7 November 2007

The acid test

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It's been banned for 35 years, but some scientists argue that a comeback for the therapeutic use of psychedelic drugs is overdue. Is there a place for LSD in medicine today?
The acid test

Credit: iStockphoto

Cycling home from the Sandoz Pharmaceutical Laboratories in 1943, the Swiss biochemist Albert Hofmann found himself on the trip of his life. The familiar route had unexpectedly been transformed into an undulating boulevard like a Salvador Dali painting, fringed by buildings that yawned and rippled, “as if seen in a curved mirror”.

This was not a fantastical dream, but the result of a rather unorthodox experiment. Five years earlier, in a search for novel therapeutic agents to treat migraines, Hofmann had combined an ergot alkaloid, lysergic acid, with a diethylamine building block to create the 25th molecule in a series of lysergic acid compounds. At the time, pharmacological assessment of the new molecule, lysergic acid diethylamide (LSD), had revealed nothing of interest.

Hofmann did not realise he had stumbled upon a compound with mind-altering properties that would change both the scientific and social world until he resynthesised the substance on April 16, 1943 and accidentally absorbed some through his skin. Intrigued by the effects he experienced, Hofmann ran a series of experiments on himself, starting with the famous bicycle ‘trip’. He took 0.25 milligrams of LSD — which he believed to be a miniscule dose. Today it is known that one-thousandth of that amount is enough to produce psychedelic effects.

The first experiment immersed Hofmann in an enchanting world of perceptual distortions in which objects morphed into surreal images, and sounds transposed into colourful kaleidoscopic visions. But the inner distortion of his mind reached such frightening proportions that Hofmann feared for his sanity and his life.

“Familiar objects and pieces of furniture assumed grotesque, threatening forms. Every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort,” Hofmann wrote in his 1980 seminal work, LSD: My Problem Child. “A demon had invaded me. I jumped up and screamed, trying to free myself from him… my body seemed to be without sensation, lifeless, strange. Was I dying?

“Another reflection took shape, an idea full of bitter irony: if I was now forced to leave this world prematurely, it was because of this lysergic acid diethylamide that I myself had brought forth into the world.”

Hofmann had not only brought forth a new drug, he had given birth to a new field of scientific research — psychedelic medicine — which scientists and physicians of the day embraced with great enthusiasm.

Barely able to believe Hofmann’s reports of the drug’s vivid effects, Ernst Rothlin, the director of the pharmacology department at Sandoz at the time, and two colleagues, conducted similar self-experimentation using one third of Hofmann’s dose. Rothlin too found himself plunged into a world that the Beatles famously described as full of “tangerine trees and marmalade skies”. His experience included frightening demonic twists and turns of his mind They agreed that LSD, the hallucinogenic effects of which can last for 6 to 12 hours, had extraordinary potency.

Believing LSD could be of great value to psychiatry, Sandoz made the drug readily available to scientific and clinical investigators for medical research under the trade name Delysid.

THE FLURRY OF RESEARCH that ensued suggested that LSD might encourage the release of memories or reveal the unconscious in psychoanalysis; or help psychotherapy patients to reach new levels of self-awareness. Many psychiatrists were encouraged to take the drug to enable them to subjectively understand schizophrenia or share psychedelic experiences with their patients.

Patients were given LSD for conditions ranging from anxiety disorders, obsessive-compulsive disorders, depression and bereavement to sexual dysfunction. The early literature even describes attempts to fix what was termed ‘frigidity’, using LSD to release repressed memories of abuse, while noting that the compound accentuated anxiety in some patients.

Inevitably, LSD escaped from the lab. As the drug counter-culture gathered momentum in the 1960s, the boundary between scientific inquiry and the quest for ‘spiritual enlightenment’ began to blur — and the scientific community distanced itself from the drug.

One of the best-known catalysts in this transition was Timothy Leary, a doctoral psychologist from Harvard University, who turned LSD from a scientific interest into a cult. Recruiting Harvard students as disciples, Leary’s clinical LSD experiments at Harvard in the 1960s attracted more willing participants than could be accommodated, creating a black market for the drug on campus among those who missed out.

By 1967, Leary had abandoned any pretense to scientific research. To a gathering of 30,000 hippies at the Golden Gate Bridge in San Francisco, he prescribed the catch phrase, “turn on, tune in, drop out”.

As LSD became increasingly associated with drug abuse, student riots and anti-war demonstrations, the U.S. Food and Drug Administration (FDA) moved swiftly to classify LSD as a Schedule 1 drug under the Federal Controlled Substances Act of 1970. Worldwide prohibition followed in 1971.

Swiss chemist Albert Hoffman with a model of the LSD molecule.


FOR A VOCAL GROUP of LSD enthusiasts, the psychedelic dream lives on. Contemporary advocates, who include scientists and medical practitioners, believe LSD has therapeutic potential in the treatment of severe pain and as an adjunct to psychotherapy; especially for post-traumatic stress disorder and substance addiction.

A leader in the LSD revival is Rick Doblin, a Harvard graduate with a doctorate in public policy, who describes his work as “fixing sick policies”. Doblin founded the Multidisciplinary Association for Psychedelic Studies (MAPS) in Boston in 1986 with the goal of supporting clinical research into hallucinogenic drugs and marijuana. He is determined MAPS will become a pharmaceutical company that will develop, manufacture and market these drugs as prescription medicines.

“I think there’s a role for a low-dose daily psychedelic as an energiser, or as a low-dose pain reliever,” Doblin says. “Low dose LSD or low-dose psilocybin [the active agent in 'magic mushrooms'] — which is going to be more helpful in terms of pain? Nobody knows. This is the problem of almost 40 years of suppression of research.”

MAPS, which receives its income from tax-deductible donations, has poured around US$1.5 million into research on hallucinogenic drugs since 2000. It has funded two FDA-approved research projects in the U.S. using the hallucinogen methylenedioxymethamphetamine or MDMA (also known as ecstasy) to facilitate psychotherapy in cancer patients with end-of-life anxiety and in those experiencing post-traumatic stress disorder.

Doblin says MAPS has also sponsored preclinical LSD trials in the U.S., Israel and Switzerland and predicts licences for research using human subjects will follow. When this happens, MAPS plans to fund an LSD-assisted psychotherapy study for people with terminal cancer-related anxiety in Switzerland as early as 2007.

“There is a race in our own minds to see who is going to be the first [research team] to give LSD to a human subject. Because LSD is the quintessential drug associated with the counter-culture and Timothy Leary, it’s the last to be approved,” he says.

Doblin, who admits he has taken about 100 LSD ‘trips’, is adamant that MAPS and the LSD renaissance is not just a vehicle for nostalgic ex-hippies to legitimise their drug interests. “Post-traumatic stress disorders or anxiety associated with end-of-life illnesses are not things that appeal to people who can be just dismissed as hedonists or hippies,” he says. “We’re going to find out that once the stigma is taken away from these drugs, they’re going to be tremendously useful in ways we don’t even know about.”

Even before its ban, medical use of LSD had slowed to a crawl in the late 1960s following reports of long-term adverse psychological effects and only limited evidence of therapeutic benefit. But Doblin asserts that risks can be minimised in a controlled therapeutic setting.

“LSD is incredibly benign to the human body. It’s the human psyche that is the issue. If you look at somebody who is doing LSD, high-dose LSD, you could say there are things there that look pretty similar to mental illness,” Doblin says. “How you handle the psyche and how you enable people to have experiences — that’s the art of psychotherapy.”


Jerry Frankenheim, a pharmacologist at the National Institute on Drug Abuse (NIDA), the peak American body for research into drug abuse, says NIDA does not endorse MAPS’ arguments and warns that the neurotoxicity of LSD and other hallucinogens could be underestimated. “LSD has a reputation for producing long-lasting psychoses [severe impairment of thought and perception long after the drug has worn off] when used for the therapy of alcoholism and other refractory diseases,” says Frankenheim. “Post-LSD psychoses, which resemble schizo-affective disorders, are unpredictable and can be accompanied by visual disturbances. This can sometimes follow a single dose, but is more common in people with prior psychopathology.

“MDMA damages brain serotonergic neurons, while LSD-induced psychoses and hallucinogen persisting perception disorder [flashbacks] could be caused by subtle damage to the brain,” he adds.

The flashbacks that LSD users report are recurrences of certain aspects of a person’s LSD experience, without the user having taken the drug again. Robert Batey, a professor of medicine at the University of New South Wales in Sydney and clinical advisor to the New South Wales Centre for Drug and Alcohol, cautions that flashbacks, which occur in about 25 per cent of LSD users, can be highly unpredictable and therefore potentially harmful.

“Flashbacks can occur as much as a year after taking LSD. You only have to hear that a few patients have experienced flashbacks from times they’ve used LSD to realise it would have to be a very brave ethics committee to approve the use of a drug that could cause harm,” he says.

Batey has some experience with LSD. When mainstream acceptance of the drug was filtering through medical schools in the early 1960s, it was handed out to students for study. One of them was Batey, then a 20-year-old medical student at the University of Sydney who, in 1964, investigated the drug’s relaxant effect on smooth muscle in rats.

He says early beliefs that LSD was going to revolutionise psychiatry hold little water. “LSD provided some insight into neuromuscular transmission, and may well provide insight into how the brain works. But I can’t see any benefits of people being forced to hallucinate,” he says. “We don’t understand enough about harms that might eventuate and what litigation might ensue by somebody who is rendered different by an experience [with LSD].”

Doblin believes that LSD is sufficiently safe to meet ethics protocols — citing a trial that used psilocybin to study mystical experiences in healthy participants, which gained approval from the ethics committee of the prestigious Johns Hopkins University in Baltimore in 2001.

“It does not require a brave team to go before an ethics committee; it requires an educated, knowledgeable and energetic team. Nobody tries to claim any more that there is brain damage from LSD. The U.S. government’s NIDA doesn’t even claim that,” says Doblin. “The risks are psychological and you show a risk-benefit analysis. It is the prejudices you are going up against, not the scientific data.”


The quality of the scientific data, however, has been a point of contention in the scientific community. During LSD’s early years as a subject of research, more than 2,000 scientific papers were published describing positive results in more than 40,000 patients. But most of the published data referred to anecdotal case reports — less valued today because they lack randomisation, placebo-control or sufficient follow-up. Doblin says MAPS-sponsored LSD clinical trials will be randomised, controlled and double-blinded. But his critics argue that many contemporary trials on the clinical use of LSD often make dubious conclusions from flimsy methodology.

A study published in the respected journal Neurology in March 2006 reported that LSD appeared to help prevent or reduce pain attacks in people with cluster headaches — a particularly severe form of migraine involving several intense headaches per week.

The researchers recruited 53 cluster headache patients who were already self-medicating with LSD or psilocybin. Based on self-reports from eight of the nine LSD users, the researchers said LSD ended the episode of attacks, and for five LSD users, using the substance extended the period of time between attacks.

Batey is sceptical of these anecdotal case studies, despite their publication in peer-reviewed journals. “One could never build a career or a policy on one or two patients’ experiences of any drug,” he says. “Like the story of cannabis, which people have been pushing to get medically available for the last 20 years, if it is as good as the protagonists suggest, it would have been taken up by drug companies a long time ago.”

Nevertheless, the case for medical cannabis appears to have advanced. In 2003, the New South Wales state government saw sufficient pre-clinical evidence to approve a four-year controlled clinical trial of the medicinal use of cannabis. In Britain and elsewhere, wide-scale trials testing the safety and efficacy of cannabis extracts are underway.

Will hallucinogenic drugs follow the same path? Trevor Norman, a pharmacologist in the department of psychiatry at the Austin Hospital in Melbourne, thinks not. “In the case of cluster headaches, there are other compounds around that solve the job by acting in a similar sort of mechanism without the possibility of flashbacks.

“LSD could be effective in treating pain, however, because of its ability to influence serotonergic receptors in the brain,” Norman adds. “The problem is, you’d need to control the dose extremely carefully because the amount of compound required for the hallucinogen experience is very minor indeed, only a few micrograms.

“In a psychiatric setting, the [hallucinogenic] compounds are a problem, because they induce hallucinoses. As far as we’re concerned, psychiatrists would say categorically, there’s absolutely no role for any hallucinogen substance,” he says.

Most hallucinogens, including LSD, are believed to produce cognitive, perceptual and mood distortions by directly activating 5-HT2A and other brain serotonin receptors; the same receptors that are thought to be overactive in schizophrenia.

Hofmann and his colleagues didn’t have access to modern brain scanners; but PET (positron emission tomography) and MRI (magnetic resonance imaging) technology can now provide insight into how the brain responds to LSD. But to explain how LSD influences the mind, brain scanning has limitations, says Iain McGregor, director of the psychopharmacology laboratory at the University of Sydney.

“You can put in radioactive LSD to give you a much better idea of distribution and binding sites in the brain — indeed such data are available in animal studies,” he says. “You could do a brain scan to confirm that the 5-HT2A receptor is the principal mode of operation of LSD. As I tell my students, if there is a candidate for a ‘God receptor’ [in the brain], then it’s most likely to be 5-HT2A.”


IN AUSTRALIA, THERE HAVE been no applications for research licences for LSD, according to the Therapeutic Goods Administration. Its use in scientific or medical research remains prohibited. But McGregor believes the winds of change are coming. “I think we’ve almost reached a stage where the baby boomers are in control,” he says. “So the ones who were trippin’ out at Woodstock are going to be in power— or not quite yet — but I think the next generation will be there.

“It may be that we can use LSD to answer questions like: what is a religious experience? What is consciousness? What is sense of self? What stops us spending a whole afternoon looking at one leaf on a tree?” McGregor adds. “I don’t think LSD will be given out for free to primary school children — and I don’t think it should be either. But I think there will be more of a relaxed approach to the utility of these things in treating psychological problems.”

The two thousand delegates who attended the world’s first scientific symposium on LSD would like to think so. Over three days in January 2006, scientists and counter-culture enthusiasts attended the meeting in Basel, Switzerland, to mark the 100th birthday of Albert Hofmann — the man who stumbled across the drug in his laboratory 63 years ago and, as a result, had the most unusual bicycle ride of his life.

A frail but sharp Albert Hofmann addressed the melting pot of therapists, academics, doctors, writers, artists, spiritual leaders and baby boomer drug devotees who gathered in reverence of the Swiss chemist-come-spiritual father and his “problem child”, as he called LSD.

“I produced the substance as a medicine. It’s not my fault if people abused it,” Hofmann said. “Before LSD got onto the streets [in the 1960s], we were able to gather a lot of therapeutic experiences. The substance was used in the psychoanalysis of patients who couldn’t be talked to. If they were given LSD, they were stimulated enough to begin responding to analysis.

“What began as a miracle substance subsequently became a youth cult drug, and thus a political danger,” Hofmann said. “The decision of the U.S. to ban LSD was purely political. Every doctor has controlled access to heroin, morphine and even strychnine. But for LSD there’s a total prohibition.”

Hofmann continues to insist the drug should be legalised for medical treatment, particularly in psychiatric research, and is frustrated by the worldwide prohibition that has pushed it underground. “It should be a controlled substance with the same status as morphine,” he later told reporters. But he was pleased with the gathering — and the revived discussion of LSD’s potential. “This is a wonderful birthday party we are having. One could say it is a consciousness-expanding experience,” Hofmann said with a twinkle in his eye.

Alex Wilde is a science and health writer based in Sydney, Australia.
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