Category: Psychedelic Drugs

Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too. An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression. This suggests that an entirely new class of depression and anxiety drugs might be right under our noses.

"In spite of information stemming from ancient texts, constituents of Bosweilla had not been investigated for psychoactivity," said Raphael Mechoulam, one of the research study's co-authors. "We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. Apparently, most present day worshipers assume that incense burning has only a symbolic meaning."

To determine incense's psychoactive effects, the researchers administered incensole acetate to mice. They found that the compound significantly affected areas in brain areas known to be involved in emotions as well as in nerve circuits that are affected by current anxiety and depression drugs. Specifically, incensole acetate activated a protein called TRPV3, which is present in mammalian brains and also known to play a role in the perception of warmth of the skin. When mice bred without this protein were exposed to incensole acetate, the compound had no effect on their brains.

"Perhaps Marx wasn't too wrong when he called religion the opium of the people: morphine comes from poppies, cannabinoids from marijuana, and LSD from mushrooms; each of these has been used in one or another religious ceremony." said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Studies of how those psychoactive drugs work have helped us understand modern neurobiology. The discovery of how incensole acetate, purified from frankincense, works on specific targets in the brain should also help us understand diseases of the nervous system. This study also provides a biological explanation for millennia-old spiritual practices that have persisted across time, distance, culture, language, and religion–burning incense really does make you feel warm and tingly all over!"

According to the National Institutes of Health, major depressive disorder is the leading cause of disability in the United States for people ages 15–44, affecting approximately 14.8 million American adults. A less severe form of depression, dysthymic disorder, affects approximately 3.3 million American adults. Anxiety disorders affect 40 million American adults, and frequently co-occur with depressive disorders.

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Journal Reference:

1. Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. Arieh Moussaieff, Neta Rimmerman, Tatiana Bregman, Alex Straiker, Christian C. Felder, Shai Shoham, Yoel Kashman, Susan M. Huang, Hyosang Lee, Esther Shohami, Ken Mackie, Michael J. Caterina, J. Michael Walker, Ester Fride, and Raphael Mechoulam. Published online before print May 20, 2008 as doi: 10.1096/fj.07-101865. [link]

 Brain-imaging studies performed in animals at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory provide researchers with clues about why an increasingly popular recreational drug that causes hallucinations and motor-function impairment in humans is abused. Using trace amounts of Salvia divinorum – also known as "salvia," a Mexican mint plant that can be smoked in the form of dried leaves or serum – Brookhaven scientists found that the drug's behavior in the brains of primates mimics the extremely fast and brief "high" observed in humans.

Quickly gaining popularity among teenagers and young adults, salvia is legal in most states, but is grabbing the attention of municipal lawmakers. Numerous states have placed controls on salvia or salvinorin A – the plant's active component – and others, including New York, are considering restrictions.

"This is probably one of the most potent hallucinogens known," said Brookhaven chemist Jacob Hooker, the lead author of the study, which is the first to look at how the drug travels through the brain. "It's really important that we study drugs like salvia and how they affect the brain in order to understand why they are abused and to investigate their medicinal relevance, both of which can inform policy makers."

Hooker and fellow researchers used positron emission tomography, or PET scanning, to watch the distribution of salvinorin A in the brains of anesthetized primates. In this technique, the scientists administer a radioactively labeled form of salvinorin A (at concentrations far below pharmacologically active doses) and use the PET scanner to track its site-specific concentrations in various brain regions.

Within 40 seconds of administration, the researchers found a peak concentration of salvinorin A in the brain – nearly 10 times faster than the rate at which cocaine enters the brain. About 16 minutes later, the drug was essentially gone. This pattern parallels the effects described by human users, who experience an almost immediate high that starts fading away within 5 to 10 minutes.

High concentrations of the drug were localized to the cerebellum and visual cortex, which are parts of the brain responsible for motor function and vision, respectively. Based on their results and published data from human use, the scientists estimate that just 10 micrograms of salvia in the brain is needed to cause psychoactive effects in humans.

Salvia doesn't cause the typical euphoric state associated with other hallucinogens like LSD, Hooker said. The drug targets a receptor that is known to modulate pain and could be important for therapies as far reaching as mood disorders.

"Most people don't find this class of drugs very pleasurable," Hooker said. "So perhaps the main draw or reason for its appeal relates to the rapid onset and short duration of its effects, which are incredibly unique. The kinetics are often as important as the abused drug itself."

The Brookhaven team plans to conduct further studies related to salvia's abuse potential. The scientists also hope to develop radioactive tracers that can better probe the brain receptors to which salvia binds. Such studies could possibly lead to therapies for chronic pain and mood disorders.

These results are now published online in the journal NeuroImage. This research was funded by the Office of Biological and Environmental Research within DOE's Office of Science. DOE has a long-standing interest in research on brain chemistry gained through brain-imaging studies. Brain-imaging techniques such as PET are a direct outgrowth of DOE's support of basic physics and chemistry research.

— Mount Sinai researchers have identified a new receptor complex in the brain that responds to several types of antipsychotic drugs used to treat schizophrenia and also reacts to hallucinogenic drugs such as LSD. Stuart Sealfon, MD, Professor of Neurology and Director of the Center for Translational Systems Biology at Mount Sinai School of Medicine and colleagues discovered the receptor complex, which could help provide new treatments for schizophrenia and other diseases associated with psychosis. 

“The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. The discovery of this receptor complex could provide a new target for developing drugs to treat schizophrenia,” said Dr. Sealfon.

The study done in mice identified that the two receptors, neurotransmitters glutamate and serotonin, interact and work as a hybrid complex. Hallucinogenic drugs, such as LSD and psilocybin, act at serotonin receptors to cause responses similar to some of the core symptoms of schizophrenia. The researchers showed that the glutamate receptor interacts with the serotonin receptor to form functional complexes in brain cortex. This receptor complex triggers unique cellular responses when targeted by hallucinogenic drugs.

Activation of the glutamate receptor blocks hallucinogen-specific signaling and changes behavioral responses in mice.

In untreated schizophrenics, the serotonin receptor is up-regulated and the glutamate receptor is downregulated, a pattern that could predispose to psychosis. These findings suggest that the newly identified serotonin/glutamate complex may be involved in the altered cortical processes of schizophrenia.

“The findings further our understanding of how hallucinations occur. They suggest a brain abnormality that may contribute to the abnormal brain function in schizophrenia,” said Dr. Sealfon. “We can now use this information to do further study and hopefully develop more specific drug therapies for treating patients who suffer from hallucinations and psychosis.”

This new study was published online in Nature.

About  3.1 million people in the United States aged 12 to 25 (5.3 percent of this age group) have used over-the-counter (non-prescription) cough and cold medicines to get high at least once in their lifetimes, according to a report by the Substance Abuse and Mental Health Services Administration (SAMHSA). The level is comparable to LSD, and more than the reported use of methamphetamines, among those aged 12 to 25. White youths were more than three times as likely as Black youths to have misused these drugs during the past year.

Newly analyzed data from the National Survey of Drug Use and Health (NSDUH) show the number is comparable to those who say they have used LSD (3.1 million), and is significantly greater than the number who reported having tried methamphetamines (2.4 million).

Overdosing on many cough and cold medications may result in serious life-threatening adverse reactions. Adverse reactions include blurred vision, loss of physical coordination, intense abdominal pain, vomiting, uncontrolled violent muscle spasms, irregular heartbeat, delirium and death.

The NSDUH survey also found that the number of 12- to-25-year-olds who reported misuse of non-prescription cough and cold medicines in the past year (1 million) exceeded the number claiming to have used methamphetamines (740,000) and LSD (485,000) in the past year. The number was somewhat lower than the number of young people reporting that they had used the drug Ecstasy (1.5 million) in the past year.

The survey, conducted by SAMHSA, is the largest of its kind and involves interviewing nearly 67,000 people from around the nation, including almost 45,000 persons aged 12 to 25.

Patterns of misuse of non-prescription drugs varied among demographic groups. Females aged 12 to 17 were more likely than their male counterparts to have misused these drugs within the past year (2.3 percent vs. 1.5 percent). But among those aged 18 to 25, more males had misused these drugs in the past year than females (1.8 percent vs. 1.3 percent).  Among all persons aged 12 to 25, the rate of past year misuse among whites (2.1 percent) was three times higher than among blacks (0.6 percent) and significantly higher than among Hispanics (1.4 percent). 

“While increasing attention has been paid to the public health risk of prescription drug abuse, we also need to be aware of the growing dangers of misuse of over-the-counter cough and cold medications, especially among young people,” said SAMHSA Administrator Terry Cline, Ph.D.  “The scope and danger posed by these medications requires a broad scale public health campaign–a campaign involving everyone, including the medical community, industry, parents and young people.”

Although non-prescription cough and cold medications are generally safe when taken for medicinal purposes and as directed on their labeling, they can induce severe dissociative, “out-of-body” experiences when they are consumed in amounts far in excess of their recommended dosages. These reactions are similar to the effects of the well-known hallucinogens phencyclidine (PCP) and ketamine (“Special K”).

The full report on non-prescription cough and cold medication is available on the Web at http://oas.samhsa.gov/2k8/cough/cough.cfm.

 Drugs that treat depression, schizophrenia and other psychotic conditions and that target a particular protein on brain cells might not be triggering the most appropriate response in those cells, new research suggests.

The study by researchers at The Ohio State University Medical Center examined the serotonin 2A receptor, a protein on brain cells sensitive to the neurotransmitter serotonin.

This study examined the early chemical events that happen inside neurons when the 2A receptor is stimulated by serotonin and by a synthetic hallucinogenic agent that is thought to mimic serotonin.

The findings, published online in the early edition of the Proceedings of the National Academy of Sciences with an accompanying editorial, show that although both compounds combine with and activate this receptor, they trigger different chemical pathways inside the neuron.

Researchers say that the work could have important implications for the development of drugs that affect the serotonin 2A receptor, a key target in the treatment of several important mental disorders.

"This new insight into how serotonin and a hallucinogenic drug affect this serotonin receptor could lead to changes in how new drugs are screened and developed for depression, schizophrenia and other neuropsychiatric disorders," says study leader Laura M. Bohn, an associate professor of pharmacology and psychiatry.

Currently, it is thought that when serotonin binds with the receptor, it sends a signal that activates molecules inside the cell called G proteins.

This study shows, however, that the receptor responds to serotonin by also activating a protein called beta-arrestin inside the cell. The synthetic hallucinogen, on the other hand, causes the receptor to activate only the G proteins. The hallucinogen does not seem to use beta-arrestins to cause its effects.

For this study, Bohn and her colleagues used laboratory-grown cells and a strain of mice that lacked beta-arrestin. The hallucinogen was a hallucinogenic amphetamine called DOI.

When the researchers injected normal (i.e., control) and experimental mice with DOI, both groups showed a head-twitch behavior, a characteristic response in mice to hallucinogens.

But when the mice were given high doses of serotonin, which typically also causes the head-twitch behavior, the behavior occurred in the control animals only, and not in the mice lacking beta-arrestin.

"That demonstrates that the signal for serotonin requires beta-arrestin for that biological effect," Bohn says. "The synthetic hallucinogen, on the other hand, induces the head-twitch behavior whether beta-arrestin is present or not.

"Overall, our findings suggest that the screening of agents intended to be serotonin mimics must also determine if the agent signals through beta-arrestin," Bohn says. "That isn't done now."

Heather Hallen spent eight years looking for poison in all the wrong places.

Alpha-amanitin is the poison of the death cap mushroom, Amanita phalloides. The Michigan State University plant biology research associate was looking for a big gene that makes a big enzyme that produces alpha-amanitin, since that's how other fungi produce similar compounds. But after years of defeat, she and her team called in the big guns — new technology that sequences DNA about as fast as a death cap mushroom can kill.

The results: The discovery of remarkably small genes that produce the toxin — a unique pathway previously unknown in fungi.

The discovery is reported in today's Proceedings of the National Academy of Sciences. It is work that not only solves a mystery of how some mushrooms make the toxin — but also sheds light on the underlying biochemical machinery. It might be possible one day to harness the mushroom genes to make novel chemicals that would be useful as new drugs.

"We think we have a factory that spits out lots of little sequences to make chemicals in Amanita mushrooms," said Jonathan Walton, MSU plant biology professor who leads Hallen's team. "Our work indicates that these mushrooms have evolved a mechanism to make dozens or even hundreds of new, previously unknown chemicals, besides the toxins that we know about."

Of the thousands of species of mushrooms, only about 30 produce alpha-amanitin. Most of them look much like their edible cousins. But poisonous mushrooms are powerful in folklore and in history. In 54 A.D., Emperor Tiberius Claudius was fed a death cap mushroom by his wife Agrippina to put her son Nero on the throne of Rome.

Alpha-amanitin kills people by inhibiting an enzyme necessary for expression of most genes. Without the ability to synthesize new proteins, cells quickly grind to a halt. The intestinal tract and the liver are the hardest hit as they come into first contact with the toxin. By the time symptoms show up, a liver transplant is often the only hope.

Hallen, a mycologist, gathers mushrooms in the Michigan woods and often is called upon to help identify mushroom species for veterinarians, parents of small children and local hospitals — often in a desperate race to beat alpha-amanitin's effects.

Walton's lab works to understand the biochemical pathways by which natural products are synthesized in fungi. Fungal natural products that benefit human health include penicillin and the immunosuppressant drug cyclosporin. Studying their biosynthesis could lead to the discovery and development of new medicines.

To find the elusive gene for alpha-amanitin, they used what they term "brute force" — a new machine at MSU that can sequence immense quantities of DNA quickly. The 454 LifeSciences pyrosequencer generates 100 Mb DNA sequence in one overnight run – twice the size of a fungal genome. Traditional sequencing methods require months to yield the same quantities. What they found was a gene that encodes the toxin directly — with no need to first synthesize an enzyme that in turn would make the toxin.

"The RNA goes in, and out comes the backbone of the toxin," Hallen said. After its initial synthesis, the toxin is then modified in several ways by the mushroom to make it exceptionally poisonous.

Walton said the discovery poses some interesting evolutionary questions. For example, why do only some mushrooms produce this toxin" And how did a handful of other, unrelated mushrooms evolve the same trait" Finding the genes points to how the trait could appear in one mushroom, but not how it evolved in mushrooms that aren't related to Amanita.

Hallen and Walton also see the doors opening to a diagnostic test that could use DNA to determine if a mushroom is toxic or not. Identifying a mushroom by shape and color alone is often impossible if the mushroom has been cooked or partially digested, yet rapid and accurate identification in an emergency room situation is critical.

The work was funded by a grant from the U.S. Department of Energy to the Plant Research Lab, the MSU Michigan Agricultural Experiment Station and a Strategic Partnership Grant from the MSU Foundation.

Scientists at the University of Cambridge have discovered why some individuals may be predisposed to drug addiction and believe it may lead to better treatments for this brain disorder.

The new findings, published in today's edition of Science, may lead to more targeted treatments for addiction and other compulsive behaviour disorders with fewer side effects than current alternatives.

Certain changes in brain chemistry have been linked with drug addiction in humans. However, previous studies were unable to conclude whether individuals were predisposed to drug addiction because of these chemical changes or if chronic drug use itself caused the chemical changes in the brain.

Dr Jeff Dalley and colleagues, at the Behavioural and Clinical Neuroscience Institute, may have resolved this debate by demonstrating that changes in a neurotransmitter receptor in a particular part of the brain actually pre-dates drug use. Using positron emission tomography (a PET scan), they discovered that rats that were behaviourally impulsive, but which had not been exposed to drugs, had significantly less brain dopamine receptors than their more restrained counterparts. Additionally, these same impulsive rats were found to be considerably more likely to self-administer cocaine intravenously, thus linking impulsive behaviour with drug addiction vulnerability.

Dr Dalley's research, funded by the Medical Research Council and the Wellcome Trust, demonstrates that the changes in dopamine receptors and impulsivity pre-date drug use and do not emerge as a result of prolonged addiction. His findings may have important ramifications for a range of addictive substances, including nicotine and opiates, where high consumption rates have also been linked to a similar reduction in this particular brain receptor.

Dr Dalley said, "The next step is identifying the gene or genes that cause this diminished supply of brain receptors. This may provide important new leads in the search for improved therapies for attention deficit/hyperactivity disorder (ADHD) and compulsive brain disorders such as drug addiction and pathological gambling."

Government reports estimate there are between 281,000 and 506,000 individuals addicted to Class A drugs (to include ecstasy, LSD, heroin, cocaine, crack, mushrooms and injectable amphetamines) in England and Wales.

The brain mechanism underlying the mind-bending effects of hallucinogens such as LSD, mescaline, and psilocybin has been discovered by neuroscientists. They said their discoveries not only shed light on the longtime mystery of how hallucinogens work, but that the findings also offer a pathway to understanding the function of drugs used to treat neuropsychiatric disorders, which are now being used largely without an understanding of their fundamental mechanism.

Stuart Sealfon, Jay Gingrich, and colleagues published their findings in the February 1, 2007 issue of the journal Neuron, published by Cell Press.

Researchers have long known that hallucinogens activate specific receptors in the brain, called 5-HT2A receptors (2ARs), that are normally triggered by the neurotransmitter serotonin. Neurotransmitters are chemicals that one brain cell launches at receptors on another to trigger a nerve impulse in the receiving cell. However, a fundamental mystery has been why other compounds that activate the same receptors are not hallucinogenic.

In their studies, the researchers compared the differences between the effects of LSD and a nonhallucinogenic chemical that also activates 2AR receptors on the mouse neural machinery. Since the animals could not report the kinds of perception-altering effects that humans experience on hallucinogens, the researchers determined hallucinogenic properties by measuring a head twitch response the mice characteristically showed when under hallucinogens but not when under nonhallucinogens.

The scientists concentrated their studies on the cortex of the brain, which earlier studies had shown to be the center for action of the hallucinogens. Their analysis revealed that LSD produced genetic, electrophysiological, and internal cellular signaling responses that were distinctively different from those induced by a nonhallucinogenic compound.

They also explored whether 2ARs were central to the hallucinogenic effect of LSD by producing mice lacking the receptors, but in which receptor activity could be selectively restored in the cortex. The researchers found that mice without functioning receptors showed no hallucinogenic response to LSD, but restoring the receptors rendered LSD hallucinogenic in the animals.

The researchers wrote that "These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens."

They also concluded that "The strategy we developed to elucidate [hallucinogen] action should be applicable to [central nervous system]-active compounds, with therapeutic potential in other disorders. Thus, our findings may advance the understanding of neuropsychiatric disorders that have specific pharmacological treatments whose mechanisms of action are not fully understood."

For the past five years, Dr. Erika Dyck has been unearthing some intriguing facts related to a group of pioneering psychiatrists who worked in Saskatchewan, Canada in the '50s and '60s.

Among other things, the University of Alberta history of medicine professor has found records of the psychiatrists' research that indicate a single dose of the hallucinogenic drug LSD, provided in a clinical, nurturing environment, can be an effective treatment for alcoholism.

Her findings are published this month in the journal Social History of Medicine.

After perceiving similarities in the experiences of people on LSD and people going through delirium tremens, the psychiatrists undertook a series of experiments. They noted that delirium tremens, also know as DTs, often marked a "rock bottom" or turning point in the behavior of alcoholics, and they felt LSD may be able to trigger such a turnaround without engendering the painful physical effects associated with DTs.

As it turns out, they were largely correct.

"The LSD somehow gave these people experiences that psychologically took them outside of themselves and allowed them to see their own unhealthy behavior more objectively, and then determine to change it," said Dyck, who read the researchers' published and private papers and recently interviewed some of the patients involved in the original studies–many of whom had not had a sip of alcohol since their single LSD experience 40 years earlier.

According to one study conducted in 1962, 65 per cent of the alcoholics in the experiment stopped drinking for at least a year-and-a-half (the duration of the study) after taking one dose of LSD. The controlled trial also concluded that less than 25 per cent of alcoholics quit drinking for the same period after receiving group therapy, and less than 12 per cent quit in response to traditional psychotherapy techniques commonly used at that time.

Published in the Quarterly Journal for Studies on Alcohol, the 1962 study was received with much skepticism. One research group in Toronto tried to replicate the results of the study, but wanted to observe the effect of LSD on the patients in isolation, so they blindfolded or tied up the patients before giving them the drug. Under such circumstances, the Toronto researchers determined LSD was not effective in treating alcoholism.

The Saskatchewan group argued that the drug needed to be provided in a nurturing environment to be effective. However, the Toronto researchers held more credibility than the Saskatchewan researchers–who were led by a controversial, British psychiatrist, Dr. Humphry Osmond–and the Saskatchewan group's research was essentially buried.

But Dyck believes there is value in the Saskatchewan group's experiments.

"The LSD experience appeared to allow the patients to go through a spiritual journey that ultimately empowered them to heal themselves, and that's really quite an amazing therapy regimen," Dyck said. "Even interviewing the patients 40 years after their experience, I was surprised at how loyal they were to the doctors who treated them, and how powerful they said the experience was for them–some even felt the experience saved their lives."

In spite of the promise LSD showed as psychotherapy tool, its subsequent popularity as a street drug, and the perception of it as a threat to public safety, triggered a worldwide ban in the late 1960s–including its use in medical experiments. However, the ban on its use in medical experiments appears to be lifting, Dyck noted. A few groups of researchers in the U.S., including a team at Harvard, have recently been granted permission to conduct experiments with LSD.

"We accept all sorts of drugs, but I think LSD's 'street' popularity ultimately led to its demise," Dyck said. "And that's too bad, because I think the researchers in Saskatchewan, among others, showed the drug is unique and has some intriguing properties that need to be explored further."

— Using unusually rigorous scientific conditions and measures, Johns Hopkins researchers have shown that the active agent in "sacred mushrooms" can induce mystical/spiritual experiences descriptively identical to spontaneous ones people have reported for centuries.

The resulting experiences apparently prompt positive changes in behavior and attitude that last several months, at least.

The agent, a plant alkaloid called psilocybin, mimics the effect of serotonin on brain receptors-as do some other hallucinogens-but precisely where in the brain and in what manner are unknown.

An account of the study, accompanied by an editorial and four experts' commentaries, appears online today in the journal Psychopharmacology.

Cited as "landmark" in the commentary by former National Institute on Drug Abuse (NIDA) director, Charles Schuster, the research marks a new systematic approach to studying certain hallucinogenic compounds that, in the 1950s, showed signs of therapeutic potential or value in research into the nature of consciousness and sensory perception. "Human consciousness…is a function of the ebb and flow of neural impulses in various regions of the brain-the very substrate that drugs such as psilocybin act upon," Schuster says. "Understanding what mediates these effects is clearly within the realm of neuroscience and deserves investigation."

"A vast gap exists between what we know of these drugs-mostly from descriptive anthropology-and what we believe we can understand using modern clinical pharmacology techniques," says study leader Roland Griffiths, Ph.D., a professor with Hopkins' departments of Neuroscience and Psychiatry and Behavioral Biology. "That gap is large because, as a reaction to the excesses of the 1960s, human research with hallucinogens has been basically frozen in time these last forty years."

All of the study's authors caution about substantial risks of taking psilocybin under conditions not appropriately supervised. "Even in this study, where we greatly controlled conditions to minimize adverse effects, about a third of subjects reported significant fear, with some also reporting transient feelings of paranoia," says Griffiths. "Under unmonitored conditions, it's not hard to imagine those emotions escalating to panic and dangerous behavior."

The researchers' message isn't just that psilocybin can produce mystical experiences. "I had a healthy skepticism going into this," says Griffiths, "and that finding alone was a surprise." But, as important, he says, "is that, under very defined conditions, with careful preparation, you can safely and fairly reliably occasion what's called a primary mystical experience that may lead to positive changes in a person. It's an early step in what we hope will be a large body of scientific work that will ultimately help people."

The authors acknowledge the unusual nature of the work, treading, as it does, a fine line between neuroscience and areas most would consider outside science's realm. "But establishing the basic science here is necessary," says Griffiths, "to take advantage of the possible benefits psilocybin can bring to our understanding of how thought, emotion, and ultimately behavior are grounded in biology."

Griffiths is quick to emphasize the scientific intent of the study. "We're just measuring what can be observed," he says; "We're not entering into 'Does God exist or not exist.' This work can't and won't go there."

In the study, more than 60 percent of subjects described the effects of psilocybin in ways that met criteria for a "full mystical experience" as measured by established psychological scales. One third said the experience was the single most spiritually significant of their lifetimes; and more than two-thirds rated it among their five most meaningful and spiritually significant. Griffiths says subjects liken it to the importance of the birth of their first child or the death of a parent.

Two months later, 79 percent of subjects reported moderately or greatly increased well-being or life satisfaction compared with those given a placebo at the same test session. A majority said their mood, attitudes and behaviors had changed for the better. Structured interviews with family members, friends and co-workers generally confirmed the subjects' remarks. Results of a year-long followup are being readied for publication.

Psychological tests and subjects' own reports showed no harm to study participants, though some admitted extreme anxiety or other unpleasant effects in the hours following the psilocybin capsule. The drug has not been observed to be addictive or physically toxic in animal studies or human populations. "In this regard," says Griffiths, a psychopharmacologist, "it contrasts with MDMA (ecstasy), amphetamines or alcohol."

The study isn't the first with psilocybin, the researchers say, though some of the earlier ones, done elsewhere, had notably less rigorous design, were less thorough in measuring outcomes or lacked longer-term follow-up.

In the present work, 36 healthy, well-educated volunteers-most of them middle-aged-with no family history of psychosis or bipolar disorder were selected. All had active spiritual practices. "We thought a familiarity with spiritual practice would give them a framework for interpreting their experiences and that they'd be less likely to be confused or troubled by them," Griffiths says. All gave informed consent to the study approved by Hopkins' institutional review board.

Each of thirty of the subjects attended two separate 8-hour drug sessions, at two month intervals. On one they received psilocybin, on another, methylphenidate (Ritalin), the active placebo.

In designing the study, researchers had to overcome or at least, greatly minimize two hurdles: the risk of adverse side-effects and the likelihood that the expectations of getting the test drug or the placebo would influence subjects' perceptions.

To lessen the former, each subject met several times, before drug sessions began, with a reassuring "monitor," a medical professional experienced in observing drug study participants. Monitors stayed with them during the capsule-taking sessions. Actual trials took place in a room outfitted like a comfortable, slightly upscale living room, with soft music and indirect, non-laboratory lighting. Heart rate and blood pressure were measured throughout.

The researchers countered "expectancy" by having both monitors and subjects "blinded" to what substance would be given. For ethical reasons, subjects were told about hallucinogens' possible effects, butalso learned they could, instead, get other substances-weak or strong-that might change perception or consciousness. Most important, a third "red herring" group of six subjects had two blinded placebo sessions, then were told they'd receive psilocybin at a third. This tactic-questionnaires later verified-kept participants and monitors in the dark at the first two sessions about each capsule's contents.

Nine established questionnaires and a new, specially createdfollowup survey were used to rate experiences at appropriate times in the study. They included those that differentiate effects of psychoactive drugs, that detect altered states of consciousness, that rate mystical experiences and assess changes in outlook.

The study, Griffiths adds, has advanced understanding of hallucinogen abuse.

As for where the work could lead, the team is planning a trial of patients suffering from advanced cancer-related depression or anxiety, following up suggestive research several decades ago. They're also designing studies to test a role for psilocybin in treating drug dependence.

The study was funded by grants from NIDA and the Council on Spiritual Practices.

Una McCann, M.D., William Richards, Ph.D., of the Johns Hopkins Medical Institutions and Robert Jesse of the Council on Spiritual Practices, San Francisco, were co-researchers.