis on a previously published data set (Carhart-Harris et al., 2012a,b). This was a within-subjects placebo-controlled study that was approved by a local NHS Research Ethics Committee and Research and Development department, and conducted in accordance with Good Clinical Practice guidelines. A Home Office License was obtained for storage and handling of a Schedule 1 drug. The University of Bristol sponsored the research. The research was carried out at CUBRIC, University of Cardiff.

MDMA

This is also an entirely new analysis on a previously published dataset (Carhart-Harris et al., 2014b). This was a within-subjects, double-blind, randomized, placebo-controlled study. Participants were scanned twice, 7 days apart, once after MDMA and once after placebo. The study was approved by NRES West London Research Ethics Committee, Imperial College London's Joint Compliance and Research Office (JCRO), Imperial College's Research Ethics Committee (ICREC), the Head of Imperial College's Department of Medicine, Imanova Center for Imaging Science and Imperial College London's Faculty of Medicine, and was conducted in accordance with Good Clinical Practice guidelines. A Home Office License was obtained for the storage and handling of a Schedule 1 drug and Imperial College London sponsored the research.

Participants

Psilocybin

Fifteen healthy subjects took part: 13 males and 2 females (mean age = 32, SD = 8.9). Recruitment was via word of mouth. All subjects were required to give informed consent and undergo health screens prior to enrolment. Entry criteria were: at least 21 years of age, no personal or immediate family history of a major psychiatric disorder, substance dependence, cardiovascular disease, and no history of a significant adverse response to a hallucinogenic drug. All of the subjects had used psilocybin at least once before (mean number of uses per subject = 16.4, SD = 27.2) but not within 6 weeks of the study.

MDMA

The original study sample comprised of 25 healthy participants (mean age = 34, SD = 11, 7 females) with at least 1 previous experience with MDMA. None of the participants had used MDMA for at least 7 days and other drugs for at least 48 h, and this was confirmed by a urine screen. As a conservative step to control for between-study differences in the global intensity of the subjective effects produced by the different drugs, 11 subjects who gave ratings of <50% for the intensity of MDMA's effects were excluded from the analysis. This step meant that ratings of drug effects intensity were comparable across the two studies (i.e., the mean intensity of psilocybin's subjective effects was 67 ± 19 at peak and MDMA's was 69 ± 15). An additional subject was excluded because of significant head movements (mean head motion > one voxel width). Thus, a total of 13 subjects were included in the analysis (i.e., 12 excluded). An alcohol Breathalyzer test confirmed that none of the participants had recently consumed alcohol. For the sample of 13, participants had used MDMA an average of 29 (±35) times before (range = 1–100) and the mean time since last use was 983 (±1998) days (range = 7–6570 days). Participants were screened for general health, MR-compatibility and present mental health. Screening involved routine blood tests, electrocardiogram, heart rate, blood pressure and a brief neurological exam. All subjects were deemed physically and mentally healthy at the time of study entry and none had any history of drug or alcohol dependence.

Anatomical Scans

Psilocybin

Imaging was performed on a 3T GE HDx system. Anatomical scans were performed before each functional scan. These were 3D fast spoiled gradient echo scans in an axial orientation, (1 mm isotropic voxels).

MDMA

Imaging was performed on a 3T Siemens Tim Trio (Siemens Healthcare, Erlangen, Germany) using a 32-channel phased array head coil. Anatomical reference images were acquired using the ADNI-GO recommended MPRAGE parameters (1 mm isotropic voxels).

Drug and Scanning Parameters

Psilocybin

All subjects underwent two 12-min eyes-closed resting-state blood oxygen–level dependent (BOLD) fMRI scans on 2 separate occasions at least 7 days apart: placebo (10 ml saline, 60-s intravenous injection) was given on 1 occasion and psilocybin (2 mg dissolved in 10 ml saline) on the other. Seven of the subjects received psilocybin in scan 1, and 8 received it in scan 2. Injections were given manually by a study doctor situated within the scanning suite. The 60-s infusions began exactly 6 min after the start of the 12-min scans. Subjective ratings were given post-scan using visual analog scales (VAS). The subjective effects of psilocybin were felt almost immediately after injection and were sustained for the duration of the scan.

MDMA

Two BOLD resting-state scans were performed during each functional scanning session (duration of functioning scanning = 60 min). The first resting-state BOLD scan took place 60 min after capsule ingestion and the second resting-state BOLD scan occurred 113 min after capsule ingestion. Peak subjective effects were reported 100 min post administration of MDMA, generally consistent with the plasma t-max of MDMA (Kolbrich et al., 2008). The order of MDMA and placebo administration was counterbalanced.

fMRI Data Acquisition

Psilocybin

BOLD-weighted fMRI data were acquired using a gradient echo planar imaging sequence, 3 mm isotropic voxels, TR = 3000 ms, TE = 35 ms, field-of-view = 192 mm, 90° flip angle, 53 axial slices in each TR, parallel acceleration factor = 2, 64 × 64 acquisition matrix. The psilocybin and placebo scans for this analysis were of 5 min (1 min post infusion).

MDMA

BOLD-weighted fMRI data were acquired using a gradient echo planar imaging sequence, 3 mm isotropic voxels, TR = 2000 ms, TE = 31 ms, field-of-view = 192 mm, 80° flip angle, 36 axial slices in each TR, GRAPPA acceleration = 2, bandwidth = 2298 Hz/pixel. For each condition, MDMA and placebo, two scans were used for the analysis, each one of 6 min (performed 60 min and 113 min post-capsule ingestion)

Resting State Networks (RSN)

We used RSNs that were identified in Smith et al. (2009) using ICA (Figure 1). Ten of these components were given functional labels based on their correspondence to the BrainMap database of functional imaging studies, involving task-evoked FMRI data from nearly 30,000 human subjects. These networks were: Visual-Medial Network (VisM), Visual-Lateral Network (VisL), Visual-Occipital pole Network (VisO), Auditory Network (AUD), Sensorimotor Network (SM), Default Mode Network (DMN), Executive Control Network (ECN), Left frontoparietal Network(lFP), Right frontoparietal Network (rFP) and Cerebellar network. In addition, we used three more components from Smith et al, that we named DMN2 (an anterior DMN and ECN hybrid), Dorsal Attention Network 1 and 2 (DAN1 and DAN2). Another 6 components were identified as non-neural noise (likely generated by head motion and non-neural physiological fluctuations).

FIGURE 1  

Figure 1. Non-noise resting State Networks (RSN) from Smith et al., 2009: (1) Visual–Medial (VisM), (2) Visual–Lateral (VisL), (3) Visual–Occipital pole (VisO), (4) Auditory (AUD), (5) Sensorimotor (SM), (6) Default Mode Network (DMN), (7) DMN2–A hybrid of anterior DMN and Executive Control Network, (8) Executive Control Network (ECN), (9) left Frontoparietal Network (lFP), (10) right Frontoparietal Network (rFP), (11) Dorsal Attention Network (DAN), (12) DAN2, (13) Cerebellum. Ten of these components were given functional labels based on their correspondence to the BrainMap database of functional imaging studies. (RSNs 1, 2, 3, 4, 5, 6, 8, 9, 10, 13), additional networks (7, 11, 12) were labeled by the experimenters in the current study based on the regional distribution of activity.

Preprocessing

All analyses were performed using the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL, www.fmrib.ox.ac.uk/fsl) (Smith et al., 2004). We used the standard imaging preprocessing FSL pipeline that involved brain extraction (Smith, 2002), motion correction using MCFLIRT (Jenkinson et al., 2002), spatial smoothing (FWHM) of 5 mm (Smith and Brady, 1997) and a high-pass filter of 100 s. The scans were registered to the subjects' T1-weighted high-resolution (2 × 2 × 2 mm) anatomical scans and were then registered to the Montreal Neurological Institute standard brain (2 × 2 × 2 mm) (Jenkinson et al., 2002). The data was resampled into 4 mm space as part of the default processing pipeline for Melodic and was done to make the analysis more computational efficient.

Between Networks Functional Connectivity (FC)

Psilocybin

To extract time courses for each subject for each RSN and for each condition, we back-projected the components from Smith et al. (2009) into each 4D fMRI dataset using a general linear model. Specifically, we took the 20 components ICA map from Smith et al. as the set of template ICAs for the dual regression pipeline. The first step of the “dual regression” pipeline was then applied to each 4D dataset, resulting in a specific timecourse for each component for each dataset (Beckmann et al., 2009). Between-RSN coupling was presented graphically using a 13 × 13 correlation (or more strictly, regression) matrix in which the color in each square represents a beta weight or coupling strength for the corresponding RSN-RSN pair. Specifically, these weights were calculated by entering the time course for a specific RSN as a dependent variable in a general linear model, with the time course of another RSN entered as an independent variable—with this procedure repeated for each RSN pair. The mean head motion under psilocybin and its placebo condition were 0.1 ± 0.05 mm and 0.06 ± 0.015 mm, respectively (p < 0.01). Therefore, to further partial out non-neural noise confounds, six motion time courses (estimated from the motion correction) and motion outliers (estimated using the “fsl_motionoutlier” command implemented in FSL), as well as the time courses for 6 non-neural noise components were entered as confounds (some of this noise is driven by head motion). The model resulted in a parameter estimate or unstandardized beta weight (β) representing the strength of functional coupling between each RSN pair. The general linear model was estimated twice for each RSN pair: with each RSN as dependent variable in one model and as an independent variable in the second model. Since we were not looking at effective or directed connectivity (Friston et al., 2003), we created a symmetrical connectivity matrix by averaging together each subject's two β values for each RSN pair. For each RSN pair, three results were calculated: (a) group mean β value for the placebo condition; (b) group mean β value for the psilocybin condition; (c) Paired t-test (2-tail) for the difference between the mean β values of each condition (Figure 2). To correct for multiple comparisons, a false discovery rate (FDR) threshold was calculated using q = 0.05 and q = 0.1 (N = 78).

FIGURE 2  

Figure 2. Scheme of the analysis by steps. Calculating t-values for each RSN pair that represent the change in coupling strength between placebo and drug.

MDMA

The MDMA RSFC was analyzed using the same procedure described above (Figure 2). The only difference was that there were two resting state scans in the MDMA study, so β values from the two scans (performed 60 min and 113 min post-capsule ingestion) were averaged together before comparing between the placebo and drug conditions. The mean head motion under MDMA and its placebo condition were 0.083 ± 0.036 mm and 0.061 ± 0.019 mm, respectively (p = 0.047). The same procedure to control for motion in the psilocybin analysis was used for MDMA.

Results

Subjective Effects

Psilocybin

The subjective effects of psilocybin have been documented elsewhere (Carhart-Harris et al., 2011, 2012a). Briefly, the subjective effects of 2 mg psilocybin given as an intravenous injection over 60 s begin at the end of the injection period, reach a sustained peak after approximately 5 min, and subside completely after 45–60 min. Primary subjective effects include altered visual perception (e.g., hallucinated motion and geometric patterns), an altered sense of space and time, and vivified imagination. The intensity of psilocybin's global subjective effects was rated using a VAS format. The mean intensity at peak effects (5 min post-infusion) was 67% ±19.

MDMA

The subjective effects of MDMA are reported in a separate paper (Carhart-Harris et al., 2014b). At their peak, the average intensity of MDMA's global subjective effects was 69% ±15 (n = 13). There was no significant difference between intensity ratings under the two different drugs.

Between Networks FC

Psilocybin

The coupling strengths (β) for each condition can be seen graphically in the correlation matrixes in Figure 3 and numerically in the Supplementary material. For the placebo condition, see Figure 3A and Supplementary Table 1A and for the psilocybin condition see Figure 3B and Supplementary Table 1B. A paired t-test (2-tail) was done across subjects to compare the β values for each RSN pair in the drug and placebo (Figure 3C and Supplementary Table 1C). The results were corrected for multiple comparisons using FDR with q = 0.05 (resulting in a threshold of p < 0.0167) and q = 0.1 (resulting a threshold of p < 0.042). The RSN pairs that showed a significant decrease in coupling under psilocybin were: SM-VisM (p = 0.0265), SM-VisL (p = 0.0051) and SM-VisO (p = 0.0151). The RSN pairs that showed a significant increase in coupling were: VisM-lFP (p = 0.0001), VisM-DAN (p = 0.0156), VisM-rFP (p = 0.0023), VisM-DAN2 (p = 0.0002), VisM-Cerebellum (p = 0.0108), VisL-DMN (p = 0.0046), VisL-lFP (p = 0.0056), VisL-rFP (p = 0.0031), VisL-DAN2 (p = 0.0142), VisO-DAN2 (p = 0.0256), AUD-DMN (p = 0.028), AUD-ECN (p = 0.0323), AUD-lFP (p = 0.0029), AUD-rFP (p = 0.0001), AUD-DAN2 (p = 0.0005), SM-ECN (p = 0.0105), SM-lFP (p = 0.022), SM-rFP (p = 0.0026), SM-DAN2 (p = 0.034), DMN-lFP (p = 0.0029), DMN-DAN (p = 0.0058), DMN2-ECN (p = 0.0071) DMN2-lFP (p = 0.0101), DMN2-DAN (p = 0.0005), DMN2-DAN2 (p = 0.0091), ECN-lFP (p = 0.0077), ECN-rFP (p = 0.0098), lFP-DAN (p = 0.0026), rFP-DAN (p = 0.0187), and DAN-DAN2 (p = 0.0161).

FIGURE 3  

Figure 3. Between networks resting state functional connectivity results. Within each matrix, each colored square represents coupling between corresponding RSN pairs with the color of the square denoting the coupling strength (A,B,D,E) or change in coupling strength (C,F) between the RSN pairs (blue, negative coupling or a decrease in coupling; red, positive coupling or an increase in coupling). The six images are: (A) Group mean of β values for the placebo of psilocybin condition. (B) Group mean of β values for the psilocybin condition. (C) Paired t-test (2-tail) for the difference between the mean β values of psilocybin and placebo. (D) Group mean of β values for the placebo of MDMA condition. (E) Group mean of β values for the MDMA condition. (F) Paired t-test (2-tail) for the difference between the mean β values of MDMA and placebo. The networks from Smith et al., (2009) are: (1) Visual—Medial (VisM), (2) Visual—Lateral (VisL), (3) Visual—Occipital pole (VisO), (4) Auditory (AUD), (5) Sensorimotor (SM), (6) Default Mode Network (DMN), (7) DMN2—A hybrid of anterior DMN and Executive Control Network, (8) Executive Control Network (ECN), (9) left Frontoparietal Network (lFP), (10) right Frontoparietal Network (rFP), (11) Dorsal Attention Network (DAN), (12) DAN2, (13) Cerebellum. FDR correction for multiple comparison (N = 78) was applied on the t-tests: *0.05 < q < 0.1. **q < 0.05.

MDMA

The same analysis as above was repeated for the MDMA condition using a q of 0.05, resulting in a threshold of p < 0.0006 and q = 0.1, resulting in a threshold of p < 0.0012. Only one RSN pair showed a significant change in coupling under MDMA, i.e., increased coupling between the DMN2-ECN (p = 0.0001).

Differences in Movement

Both drugs showed significant, yet relatively modest, increased head motion between conditions. The mean head motion under psilocybin and its placebo condition were 0.1 ± 0.05 mm and 0.06 ± 0.015 mm, respectively (p < 0.01). The mean head motion under MDMA and its placebo condition were 0.083 ± 0.036 mm and 0.061 ± 0.019 mm, respectively (p = 0.047). Power et al. (2012) suggest that head motion can change the results of RSFC, therefore, in the regression analysis, we added several motion confounds: six motion time courses, motion outliers [similar to the procedure of scrubbing within regression (spike regression) mentioned by Yan et al. (2013) and Satterthwaite et al. (2013)] and time courses of RSNs that were driven by motion. However, it still remains possible that the increased movement under the drugs may have caused the changes in RSFC. Hence, we investigated if there was a relationship between the change in estimated motion (mean framewise displacement) between placebo and drug and the change in coupling strength (for pairs of RSNs that showed significant differences in coupling). For most of the RSN pairs no relationship was found (p < 0.05). However, under psilocybin, there were significant correlations with motion in the following RSN pairs: VisM-SM (p = 0.002), VisL-SM (p = 0.001), VisO-SM (p = 0.02), VisL-DMN (p = 0.03), VisM-rFN (p = 0.048), VisL-rFN (p = 0.01), VisO-DAN2, DMN-lFN (p = 0.001), DMN-DAN (p = 0.01). For that reason, the significant results of these RSN pairs should be approached with caution.

Discussion

To our knowledge, this is the first analysis to test the effects of different pharmacological agents using a standard ICA-derived template of RSNs to construct between-network functional connectivity matrixes for different drug states. This approach may have wider application, enabling researchers to determine connectivity “fingerprints” for characterizing different states of consciousness, i.e., not only those induced by pharmacological agents but sleep states and even pathological states. This will enable informed comparisons to be made between different states, potentially allowing us to categorize different states based on their connectivity profiles. Functional connectivity matrixes have been used before to differentiate between pathology states such as schizophrenia and bipolar disorder (Mamah et al., 2013) and here we suggest that they could be used more broadly to characterize states of consciousness, including those induced by psychoactive drugs.

Probably the most striking result of the present study was the marked increases in between-network RSFC under psilocybin. These increases were evident for heteromodal networks, both in terms of increased unimodal-heteromodal (e.g., AUD-rFP) and heteromodal-heteromodal network RSFC (e.g., lFP-ECN). Based on previous analyses (Carhart-Harris et al., 2012b), we had predicted that RSN pairs with weak or negative RSFC at baseline would show increased coupling post-psilocybin, and this was found (e.g., DMN-VisL). However, the increases in between-network RSFC were more fundamental than this, being evident for RSN pairs that were already positively coupled at baseline (e.g., DMN2-ECN). The increase in correlated brain activity across normally distinct brain networks was particularly true for heteromodal RSNs, where the distribution of 5-HT2A receptors is known to be highest (Erritzoe et al., 2010) and 5-HT2A receptor stimulation is linked to desynchronous cortical activity (Riba et al., 2002; Wood et al., 2012; Muthukumaraswamy et al., 2013) and network disintegration (Muthukumaraswamy et al., 2013; Carhart-Harris et al., 2014a).

The pattern of increased between-network RSFC under psilocybin did not apply universally for the whole of the brain. Decreased RSFC was observed between the three visual RSNs and the sensorimotor network [these networks are known to be highly connected (Wise et al., 1997; Van Den Heuvel et al., 2008)], and there was a general trend toward decreased unimodal-unimodal network RSFC (e.g., VisM-AUD and SM-AUD showed decreased RSFC under psilocybin but this failed to survive FDR correction, see Supplementary Table 1). However these decreases can also be explained by the changes in head motion between conditions and further work is required to test whether these decreases in sensory RSN RSFC under psilocybin relate to the drug's characteristic perceptual/hallucinatory effects.

Previous neuroimaging studies with psychedelics have so far failed to reveal a simple and compelling explanation for their characteristic hallucinogenic effects (Vollenweider et al., 1997; Carhart-Harris et al., 2012a; Muthukumaraswamy et al., 2013) (but see De Araujo et al., 2012) and so drug-induced visual hallucinations remain poorly understood. Under normal conditions, activity in the visual cortex is driven by and thus anchored to visual input. Moreover, activity in other networks (e.g., the DMN), concerned with other distinct functions (e.g., introspection), is often weakly or inversely coupled to visual activity (e.g., see the pale and blue colored squares for the visual-RSN pairs in Figures 3A,D). Thus, increased communication between the visual system and systems that are usually reserved for distinct functions may lead to erroneous perceptual associations. For example, increased DMN-visual network RSFC, may relate to an increased influence of imagination (mediated by the DMN) on visual perception (mediated by the visual networks). A similar process may occur in situations of sensory deprivation where sensory processing becomes decoupled from sensory stimulation, allowing the system to “free-wheel” with the potential for the spontaneous emergence of internally-generated percepts. Decreased cross-modality RSFC and increased unimodal to heteromodal network RSFC may be a common characteristic of such states but future studies are required to test this. For example, comparisons between the present results and changes in RSFC in the meditative state could inform these speculations.

Given reports of synesthesia-like experiences under psychedelics (e.g., participants reported that the noise of the MR scanner influenced the rate and content of their closed eye visual hallucinations Carhart-Harris et al., 2012a and see also Luke and Terhune, 2013) one may have predicted increased cross-modality communication under psilocybin rather than the decreased coupling that was observed here. However, it has yet to be determined whether synesthesia-like experiences in drug-induced altered states of consciousness are qualitatively and mechanistically related to synesthesia experienced outside of this context and it is also worth noting that increased visual to heteromodal cortical functional connectivity has been found in color-grapheme synesthesia (Dovern et al., 2012; Sinke et al., 2012) as well as in the present study.

Taking a dynamical systems theory approach to the present results, RSNs can be conceived of as “attractors,” i.e., patterns of activity into which the brain tends to gravitate for short periods of time (Deco et al., 2009; Hellyer et al., 2014). A macro-state of consciousness (such as normal waking, deep sleep or the psychedelic state) may, therefore, be graphically represented as an “attractor landscape” in which the depth of “basins of attraction” (valleys in an otherwise flat 2D-plane) reflect the stability of particular RSNs or metastable “sub-states,” i.e., more long lasting sub-states will have deep basins of attraction and unstable sub-states will have shallow ones. A recent paper (Kanamaru et al., 2013) has described brain function in these terms, suggesting that the shape of attractors depends on selective attention. In this particular model, high levels of acetylcholine activating muscarinic receptors were found to produce an attractor landscape with more stable sub-states. Relating this to the present results, the increased RSFC observed between different RSNs could be interpreted as a flattening of the attractor landscape, in which the basins of attraction are shallower, implying that the global system will move more easily between different metastable sub-states. A flattened (but not flat) attractor landscape would be consistent with increased “information” in the sense of the “information-integration” theory of consciousness (Tononi, 2012) since greater movement between metastable sub-states would imply that a larger number of these sub-states (or a broader “repertoire”) can be entered over a given time. At a critical flatness, the size of the repertoire of metastable states will be maximal but if the landscape is too flat, information will be reduced because attractors will become too unstable. This scenario is referred to as “super-criticality” (Chialvo, 2010), and if taken to the extreme, an entirely flat landscape would imply that the system has no metastable states, or just one entirely disordered one. Future studies are required to determine whether the psychedelic state is “critical” or “super-critical” in this sense (Tagliazucchi et al., 2012; Carhart-Harris et al., 2014a). Another way these results could be perceived however, is that increased between-RSN RSFC under psilocybin is representative of a “sub-critical” system, i.e., one that is more globally synchronous and therefore ordered; however, that there were also decreases in between-RSN RSFC under psilocybin, does not support this view. We intend to follow-up this matter in order to test our hypothesis that it is specifically the ease of transition (or transition probability) between RSNs/metastable sub-states that is facilitated under the drug.

In contrast to the marked changes in between-network RSFC observed with psilocybin, only one RSN-pair showed a significant change in RSFC under MDMA, i.e., increased ECN-DMN2 RSFC (Figure 3F). This result is difficult to interpret in isolation; however, it is worth noting that ECN-DMN2 RSFC was also significantly increased under psilocybin (Figure 3C). MDMA is not considered a classic psychedelic, although like psilocybin, its subjective effects are known to be significantly mediated by serotonergic mechanisms (Liechti and Vollenweider, 2001; Van Wel et al., 2011). Thus, increased ECN-DMN2 RSFC may relate to a shared aspect of these drugs' subjective effects, such as their propensity to alter mood and cognition (Carhart-Harris et al., 2014b). Pre-treatment studies with selective receptor antagonists would help to inform these matters.

There is an important caveat to be addressed about the present analysis. It should be noted that the two studies from which the data was derived employed quite different methodologies (e.g., intravenous administration of psilocybin vs. oral administration of MDMA, different MR scanners and different study samples). Thus, it would be problematic to attempt to make inferences based entirely on a comparison of their relative RSFC profiles. This analysis was not intended to be a formal comparison of the brain effects of MDMA and psilocybin and if this was the intention, then a standardized methodology would need to be employed. Rather, the present analysis has focused on understanding the neural correlates of the psychedelic state as produced by the classic psychedelic, psilocybin, and the finding that MDMA had a less marked effects on between-network RSFC has merely served to emphasize that the psychedelic state rests on a particularly profound disturbance of brain function. This does not imply that MDMA's own subjective effects are unimportant or that they do not involve some (albeit more subtle) changes in between-network RSFC.

The significant change in head movement under psilocybin implies that some of the results should be interpreted with caution, in particular the decreases in coupling strength. We have used multiple ways to model motion as a possible confound but for a subset of the RSN pairs, the changes with drug correlate with the differences in mean motion. These significant correlations do not necessarily mean that motion is responsible for these changes, since intensity of drug is likely to be associated with increased movement, meaning that disambiguating the two effects is problematic for some RSN pairs. In support of this, we found a marginally significant correlation between changes in motion and changes in the subjective intensity rating (r = 0.382, p = 0.08). Future work restricting head motion in the scanner and with larger samples is necessary to be able to demonstrate that changes in these RSN pairs that correlate with motion reflect genuine brain activity or not.

In conclusion, this new analysis has used between-network functional connectivity to investigate the effects of two distinct serotonergic compounds on spontaneous brain function. It was found that psilocybin produced marked changes in between-network RSFC, generally in the direction of increased coupling between RSNs, with an additional decrease in coupling between visual and sensorimotor networks. MDMA had a notably less marked effect on between-network RSFC implying that psilocybin's more profound effects on global brain function (at least as determined by this measure) may explain its more profound effects on consciousness. The analytic methods used in this study, i.e., using ICA templates to determine functional connectivity matrixes for different drug states, may have wider application, enabling researchers to more objectively describe and potentially categorize different states of consciousness.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

These studies received financial and intellectual support from the Beckley Foundation. We would like to thank the reviewers for their useful comments on previous versions of this manuscript.

Supplementary Material

The Supplementary Material for this article can be found online at: http://www.frontiersin.org/journal/10.3389/fnhum.2014.00204/abstract

References available at the Frontiers site.

Sam Harris - Drugs and the Meaning of Life (with commentary)

Over the last several years, it has not been often that I agree with Sam Harris about much of anything. This old 2011 article from his blog (recently reposted because he revised it and added an audio version of it), however, on the benefits of exploring altered states of consciousness (i.e., hallucinogens), is a welcome exception.

He reports the benefits he attained through his explorations of hallucinogens, but he also recounts the horrors he encountered when the previously blissful experiences became terrifying "bad trips" ("they make the notion of hell—as a metaphor if not an actual destination—seem perfectly apt").

Along the way, he makes some less-than-warranted leaps of logic:

Ingesting a powerful dose of a psychedelic drug is like strapping oneself to a rocket without a guidance system. One might wind up somewhere worth going, and, depending on the compound and one’s “set and setting,” certain trajectories are more likely than others. But however methodically one prepares for the voyage, one can still be hurled into states of mind so painful and confusing as to be indistinguishable from psychosis.

Let's begin to unpack this passage with the last comment - if you have ever spent any time with someone in a psychotic state (and I do so 2-3 hours each week), then you'll know there is little to no similarity between a bad trip and a psychotic state. The error is not Harris's, however, psychologists have made this faulty assumption for 60+ years, and in fact some of the earliest experiments on LSD were framed as attempts to understand schizophrenia.

Now to the first assertion in that passage. In my experience with hallucinogens (primarily LSD and psilocybin), if you are going to test those outer limits of consciousness, you need to be able to take control of the experience if it starts to go dark, or you need to be able to sit with the feelings and images and not be identified with them (i.e., have an observer self). In my first and last harrowing experience on LSD, I retreated from a group of friends when I began to feel very anxious, and found myself sitting on the floor in an empty dorm room surrounded by fiery demons and a complete sense of annihilation, my ego had left the building. As I sat there in terror, trying to make sense of what was happening, something shifted in me and I was no longer afraid, I was amused at the "funny" cartoon images of demons I was surrounded by. I realized that there was a deeper I of some kind that could shape the experience, that I was not "strapped to a rocket without a guidance system." I never had a bad trip again, which is not to say that I never experienced dark and disturbing images ever again, only that I was not terrified by them or at their mercy.

As a side note, I have long been amazed at how much of the psychedelic visual experience is fractal-like. I suspect that these drugs can allow us to see the deeper mathematical pattern in nature. I have found to be especially true with psilocybin mushrooms out in nature.

On the subject of MDMA, Harris cites several articles in his notes on the damage that MDMA can cause to the serotonergic system. However, he did not include the research showing that the damage is mitigated by the ingestion of alpha lipoic acid for 2 days and then 30 minutes prior to consuming the MDMA (emphasis added in the abstract):

Aguirre, Barrionuevo, Ramírez, Del Río, & Lasheras. (1999, Nov 26). "Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity." Neuroreport. 10(17):3675-80.

"A single administration of 3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg, i.p.), induced significant hyperthermia in rats and reduced 5-hydroxytryptamine (5-HT) content and [3H] paroxetine-labeled 5-HT transporter density in the frontal cortex, striatum and hippocampus by 40-60% 1 week later. MDMA treatment also increased glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus. Repeated administration of the metabolic antioxidant alpha-lipoic acid (100 mg/kg, i.p., b.i.d. for 2 consecutive days) 30 min prior to MDMA did not prevent the acute hyperthermia induced by the drug; however, it fully prevented the serotonergic deficits and the changes in the glial response induced by MDMA. These results further support the hypothesis that free radical formation is responsible for MDMA-induced neurotoxicity."   

There is additional research suggesting that even moderate doses of vitamin C (1000 mg) taken for a few days before and then 30 minutes prior to ingestion can also mitigate the serotonergic damage. The smart drug user does his research before ingesting any of these chemicals.

Finally, there is one other argument that Harris makes with which I take exception.

If the brain were merely a filter on the mind, damaging it should increase cognition. In fact, strategically damaging the brain should be the most reliable method of spiritual practice available to anyone. In almost every case, loss of brain should yield more mind. But that is not how the mind works.

Some people try to get around this by suggesting that the brain may function more like a radio, a receiver of conscious states rather than a barrier to them. At first glance, this would appear to account for the deleterious effects of neurological injury and disease, for if one smashes a radio with a hammer, it will no longer function properly. There is a problem with this metaphor, however. Those who employ it invariably forget that we are the music, not the radio. If the brain were nothing more than a receiver of conscious states, it should be impossible to diminish a person’s experience of the cosmos by damaging her brain. She might seem unconscious from the outside—like a broken radio—but, subjectively speaking, the music would play on.

Now, I do not believe in the brain as receiver hypothesis, at least in terms of consciousness or of transpersonal states of consciousness. But the argument Harris makes here is flawed - he argues that it should be impossible to damage a person's experience of the cosmos by damaging her brain, and he bases this on the brain as radio receiver metaphor.

However, if you damage a radio (especially the antenna/reception portion of the radio), it is no longer capable of receiving the information (the radio signals), while the information continues to be broadcast (so to speak). Likewise, if we damage the brain in the right way (and this would essentially mean damaging the sensory perception/reception modules of the brain), the brain can no longer receive the (external) signal and will not experience whatever information is being broadcast.

However, if we assume that this damage occurs after many years of normal function, there may be enough residual signal left to create a minimal conscious state, even when the sensory reception apparatus is damaged or shut off. This may be what happens in some forms of catatonic autism and/or catatonic schizophrenia, where the sensory input is so overwhelming that the brain shuts it off and the person is so withdrawn as to be essentially encased in an invisible shell of silence.

I only argue this point because it represents for me some of the faulty logic Harris employs in other areas of his writing.

On the whole, however, this is an honest and useful piece from Harris - I'm sorry I missed it the first time he posted it. I can't imagine how much more limited by life would be if I had not spent a few years taking psychedelics and entheogens and observing the function and structure of my mind.

Drugs and the Meaning of Life

Sam Harris | July 4, 2011

(Photo by JB Banks)

(Note 6/4/2014: I have revised this 2011 essay and added an audio version.—SH)


Everything we do is for the purpose of altering consciousness. We form friendships so that we can feel certain emotions, like love, and avoid others, like loneliness. We eat specific foods to enjoy their fleeting presence on our tongues. We read for the pleasure of thinking another person’s thoughts. Every waking moment—and even in our dreams—we struggle to direct the flow of sensation, emotion, and cognition toward states of consciousness that we value.

Drugs are another means toward this end. Some are illegal; some are stigmatized; some are dangerous—though, perversely, these sets only partially intersect. Some drugs of extraordinary power and utility, such as psilocybin (the active compound in “magic mushrooms”) and lysergic acid diethylamide (LSD), pose no apparent risk of addiction and are physically well-tolerated, and yet one can still be sent to prison for their use—whereas drugs such as tobacco and alcohol, which have ruined countless lives, are enjoyed ad libitum in almost every society on earth. There are other points on this continuum: MDMA, or Ecstasy, has remarkable therapeutic potential, but it is also susceptible to abuse, and some evidence suggests that it can be neurotoxic.^[1]

One of the great responsibilities we have as a society is to educate ourselves, along with the next generation, about which substances are worth ingesting and for what purpose and which are not. The problem, however, is that we refer to all biologically active compounds by a single term, drugs, making it nearly impossible to have an intelligent discussion about the psychological, medical, ethical, and legal issues surrounding their use. The poverty of our language has been only slightly eased by the introduction of the term psychedelics to differentiate certain visionary compounds, which can produce extraordinary insights, from narcotics and other classic agents of stupefaction and abuse.

However, we should not be too quick to feel nostalgia for the counterculture of the 1960s. Yes, crucial breakthroughs were made, socially and psychologically, and drugs were central to the process, but one need only read accounts of the time, such as Joan Didion’s Slouching Towards Bethlehem, to see the problem with a society bent upon rapture at any cost. For every insight of lasting value produced by drugs, there was an army of zombies with flowers in their hair shuffling toward failure and regret. Turning on, tuning in, and dropping out is wise, or even benign, only if you can then drop into a mode of life that makes ethical and material sense and doesn’t leave your children wandering in traffic.

Drug abuse and addiction are real problems, of course, the remedy for which is education and medical treatment, not incarceration. In fact, the most abused drugs in the United States now appear to be oxycodone and other prescription painkillers. Should these medicines be made illegal? Of course not. But people need to be informed about their hazards, and addicts need treatment. And all drugs—including alcohol, cigarettes, and aspirin—must be kept out of the hands of children.

I discuss issues of drug policy in some detail in my first book, The End of Faith, and my thinking on the subject has not changed. The “war on drugs” has been lost and should never have been waged. I can think of no right more fundamental than the right to peacefully steward the contents of one’s own consciousness. The fact that we pointlessly ruin the lives of nonviolent drug users by incarcerating them, at enormous expense, constitutes one of the great moral failures of our time. (And the fact that we make room for them in our prisons by paroling murderers, rapists, and child molesters makes one wonder whether civilization isn’t simply doomed.)

I have two daughters who will one day take drugs. Of course, I will do everything in my power to see that they choose their drugs wisely, but a life lived entirely without drugs is neither foreseeable nor, I think, desirable. I hope they someday enjoy a morning cup of tea or coffee as much as I do. If they drink alcohol as adults, as they probably will, I will encourage them to do it safely. If they choose to smoke marijuana, I will urge moderation.^[2]  Tobacco should be shunned, and I will do everything within the bounds of decent parenting to steer them away from it. Needless to say, if I knew that either of my daughters would eventually develop a fondness for methamphetamine or crack cocaine, I might never sleep again. But if they don’t try a psychedelic like psilocybin or LSD at least once in their adult lives, I will wonder whether they had missed one of the most important rites of passage a human being can experience.

This is not to say that everyone should take psychedelics. As I will make clear below, these drugs pose certain dangers. Undoubtedly, some people cannot afford to give the anchor of sanity even the slightest tug. It has been many years since I took psychedelics myself, and my abstinence is born of a healthy respect for the risks involved. However, there was a period in my early twenties when I found psilocybin and LSD to be indispensable tools, and some of the most important hours of my life were spent under their influence. Without them, I might never have discovered that there was an inner landscape of mind worth exploring.

There is no getting around the role of luck here. If you are lucky, and you take the right drug, you will know what it is to be enlightened (or to be close enough to persuade you that enlightenment is possible). If you are unlucky, you will know what it is to be clinically insane. While I do not recommend the latter experience, it does increase one’s respect for the tenuous condition of sanity, as well as one’s compassion for people who suffer from mental illness.

Human beings have ingested plant-based psychedelics for millennia, but scientific research on these compounds did not begin until the 1950s. By 1965, a thousand studies had been published, primarily on psilocybin and LSD, many of which attested to the usefulness of psychedelics in the treatment of clinical depression, obsessive-compulsive disorder, alcohol addiction, and the pain and anxiety associated with terminal cancer. Within a few years, however, this entire field of research was abolished in an effort to stem the spread of these drugs among the public. After a hiatus that lasted an entire generation, scientific research on the pharmacology and therapeutic value of psychedelics has quietly resumed.

Psychedelics such as psilocybin, LSD, DMT, and mescaline all powerfully alter cognition, perception, and mood. Most seem to exert their influence through the serotonin system in the brain, primarily by binding to 5-HT_2A receptors (though several have affinity for other receptors as well), leading to increased activity in the prefrontal cortex (PFC). Although the PFC in turn modulates subcortical dopamine production—and certain of these compounds, such as LSD, bind directly to dopamine receptors—the effect of psychedelics seems to take place largely outside dopamine pathways, which could explain why these drugs are not habit-forming.

The efficacy of psychedelics might seem to establish the material basis of mental and spiritual life beyond any doubt, for the introduction of these substances into the brain is the obvious cause of any numinous apocalypse that follows. It is possible, however, if not actually plausible, to seize this evidence from the other end and argue, as Aldous Huxley did in his classic The Doors of Perception, that the primary function of the brain may be eliminative: Its purpose may be to prevent a transpersonal dimension of mind from flooding consciousness, thereby allowing apes like ourselves to make their way in the world without being dazzled at every step by visionary phenomena that are irrelevant to their physical survival. Huxley thought of the brain as a kind of “reducing valve” for “Mind at Large.” In fact, the idea that the brain is a filter rather than the origin of mind goes back at least as far as Henri Bergson and William James. In Huxley’s view, this would explain the efficacy of psychedelics: They may simply be a material means of opening the tap.

Huxley was operating under the assumption that psychedelics decrease brain activity. Some recent data have lent support to this view; for instance, a neuroimaging study of psilocybin suggests that the drug primarily reduces activity in the anterior cingulate cortex, a region involved in a wide variety of tasks related to self-monitoring. However, other studies have found that psychedelics increase activity throughout the brain. Whatever the case, the action of these drugs does not rule out dualism, or the existence of realms of mind beyond the brain—but then, nothing does. That is one of the problems with views of this kind: They appear to be unfalsifiable.^[3]

We have reason to be skeptical of the brain-as-barrier thesis. If the brain were merely a filter on the mind, damaging it should increase cognition. In fact, strategically damaging the brain should be the most reliable method of spiritual practice available to anyone. In almost every case, loss of brain should yield more mind. But that is not how the mind works.

Some people try to get around this by suggesting that the brain may function more like a radio, a receiver of conscious states rather than a barrier to them. At first glance, this would appear to account for the deleterious effects of neurological injury and disease, for if one smashes a radio with a hammer, it will no longer function properly. There is a problem with this metaphor, however. Those who employ it invariably forget that we are the music, not the radio. If the brain were nothing more than a receiver of conscious states, it should be impossible to diminish a person’s experience of the cosmos by damaging her brain. She might seem unconscious from the outside—like a broken radio—but, subjectively speaking, the music would play on.

Specific reductions in brain activity might benefit people in certain ways, unmasking memories or abilities that are being actively inhibited by the regions in question. But there is no reason to think that the pervasive destruction of the central nervous system would leave the mind unaffected (much less improved). Medications that reduce anxiety generally work by increasing the effect of the inhibitory neurotransmitter GABA, thereby diminishing neuronal activity in various parts of the brain. But the fact that dampening arousal in this way can make people feel better does not suggest that they would feel better still if they were drugged into a coma. Similarly, it would be unsurprising if psilocybin reduced brain activity in areas responsible for self-monitoring, because that might, in part, account for the experiences that are often associated with the drug. This does not give us any reason to believe that turning off the brain entirely would yield an increased awareness of spiritual realities.

However, the brain does exclude an extraordinary amount of information from consciousness. And, like many who have taken psychedelics, I can attest that these compounds throw open the gates. Positing the existence of a Mind at Large is more tempting in some states of consciousness than in others. But these drugs can also produce mental states that are best viewed as forms of psychosis. As a general matter, I believe we should be very slow to draw conclusions about the nature of the cosmos on the basis of inner experiences—no matter how profound they may seem.

One thing is certain: The mind is vaster and more fluid than our ordinary, waking consciousness suggests. And it is simply impossible to communicate the profundity (or seeming profundity) of psychedelic states to those who have never experienced them. Indeed, it is even difficult to remind oneself of the power of these states once they have passed.

Many people wonder about the difference between meditation (and other contemplative practices) and psychedelics. Are these drugs a form of cheating, or are they the only means of authentic awakening? They are neither. All psychoactive drugs modulate the existing neurochemistry of the brain—either by mimicking specific neurotransmitters or by causing the neurotransmitters themselves to be more or less active. Everything that one can experience on a drug is, at some level, an expression of the brain’s potential. Hence, whatever one has seen or felt after ingesting LSD is likely to have been seen or felt by someone, somewhere, without it.

However, it cannot be denied that psychedelics are a uniquely potent means of altering consciousness. Teach a person to meditate, pray, chant, or do yoga, and there is no guarantee that anything will happen. Depending upon his aptitude or interest, the only reward for his efforts may be boredom and a sore back. If, however, a person ingests 100 micrograms of LSD, what happens next will depend on a variety of factors, but there is no question that something will happen. And boredom is simply not in the cards. Within the hour, the significance of his existence will bear down upon him like an avalanche. As the late Terence McKenna^[4]  never tired of pointing out, this guarantee of profound effect, for better or worse, is what separates psychedelics from every other method of spiritual inquiry.

Ingesting a powerful dose of a psychedelic drug is like strapping oneself to a rocket without a guidance system. One might wind up somewhere worth going, and, depending on the compound and one’s “set and setting,” certain trajectories are more likely than others. But however methodically one prepares for the voyage, one can still be hurled into states of mind so painful and confusing as to be indistinguishable from psychosis. Hence, the terms psychotomimetic and psychotogenic that are occasionally applied to these drugs.

I have visited both extremes on the psychedelic continuum. The positive experiences were more sublime than I could ever have imagined or than I can now faithfully recall. These chemicals disclose layers of beauty that art is powerless to capture and for which the beauty of nature itself is a mere simulacrum. It is one thing to be awestruck by the sight of a giant redwood and amazed at the details of its history and underlying biology. It is quite another to spend an apparent eternity in egoless communion with it. Positive psychedelic experiences often reveal how wondrously at ease in the universe a human being can be—and for most of us, normal waking consciousness does not offer so much as a glimmer of those deeper possibilities.

People generally come away from such experiences with a sense that conventional states of consciousness obscure and truncate sacred insights and emotions. If the patriarchs and matriarchs of the world’s religions experienced such states of mind, many of their claims about the nature of reality would make subjective sense. A beatific vision does not tell you anything about the birth of the cosmos, but it does reveal how utterly transfigured a mind can be by a full collision with the present moment.

However, as the peaks are high, the valleys are deep. My “bad trips” were, without question, the most harrowing hours I have ever endured, and they make the notion of hell—as a metaphor if not an actual destination—seem perfectly apt. If nothing else, these excruciating experiences can become a source of compassion. I think it may be impossible to imagine what it is like to suffer from mental illness without having briefly touched its shores.

At both ends of the continuum, time dilates in ways that cannot be described—apart from merely observing that these experiences can seem eternal. I have spent hours, both good and bad, in which any understanding that I had ingested a drug was lost, and all memories of my past along with it. Immersion in the present moment to this degree is synonymous with the feeling that one has always been and will always be in precisely this condition. Depending on the character of one’s experience at that point, notions of salvation or damnation may well apply. Blake’s line about beholding “eternity in an hour” neither promises nor threatens too much.

In the beginning, my experiences with psilocybin and LSD were so positive that I did not see how a bad trip could be possible. Notions of “set and setting,” admittedly vague, seemed sufficient to account for my good luck. My mental set was exactly as it needed to be—I was a spiritually serious investigator of my own mind—and my setting was generally one of either natural beauty or secure solitude.

I cannot account for why my adventures with psychedelics were uniformly pleasant until they weren’t, but once the doors to hell opened, they appeared to have been left permanently ajar. Thereafter, whether or not a trip was good in the aggregate, it generally entailed some excruciating detour on the path to sublimity. Have you ever traveled, beyond all mere metaphors, to the Mountain of Shame and stayed for a thousand years? I do not recommend it.

(Pokhara, Nepal)

On my first trip to Nepal, I took a rowboat out on Phewa Lake in Pokhara, which offers a stunning view of the Annapurna range. It was early morning, and I was alone. As the sun rose over the water, I ingested 400 micrograms of LSD. I was twenty years old and had taken the drug at least ten times previously. What could go wrong?

Everything, as it turns out. Well, not everything—I didn’t drown. I have a vague memory of drifting ashore and being surrounded by a group of Nepali soldiers. After watching me for a while, as I ogled them over the gunwale like a lunatic, they seemed on the verge of deciding what to do with me. Some polite words of Esperanto and a few mad oar strokes, and I was offshore and into oblivion. I suppose that could have ended differently.

But soon there was no lake or mountains or boat—and if I had fallen into the water, I am pretty sure there would have been no one to swim. For the next several hours my mind became a perfect instrument of self-torture. All that remained was a continuous shattering and terror for which I have no words.

An encounter like that takes something out of you. Even if LSD and similar drugs are biologically safe, they have the potential to produce extremely unpleasant and destabilizing experiences. I believe I was positively affected by my good trips, and negatively affected by the bad ones, for weeks and months.

Meditation can open the mind to a similar range of conscious states, but far less haphazardly. If LSD is like being strapped to a rocket, learning to meditate is like gently raising a sail. Yes, it is possible, even with guidance, to wind up someplace terrifying, and some people probably shouldn’t spend long periods in intensive practice. But the general effect of meditation training is of settling ever more fully into one’s own skin and suffering less there.

As I discussed in The End of Faith, I view most psychedelic experiences as potentially misleading. Psychedelics do not guarantee wisdom or a clear recognition of the selfless nature of consciousness. They merely guarantee that the contents of consciousness will change. Such visionary experiences, considered in their totality, appear to me to be ethically neutral. Therefore, it seems that psychedelic ecstasies must be steered toward our personal and collective well-being by some other principle. As Daniel Pinchbeck pointed out in his highly entertaining book Breaking Open the Head, the fact that both the Mayans and the Aztecs used psychedelics, while being enthusiastic practitioners of human sacrifice, makes any idealistic connection between plant-based shamanism and an enlightened society seem terribly naïve.

As I discuss elsewhere in my work, the form of transcendence that appears to link directly to ethical behavior and human well-being is that which occurs in the midst of ordinary waking life. It is by ceasing to cling to the contents of consciousness—to our thoughts, moods, and desires— that we make progress. This project does not in principle require that we experience more content.^[5]  The freedom from self that is both the goal and foundation of “spiritual” life is coincident with normal perception and cognition—though, admittedly, this can be difficult to realize.

The power of psychedelics, however, is that they often reveal, in the span of a few hours, depths of awe and understanding that can otherwise elude us for a lifetime. William James said it about as well as anyone:^[6]

One conclusion was forced upon my mind at that time, and my impression of its truth has ever since remained unshaken. It is that our normal waking consciousness, rational consciousness as we call it, is but one special type of consciousness, whilst all about it, parted from it by the filmiest of screens, there lie potential forms of consciousness entirely different. We may go through life without suspecting their existence; but apply the requisite stimulus, and at a touch they are there in all their completeness, definite types of mentality which probably somewhere have their field of application and adaptation. No account of the universe in its totality can be final which leaves these other forms of consciousness quite disregarded. How to regard them is the question,—for they are so discontinuous with ordinary consciousness. Yet they may determine attitudes though they cannot furnish formulas, and open a region though they fail to give a map. At any rate, they forbid a premature closing of our accounts with reality.

(The Varieties of Religious Experience, p. 388)

I believe that psychedelics may be indispensable for some people—especially those who, like me, initially need convincing that profound changes in consciousness are possible. After that, it seems wise to find ways of practicing that do not present the same risks. Happily, such methods are widely available.

NOTES:

1. A wide literature now suggests that MDMA can damage serotonin-producing neurons and decrease levels of serotonin in the brain. Here is the tip of the iceberg: 1, 2, 3, 4, 5, and 6. There are credible claims, however, that many of these studies used poor controls or dosages in lab animals that were too high to model human use of the drug. ↩
2. What is moderation? Let’s just say that I’ve never met a person who smokes marijuana every day who I thought wouldn’t benefit from smoking less (and I’ve never met someone who has never tried it who I thought wouldn’t benefit from smoking more).↩
3. Physicalism, by contrast, could be easily falsified. If science ever established the existence of ghosts, or reincarnation, or any other phenomenon which would place the human mind (in whole or in part) outside the brain, physicalism would be dead. The fact that dualists can never say what would count as evidence against their views makes this ancient philosophical position very difficult to distinguish from religious faith.↩
4. Terence McKenna is one person I regret not getting to know. Unfortunately, he died from brain cancer in 2000, at the age of 53. His books are well worth reading, and I have recommended several below, but he was, above all, an amazing speaker. It is true that his eloquence often led him to adopt positions which can only be described (charitably) as “wacky,” but the man was undeniably brilliant and always worth listening to. ↩
5. I should say, however, that there are psychedelic experiences that I have not had, which appear to deliver a different message. Rather than being states in which the boundaries of the self are dissolved, some people have experiences in which the self (in some form) appears to be transported elsewhere. This phenomenon is very common with the drug DMT, and it can lead its initiates to some very startling conclusions about the nature of reality. More than anyone else, Terence McKenna was influential in bringing the phenomenology of DMT into prominence.
   DMT is unique among psychedelics for a several reasons. Everyone who has tried it seems to agree that it is the most potent hallucinogen available (not in terms of the quantity needed for an effective dose, but in terms of its effects). It is also, paradoxically, the shortest acting. While the effects of LSD can last ten hours, the DMT trance dawns in less than a minute and subsides in ten. One reason for such steep pharmacokinetics seems to be that this compound already exists inside the human brain, and it is readily metabolized by monoaminoxidase. DMT is in the same chemical class as psilocybin and the neurotransmitter serotonin (but, in addition to having an affinity for 5-HT_2A receptors, it has been shown to bind to the sigma-1 receptor and modulate Na+ channels). Its function in the human body remains mysterious. Among the many mysteries and insults presented by DMT, it offers a final mockery of our drug laws: Not only have we criminalized naturally occurring substances, like cannabis; we have criminalized one of our own neurotransmitters.
   Many users of DMT report being thrust under its influence into an adjacent reality where they are met by alien beings who appear intent upon sharing information and demonstrating the use of inscrutable technologies. The convergence of hundreds of such reports, many from first-time users of the drug who have not been told what to expect, is certainly interesting. It is also worth noting these accounts are almost entirely free of religious imagery. One appears far more likely to meet extraterrestrials or elves on DMT than traditional saints or angels. As I have not tried DMT, and have not had an experience of the sort that its users describe, I don’t know what to make of any of this. ↩
6. Of course, James was reporting his experiences with nitrous oxide, which is an anesthetic. Other anesthetics, like ketamine hydrochloride and phencyclidine hydrochloride (PCP), have similar effects on mood and cognition at low doses. However, there are many differences between these drugs and classic psychedelics—one being that high doses of the latter do not lead to general anesthesia. ↩

Recommended Reading:

• Huxley, A. The Doors of Perception and Heaven and Hell.
• McKenna, T. Food of the Gods: The Search for the Original Tree of Knowledge A Radical History of Plants, Drugs, and Human Evolution.
• McKenna, T. The Archaic Revival: Speculations on Psychedelic Mushrooms, the Amazon, Virtual Reality, UFOs, Evolution, Shamanism, the Rebirth of the Goddess, and the End of History.
• McKenna, T. True Hallucinations: Being an Account of the Author’s Extraordinary Adventures in the Devil’s Paradise.
• Pinchbeck, D. Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism.
• Stevens, J. Storming Heaven: LSD and the American Dream.
• Ratsch, C. The Encyclopedia of Psychoactive Plants: Ethnopharmacology and Its Applications.
• Ott, J. Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History.
• Strassman, R. DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences.