There’s something slightly edgy about medical research using controlled drugs and it usually provides good media fodder. So it was towards the end of January, when there was a flurry of interest in the UK media about research on the effects of the controlled psychedelic drug psilocybin on human volunteers. Headlines such as – Magic mushrooms “could treat depression” – were seen, none of which did justice to the real substance of the work. The BBC even carried a description of one of their presenters, Michael Mosley taking the drug – for research purposes of course!
Psilocybin is one of the hallucinogenic substances in “magic mushrooms”. It has a fascinating history so I thought I would write about it.
Magic mushrooms in Green Park, London
The story starts at dawn on October 3rd 1799 when a poor man can be seen gathering field mushrooms in London’s Green Park. When he gets home, the mushrooms are cooked with flour, water and salt to provide a morning broth for him, his wife and their four children.
A few hours later Everard Brande, a doctor, is summoned to the household where the family are experiencing strange symptoms. The father has developed vertigo and disturbed vision whereas the rest of the family complain of poisoning and stomach cramps with their extremities becoming cold. Their pulse and breathing oscillate between frightening highs and lows. The family are overwhelmed with the fear of dying – all that is except eight year old Edward who is “attacked with fits of immoderate laughter”.
We know nowadays that the family must have consumed, by accident and through ignorance, some Liberty Cap mushrooms (“magic mushrooms” “shrooms”). These grow widely in the UK and continental Europe in the autumn. The 200-year old story of the family and these mushrooms opens the door to a fascinating scientific saga.
Liberty Cap mushrooms (Psilocybe semilanceata) are part of the large family of up to 200 species of Basidiomycota mushroom that contain the psychedelic drug psilocybin. These mushrooms are found in many parts of the world with the Psilocybe genus being the major type. Psilocybe have long been associated with ritual because of their ability to change human perception – the “psychedelic” effect. Evidence had been found in Algeria, Mexico and Spain for their use in religious ceremonies. The Aztecs called them teonanacatl (divine mushroom) and the mushrooms were reportedly served at the coronation of Moctezuma II in 1502. Use of Psilocybe by the Aztecs was suppressed following the Spanish conquest but they have continued to be used covertly by native Indians in this part of America.
Little was known about these ceremonies in the US and Europe until husband and wife team, Gordon and Valentina Wasson travelled to Mexico in the 1950s. Their aim was to understand the culture associated with the “divine mushroom” and they made several visits to Mexico at that time. In 1955, Gordon Wasson was one of the first westerners to participate in an indigenous mushroom ceremony. In an article in the popular magazine “Life” in 1957, Wasson described the mushroom ceremony and the sensations he experienced. On one visit they were also accompanied by the French mycologist, Roger Heim, who identified the mushrooms as Psilocybe mexicana.
In order to identify the active species in the mushrooms, samples were given to Albert Hofmann at Sandoz in Basel. Hofmann (pictured above) was already well known as the chemist who had first synthesised the related psychedelic drug LSD in 1938 and who later inadvertently experienced the effects of the drug himself. Hofmann made extracts of the Psilocybe and analysed the constituents for their psychological effects. His work was greatly helped by his readiness to test extracts on himself. In this way he showed that there were two principal active compounds in the mushrooms, psilocybin and psilocin. Once ingested, psilocybin is rapidly converted to psilocin.
The effects of psilocybin and LSD
So what are the effects of psilocybin and psilocin on humans? Psilocybin has effects rather similar to the two other principal psychedelics, mescaline and LSD, although there are differences in detail and in potency. Sol Snyder in his book “Drugs and the Brain” describes how he took LSD to document and to understand its effects. This is an excellent description from a respected scientist and he reports changes in sensory perception, especially visual effects. Objects may seem distorted, change colour or even move. Confusion between sensory modalities (synaesthesia) may also occur. Sense of time and space are altered but it is the effect on the sense of self that is particularly striking. “Boundaries between self and non-self evaporate, giving rise to a serene sense of being at one with the universe.” He goes on to speculate: “The almost predictable transcendence of ego boundaries brought on by these drugs has caused scientists to consider that there might be a neural basis for the ego.” Others report heightened awareness, super-reality and mystical experiences after taking the drug. Many people enjoy the effects produced by these drugs which sometimes offer insights not available in normal life. For others it is an unpleasant experience and a minority have injured or killed themselves as a result of disorientation caused by changed perception or loss of self. The experience may depend on the state of the individual and their environment when they take the drug (“set and setting”). More recently a five-component scale has been devised to provide a semi-quantitative measure of the effects of these drugs.
So, how are these curious effects on human consciousness achieved by these drugs? In the case of psilocybin and LSD, it is thought that the drugs hijack some of the normal processes in the brain. Brain function depends on the release of chemicals termed neurotransmitters. These are detected by their binding to specialised proteins called receptors. One neurotransmitter that is important for regulating a host of functions in the brain and elsewhere is serotonin. This neurotransmitter regulates behaviour, mood, sleep, appetite and blood flow. Psilocybin and LSD both bind to and activate receptors for serotonin so it is not surprising that they lead to widespread effects.
Therapeutic use of psilocybin
In the 1950s it was felt that drugs such as LSD and psilocybin held promise as therapeutic agents and they were used during psychotherapy to lower psychological defences and to facilitate emotional insight. In the 1960s the effects of psilocybin were studied by the Harvard Professor, Timothy Leary, who became notorious for his work on psychedelics. Leary’s eventual dismissal from Harvard fuelled the growing view at the time that use of these drugs was a form of cultural rebellion. The drugs were increasingly discussed by the media in terms of their potential for abuse and there were moves by the authorities to ban the drugs. Now, in most countries, LSD, psilocybin and mescaline are controlled drugs. Somewhat anomalously, the Psilocybe mushrooms were not initially controlled and even in the early years of the 21st century there were shops freely selling “shrooms” in London. In 2005 the law in the UK was changed and the mushrooms were included in the ban, but as with other controlled drugs nowadays, it is still possible to buy the mushrooms via internet suppliers.
When the drugs became illegal this inhibited research on their therapeutic uses almost completely. Recently there has been a resurgence of interest and several careful studies have been performed on the effects of psilocybin on humans.
Franz Vollenweider and colleagues in Zurich have carefully catalogued the effects of psilocybin on humans, describing the psychological effects using standard rating scales. They concluded that, although there is a small risk of a bad reaction to psilocybin which could include dysphoria, anxiety or panic, the administration of moderate doses of the drug to healthy, high functioning and well prepared subjects is associated with acceptable levels of risk providing it is done in a carefully monitored research environment. They did state, however, that this did not apply to recreational or less controlled studies.
Roland Griffiths and colleagues at Johns Hopkins in the US administered psilocybin to human volunteers under controlled conditions and described the acute perceptual and subjective effects. These included a complete mystical experience for 61% of those tested and/or extreme fear and anxiety in 39% of those tested. One month after testing, about two thirds of the participants rated the experience as having substantial personal and spiritual significance leading to positive change in attitude, mood and behaviour. 14 months later, these feelings were undiminished. These are fascinating observations suggesting that psilocybin has considerable potential for changing human behaviour.
Psilocybin has also been reported to have useful effects in treating obsessive-compulsive disorder, cluster headache and anxiety associated with terminal cancer.
The most recent studies
But let’s now return to the work I mentioned at the outset that caused the media flurry in the UK. This is work performed by a group lead by David Nutt at Imperial College in London in collaboration with the Beckley Foundation.
In one study, brain imaging techniques were used to try to understand how the psychological effects of psilocybin were related to changes in brain activity. Two indicators of brain activity (blood oxygenation and cerebral blood flow) were assessed in a small number of volunteers and it was found unexpectedly that psilocybin caused reductions in brain activity. For one brain region the reduction in activity correlated with the psychological effects reported. They interpreted the work in terms of an effect of psilocybin to reduce activity and connectivity in key “connector hubs” in the brain. These “connector hubs” normally act to facilitate information transfer so the authors conclude that it is not surprising that a reduction in their activity leads to profound effects on consciousness.
In a second study, the effect of the drug to facilitate access to personal memories and emotions was tested. There have been reports in the past that psychedelics lead to “relivings” of past memories and the Imperial College group had observed this before with one volunteer who had taken psilocybin. In the new study, volunteers were presented with memory cues and asked to recollect autobiographical memories. The study was performed after psilocybin administration and after placebo and participants were asked to rate the vividness of the memories evoked. Memories were found to be more vivid and more visual under psilocybin but no “relivings” occurred. This may have been because the cues were positive whereas in the past, negative cues had lead to “relivings” of negative memories. Two weeks after these tests were performed participants reported significant increases in well-being related to the vividness of the memories.
These are interesting observations but it should be pointed out that Vollenweider and colleagues have also studied brain activity after psilocybin administration and find activation, in complete opposition to what was reported by the Imperial College group. This contradiction may relate to differences in experimental technique but it certainly needs to be resolved. Another gripe I have with the Imperial College work relates to their use of the term “trend level significance” for some correlations tested. We all know this is a sanitised way of saying “no significance”. Indeed, for these examples, the P values are greater than 0.05 so there is no correlation; this should have been the conclusion and it is misleading to imply otherwise.
Where does the future take us?
The underlying aim of this kind of work on brain imaging in relation to psychological testing is to try to find correlates of psychological processes in brain activity. This is moving ahead very rapidly in a field termed neuropsychoanalysis. One of the aims here is to find neural correlates for the Freudian concepts of Id, Ego and Super Ego. This is discussed well on another blog but personally I wouldn’t want to go very far with these correlates until I had resolved the discrepancies between the brain responses to psilocybin measured using different techniques.
The Imperial College group have also speculated that psilocybin may be a novel antidepressant. This is based on their observation of effects of the drug on activity in the medial prefrontal cortex. Other antidepressant treatments have similar effects to psilocybin on this brain region leading to the speculation.
There is a lot to think about here and much promise for the future. It is difficult to avoid the conclusion that by banning psilocybin we may have missed out on many useful effects of this drug.