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Turn On, Tune In, Drop Out … Get Well?

By Jaime McCutcheon | 5.07.07

On a bitterly cold night last January, a friend and I touched down in Basel, a quaint Swiss town which straddles the Franco-German border and follows the winding course of the Rhine. We were there to attend a conference arranged to celebrate the 100th anniversary of Albert Hoffman’s birth. Hoffman was a chemist who gained notoriety a number of years after he accidentally discovered one of the most culturally important compounds in modern times. His discovery was lysergic acid diethylamide or LSD.

It was the first time either of us had been to Switzerland. After roaming the streets for several hours in sub-zero temperatures attempting to find a hotel that would take us without reservations, we began to get a handle on the Swiss psyche. Being seasoned travelers, we were taken aback with the incredulity that met us. The idea that somebody would spontaneously travel to a foreign city without making sleeping reservations at least four weeks beforehand seemed like insanity to the hoteliers we encountered (with reflection, I suppose there was an international conference about to start - maybe they had a point). Regardless, it set us to wondering; how would the pleasant yet conservative residents take to having their city used as the forum for a three day celebration and exploration into psychedelic drugs?

The next morning, while registering for the conference, we were given a taste of what the ensuing weekend would be like. At first glance, it seemed that the centre had been double-booked as the lobby was teeming with a mixture of math teachers and Caucasian dreadlocks. Welcome to LSD 2006. This strange juxtaposition of conservative, anarchic, liberal, restrained, credible, and frankly ridiculous continued throughout the meeting. It was not uncommon for seminars to veer between topics as diverse as hardcore organic chemistry, astrology, and Greek mythology. However, the major thrust of the meeting, and the main reason that we had attended, was to review the evidence pertaining to the re-emergence of research projects examining LSD and the other hallucinogenic drugs in a psychotherapeutic setting.


Acid is not the sort of drug patients would normally expect to be offered in a doctor’s surgery. Maybe at an Incredible String Band reunion tour. Or even a luncheon at Buckingham Palace. But most people will not have had their general practitioner write them an LSD prescription. However, for a number of years there was hope in the psychiatric community that the mind-altering substances we now know as psychedelic drugs would prove to be as indispensable to psychiatry as the microscope to a cell biologist or the telescope to an astrologist. So why are we so shocked to hear about LSD mentioned in a clinical setting now? Let’s explore its history as a medicine.

LSD was first discovered in 1938 by Hoffman while he was working at the Sandoz laboratories in Basel. At the time, his research group was working on a number of derivatives of ergot, a rye-based fungus, in pursuit of a compound that would have the admirable (if staid in retrospect) effect of contracting blood vessels. As the somewhat apocryphal story goes, Hoffman took a minuscule amount of one such derivative on a sunny day before attempting his usual bicycle ride home. By the time he arrived at his house – depending on who you talk to – the Beatles had been born, America had lost the Vietnam War, and human kind had entered a new astrological age.

Despite – or in part because of – the intense psychedelic experience Hoffman had been subjected to, research into the properties of LSD progressed unabated in the hope that this compound could be of benefit to the medical establishment. In a relatively short time following the drug’s discovery (especially when compared to the lengthy requirements for modern drug regulatory bodies), LSD had been licensed to psychiatrists as a tool for releasing repressed material under the name Delysid. According to the original accompanying prospectus, “The administration of very small doses of Delysid … results in transitory disturbances of affect, hallucinations, depersonalization, reliving of repressed memories, and mild neurovegetative symptoms.

Initial studies of LSD classified it as a psychomimetic, a drug that could induce psychosis, and described the hallucinations it produced using generally negative terminology. In 1892, Emil Kraepelin had been the first to suggest that an endogenous chemical in the brain could produce the symptoms of madness and scientists were still keen to discover what this substance was. In fact, LSD, as it is now known, exerts its effects through activation of various serotonin receptors, particularly the 2A subtype. Most common anti-depressants also work via the serotonin system, although generally by increasing levels of the neurotransmitter rather than directly activating its receptors. Activation of the 2A receptor seems common to many of the other hallucinogenic compounds. What has been more of a puzzle, however, is why LSD is active in such minute doses. Other compounds which also activate the 2A receptor in similar ranges have no hallucinogenic properties. A recent study may have gone some way towards resolving this mismatch, suggesting a unique ability of hallucinogens to affect cellular processes directly, in addition to direct effects via the receptor.

Another party of early interest in LSD’s potential was the CIA, who were in hot pursuit of a reliable “truth” drug in the Cold War era. After funding several years of research, including a number of prominent scandals due to the ethically dubious nature of some studies, they shelved their plans, citing the unpredictability of the drug’s effects. The British army is also believed to have trialed the drug for use in the field, again, with unpredictable, if comic, effects.

In the 1950s, research using hallucinogens could be broadly divided into two camps: psycholytic and psychedelic therapy. Psycholytic therapy was developed in England and Germany most prominently by Ronald Sandison and Hanscarl Leuner, respectively. Based on traditional Freudian psychoanalysis, it uses small doses of LSD to loosen the ego and break down natural mental defenses allowing the patient to explore uncomfortable emotional material. Psychedelic therapy, on the other hand, was developed by Abram Hoffer and Humphrey Osmond in Canada, originally for the treatment of alcoholism, and used large doses of LSD to induce a mystical experience with life-changing properties. The term “psychedelic” was in fact created by Osmond while in correspondence with the author and long-term advocate of the psychedelic experience, Aldous Huxley.

Hoffer and Osmond were also the first people to describe the importance of “set and setting” to the outcome of the psychedelic experience. The “set” refers to one’s internal feelings, anticipations, and hang-ups that a person might bring to the experience. The “setting” refers to the external features of the environment where the experience is to happen. Subsequently, a large number of studies were conducted in both therapeutic branches with the majority of them reporting very positive results. However, compared to modern scientific work, most of these were experimentally flawed, despite the circulation of handbooks which attempted to guide therapists through usage of the drug. Follow-up trials were rare, meaning that long-term side effects of the treatment were unknown, as was the longevity of the drug-induced benefits. Additionally, the protocols supplied were often sparse and, given the importance of environmental factors such as set and setting, this made studies difficult or impossible to replicate. Finally, much of the work relied on case studies and anecdotal accounts rather than the strict, placebo-controlled, double-blind studies which are de rigeur now.

In the mid to late sixties, psychedelic science became even less rigorous, as well as more controversial, as LSD escaped from the clinic. Unqualified “therapists” could acquire the drug relatively easily and began setting up private clinics where the care and attention to “set and setting” provided by experienced researchers was often absent. Additionally, the writing of authors such as Huxley and Tim Leary led to an awareness of the drug, and curiosity about its effects began to grow in the general public. By the late sixties, when recreational use of LSD as well as other mind-altering substances had become strongly associated with the emergence of the counter-culture and Ken Kesey had driven his magic bus back and forth across the United States urging willing volunteers to drink acid-laced Kool-Aid, the government decided to take action. In 1968, the NIMH Division of Narcotics Addiction and Drug Abuse was created, with the Controlled Substances Act coming into force two years later in 1970. This act placed LSD in Schedule I, the most restrictive category, requiring a special license from the FDA to possess or use in experiments, and the drug was defined as having no medical use and as being unsafe to use, even under medical supervision, with a high potential for abuse.

Reanalysis of this period has led many to conclude that this legislature was motivated by social concerns rather than medical ones. Very few reports of serious complications were cited in the report provided by Sidney Cohen, the doctor who was appointed as the first head of the Narcotics Division. Cohen himself at the Congressional hearing in 1966 said, “We have seen something which in a way is most alarming, more alarming than death in a way. And that is the loss of all cultural values ... these people ... are deculturated, lost to society, lost to themselves”.

No further (legal) human research using hallucinogenic drugs would take place in the US for the next two decades. As the US placed pressure on other countries to adopt similar controls this prohibition also became the case in much of the world. The exceptions were some nations in Europe, most notably Germany, where Leuner continued to use LSD, ketamine, and MDMA analogues in psycholytic therapy until his death in 1996. Although research using animals continued in the US, these studies mainly focused on the toxicity of hallucinogenic compounds.

It is not quite true to state that no research continued in the US, however. Working in his own laboratory, a former industrial chemist named Alexander Shulgin produced a vast number of derivatives of known hallucinogens and proceeded to test them on himself and his close friends. One of these was MDMA, which left his laboratory and spread into the psychotherapeutic community where it was taken up as an adjunct to therapy. However, after a surprisingly long period in which Shulgin enjoyed relative freedom to research these compounds and distribute them, the government again decided to clamp down. First, MDMA was made a Schedule I drug in 1985 and then in 1986 the Anti-Drug Abuse Act was introduced, containing a section banning the manufacture or possession of any substance considered analogous to an already scheduled drug. Analogous in this case refers to having a similar chemical structure or producing a similar hallucinogenic, stimulant, or depressant effect as a scheduled drug.


However, in the last decade, restrictions have been slowly loosening and we are seeing a renewal of interest in the field of psychedelic research. Scientists have been re-examining long-ignored earlier studies, prompting a growing acceptance by the academic community of the therapeutic potential of psychedelic drugs. A major factor was a conscious shift in the political attitudes of the FDA at the beginning of the 1990s when it was challenged by NIDA to examine whether it was proper to treat the class of hallucinogenic compounds as more dangerous than other drugs.

The first of a new wave of American studies into these compounds was led by Rick Strassman, a researcher from the University of New Mexico. His groundbreaking work showed that it was possible in this new, less conservative political climate to gain approval from the authorities to carry out research on these previously forbidden substances. He was able to clear a simple study to investigate the physiological effects of the relatively obscure hallucinogen DMT in human subjects. His results show that DMT had physiological effects consistent with its hypothesised serotonergic action and was safe at the hallucinogenic doses tested. After conducting further work with the compound, Strassman also noted the preponderance of drug-induced spiritual experiences which exhibited striking similarites between subjects.

From this springboard, other groups became interested in potential studies which had previously been considered too fringe for the mainstream scientific community. However, one of the biggest problems facing researchers in this field is the difficulty in receiving funding from traditional sources, which are often reluctant to sponsor research into politically charged areas in fear of attracting adverse media attention. This issue led to the founding of the Multidisciplinary Association for Psychedelic Studies, or MAPS, by Rick Doblin in 1986 (see Sidebar interview). This organization exists to “assist scientists to design, obtain approval for, fund, conduct and report on research into the healing and spiritual potentials of psychedelics and marijuana.” A similar body which helps those wishing to carry out psychedelic-based research is the Hefter Institute which was set up in 1993.

At the moment there are several separate studies either in progress or at the application stage in the US as well as in other countries. A few studies have been chosen below but information on any of the others including those in Spain, Israel, Switzerland and Germany can be found at the MAPS website.

Between 1992 and 1995, Dr. Charles Grob at UCLA conducted the first government-sanctioned study into the effects of MDMA in humans. Currently his research is focused on using psilocybin, the hallucinogenic compound found in magic mushrooms, to treat the anxiety suffered by patients with terminal cancer. This study highlights a number of features that are common to many of the studies using psychedelics. First, the choice of patient group is essential to ensure approval for a study. Although the most tempting experiment might be to use a compound such as MDMA during a process such as marriage counselling, the licensing bodies are unlikely to give the go-ahead unless the intended patient group are either extremely refractory to any other possible intervention or, to put it bluntly, on the verge of death. Second, it will be noted that Dr Grob decided to use psilocybin rather than LSD. Although there may be some reasons (generally pertaining to the time course of its action and differences in the particular character of the experience) why the drug itself may be preferable to LSD in this situation, the main reason is because of the controversial baggage those three little letters carry. This is the primary reason why Strassman chose DMT for his work and why, even after MDMA has received a lot of negative media attention, that drug continues to be used in experiments more often than LSD.

Another reason why researchers prefer to use MDMA rather than LSD in their studies is due to the different nature of the “high.” Rather than being a true psychedelic, MDMA is often termed an empathogen and results in the same loosening of the ego as other drugs while allowing for the exploration of repressed memories and difficult emotional material. It also enables bonding and feelings of closeness to form between the patient and therapist. There are currently a number of studies that have been approved or that are awaiting approval to use MDMA in the treatment of post-traumatic stress disorder (PTSD). The most prominent of these is being run by Dr. Michael Mithoefer in South Carolina, and a glance at the protocol reveals the rigour used in this sort of study now. These include standardised outcome measures, large sample size and the blinded use of a placebo (although reports from the front-line suggest that you can pretty much tell which group is the placebo group). Importantly, the treatment comprises only two sessions of MDMA-assisted therapy interspersed with non-drug sessions. There are similar projects enrolling subjects at the moment in Switzerland and in Israel, with the latter looking specifically at subjects with war- and terrorism-related PTSD.

One of the more unexpected putative uses for LSD and psilocybin might be in the treatment of cluster headaches. Cluster headaches are a rare, incredibly painful type of headache related to the more common migraine. Their name originates from the fact that they tend to occur temporally in clusters lasting four to eight weeks and occurring on average once or twice a year. During this period, sufferers will experience anything from one headache per week to six per day, each lasting 30 to 120 minutes. The pain is excruciating, and although some treatments do exist such as oxygen inhalation or the use of a topical anaesthetic, these are, for many reasons, suboptimal. The suggestion that psychedelic drugs could be of use in treating this condition arose via internet message boards where sufferers shared tips and advice. Although the evidence at the moment is anecdotal, a study is planned by John Halpern and Andrew Sewell at McLean Hospital, a research hospital affiliated with Harvard Medical School. The mechanism by which LSD and psilocybin may be helping prevent cluster headache attacks will also remain mysterious until more work has been carried out, but one possible candidate system is the serotonergic pathway. Sufferers are known to have alterations in serotonin signalling and, as mentioned earlier, LSD and psilocybin both act at the serotonin 2A receptor. This work is quite different to all of the other studies discussed here as it also appears that a sub-psychoactive dose may be effective. In this respect, we may be looking at a purely physiological effect of these drugs.

There have also been recent articles in broader scientific journals such as the British Journal of Psychiatry and the Journal of Psychopharmacology which have discussed the potential therapeutic uses of hallucinogens and have generally been received favourably. However, there is frequently a cautious tone to some of the correspondence that advises researchers caught up in this new wave of research not to make the same mistakes that their predecessors did in adopting a messianic attitude. Rather, it is suggested that researchers should take a dispassionate role which will aid acceptance by skeptical peers and public.

There are of course those that believe that even in non-pathological situations psychedelic drugs can have beneficial effects. Last year saw the publication of a study examining the mystical-type experiences induced by psilocybin in healthy volunteers. Others such as Terence McKenna promote the idea that the psychedelic experience can be a useful, educational tool that will help further the cause of the human race. There is a huge amount of anthropological research into the cultural use of hallucinogenic substances as part of ritualised worship, for example, ayhuasca by Mexican or Amazonian shamans. A journey performed as a rite of passage by a certain sect of Ancient Greeks some say also culminated in a hallucinogenic experience. Even more outlandish are readings of the Bible which see a psychedelic subtext in the early Christian experience and theories of evolution which hand the trigger for human evolution to the consumption of hallucinogenic plants. However, these remain the preserve of liberal Human Sciences departments, and scientists studying medicinal benefits are likely to distance themselves from these projects. Nevertheless, such theories often make fascinating and occasionally amusing reading.

It will take true dedication for scientists to convince the public, and more importantly the media, that these drugs deserve a place in medicine. Research is unlikely to be funded by pharmaceutical companies, as most of these drugs were synthesised long enough ago to be out of patent. Additionally, compared with recent big-sellers such as Prozac, these compounds are very unlikely to ever be given more than a few times to an individual, certainly not every day. In fact, one of LSD’s properties is its rapid tolerance and as such there is a refractory period following its use in which additional dosing has no effect. This is one reason that it does not have addictive properties. Indeed, many advocates of its introduction into psychiatry find it strange that these non-addictive compounds are prohibited whilst opiates and cocaine are placed in less restrictive Schedules and are, in fact, considered essential to medical practitioners.


To finish, we return to Albert Hoffman, the scientist who invented, self-administered and experienced LSD for the first time. After his initial discovery of LSD, Hoffman became interested in seeking to derive the hallucinogenic elements of other plants and became the first person to synthesise psilocybin from mushrooms. He has remained living in Switzerland enjoying nature and has maintained some contact with the field of psychedelic research. In 1983, he published a book, LSD: My Problem Child, a memoir of sorts describing his discovery as well as his hopes for the future. At the close of the conference last January he took the stage to rapturous applause (unfortunately I wasn’t present having elected to have some down time and “experience” Basle). In many ways the Swiss attitude towards life seems to have produced, in Hoffman, the most balanced, considered and thoughtful proponent (and taking his age into account, advertisement) for LSD. He has never sought to dismiss his creation and continues to campaign for its legalisation for medical usage. At the same time he remains cautious and admits that although he has had beautiful times he has also experienced many distressing episodes. As part of his eloquent and moving speech on the final day of the conference Hoffman said, "It is still my problem child, but very often they turn into wonder children. I hope that it can be possible in time for LSD to find the place in society that it deserves."

References

Gonzalez-Maeso J, Weisstaub NV, Zhou M, et al. 2007. Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53(3): 439-52.

Griffiths RR, Richards WA, McCann U, Jesse R. 2006. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology 187(3): 268-83.

Grob CS, Poland RE, Chang L, Ernst T. 1996. Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations. Behav Brain Res. 73(1-2): 103-7.

Hofmann A. 1983. LSD: My Problem Child. Los Angeles: J.P. Tarcher.

Sessa B. 2007. Is there a case for MDMA-assisted psychotherapy in the UK? J Psychopharmacol. 21(2): 220-4.

Sessa B. 2005. Can psychedelics have a role in psychiatry once again? Br J Psychiatry 186: 457-8.

Sewell RA, Halpern JH, Pope HG Jr. 2006. Response of cluster headache to psilocybin and LSD. Neurology 66(12): 1920-2.

Strassman RJ, Qualls CR. 1994. Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Arch Gen Psychiatry. 51: 85-97.

Williams L. 1999. Human Psychedelic Research: A Historical And Sociological Analysis. Thesis, Cambridge University.