Dream drug or Demon brew?

Dream Drug or Demon Brew?
New Scientist vol 182 issue 2453 - 26 June 2004, page 42
By Lisa Melton


A mind-altering substance used in shamanistic rituals may hold clues todreaming and a natural way of alleviating depression but could also
trigger schizophrenic hallucinations.

Lisa Melton investigates

IN THE brightly lit chapel, the ceremony is due to begin. Dennis McKenna lines up with 500 others to sip the sacrament. It takes 45 minutes before it hits him. Then, eyes closed, he finds himself hovering above the Amazon basin, aware of the massive forests and the meandering rivers beneath. A giant vine winds up towards him and he hurtles down it, shrinking as he goesuntil the leaves themselves seem the size of trees. Shrinking further, he finds himself surrounded by a new forest made up of molecules engaged in photosynthesis. McKenna, an ethnobotanist from the University of Minnesota in Minneapolis, is high on ayahuasca.

Ayahuasca is not the latest party drug but a foul-tasting plant concoction Amazonian people have been downing for centuries. It is the stuff of legends, credited with sending people on the most incredible trips. Today this bitter tea, also known as hoasca, has become the sacramental ritual of two modern religions in Brazil; one of them, the Unio do Vegetal (UDV) church, has invited McKenna, an expert on psychoactive plants, and other research teams, to scrutinise this sacred brew. Their fascination with ayahuasca stems from a little-known mind-altering compound called dimethyltryptamine, or DMT, a substance the sacred tea contains by the bucketload. When it comes to psychedelic compounds, DMT is in a league of its own, as the only hallucinogen our body produces naturally.

Scientists have found DMT pretty much everywhere they've looked in animals, plants and fungi. But despite its ubiquity, DMT's role remains a mystery. Some believe it fuels vivid dreams, mystical revelations and religious exaltation, as well as playing a part in memory. The more sinister possibility is that over-producing DMT could tip a person over the edge into insanity, inducing the psychotic symptoms of schizophrenia. McKenna and his colleagues hope the tripping churchgoers could help them find the answers. DMT doesn't hang around long enough for people to study it easily. It acts rapidly and is broken down swiftly by the enzyme monoamine oxidase (MAO). Normally if you eat or drink it, DMT doesn't stand a chance of getting into the brain as MAO in the gut breaks it down.

Cocktail effect

Shamans, McKenna discovered, overcame this problem by carefully combining plants in the ayahuasca brew. One is the Psychotria viridis bush, which is packed with DMT. The other is the vine Banisteriopsis caapi, which contains harmine, one of the most effective MAO inhibitors. By inactivating MAO with the vine bark, DMT can be absorbed from the gut and crosses the blood-brain barrier to trigger a psychedelic response.

It turns out that harmine-like compounds are also ubiquitous in our bodies. This led some researchers to suggest that maybe our bodies regulate the levels of DMT in the same way as in the tea, sometimes boosting its activity by knocking out MAO so it can fulfil some sort of physiological role. Pharmacologist Jordi Riba from the University of Barcelona, Spain, has been trying to work out what that physiological role might be, using brain scans to study its effect on brain activity. His preliminary results are tantalising, showing areas lighting up that are related to memory. Riba
believes DMT may be involved in retrieving facts and experiences. "When you give people ayahuasca, they re-experience memories that are there already. It's like pressing a random access button to your stored memories," he says..

Jace Callaway from the University of Kuopio in Finland has another idea. He suggests that endogenous DMT and harmine-like substances may play a role in generating dream imagery. "We experience psychedelic states on a regular basis while dreaming," he says. But while its natural role is still uncertain, a more unnatural role is coming to the fore. The effects produced by psychedelic drugs are strikingly similar to the symptoms of psychosis. In the 1950s, these similarities led to the suggestion that psychoactive compounds like DMT were the cause of schizophrenia.

According to the theory, an enzymatic disturbance in the body could lead to overproduction of hallucinogenic compounds. And if MAO activity is low, as suspected in people with schizophrenia, the compounds would linger and the hallucinations they trigger seep into everyday existence. But researchers had always failed to detect consistent differences in DMT levels between patients and controls. "I spent my youth collecting and analysing gallons of urine from people with schizophrenia," recalls Robin Murray from the Institute of Psychiatry in London. "The endogenous DMT hypothesis of schizophrenia was never disproved but was just overtaken by the dopamine theory, which was more immediately plausible."

But the theory is enjoying something of a comeback. Alicia Pomilio, an organic chemist, and Jorge Ciprian-Ollivier, a psychiatrist, at the
University of Buenos Aires in Argentina realised that the church congregation members could help them to look for the signature of DMT in the
urine using gas chromatography and mass spectrometry. Once they knew what to look for, they were able to detect traces in the urine of patients with active schizophrenia but not in controls. It is not clear whether people with schizophrenia are producing too much DMT, or too little MAO the result would be the same. But the discovery is exciting in that it paves the way to finding new drugs to treat schizophrenia.

But if DMT might be the cause of one medical problem, it could be the cure for others. McKenna has found that DMT exerts its effect by attaching mainly to one particular type of serotonin uptake site called 5-HT2A, as do other psychedelic drugs such as LSD, psilocybin and mescaline. Serotonin is a mood-altering neurotransmitter, also known to influence sleep, appetite, aggression and love. The newest class of antidepressant drugs, including Prozac, are thought to work by blocking the uptake of serotonin into nerve cells. Callaway's recent studies suggest that ayahuasca might have some of the effects of antidepressant drugs nature's very own Prozac.

He measured serotonin levels in rats after giving them ayahuasca and says the levels of the neurotransmitter "go through the roof". After
drinking hoasca tea users report a feel-good effect that can last for days. Callaway found that hoasca drinkers had a greater than normal density of serotonin uptake sites on their blood platelets, where they are easier to measure than in the brain. People seem to respond, he says, by creating more receptors. When they are not getting a buzz from the tea, the additional receptors hunger for more serotonin, pushing the body to produce more.

But does the brain bump up its number of serotonin uptake sites too?

Using a brain imaging technique that labels serotonin receptors, Callaway has now tested one person, and found signs of a similar upregulation in a serotonin-rich region of the brain. Of course, this observation needs following up, but it's an encouraging sign. "It's a true tonic effect," says Callaway. The sacred tea "apparently does what antidepressants fail to do. It could lead to long-term plastic changes in the brain without having to pop a pill every day."

Charles Grob, a psychiatrist at the University of California, Los Angeles, School of Medicine, reckons that this sustained effect on mood makes
ayahuasca a good candidate for treating addictions as well as alleviating depression. People with serious alcohol problems and mood disorders
were transformed by the church. All religions boast life-changing stories, but Grob believes the tea itself is important. There is already one centre in Peru testing ayahuasca in clinical trials for drug abuse.

But the researchers are proceeding cautiously. Many people have been taking the hallucinogen within the supportive setting of the UDV for 30 years with seemingly no adverse side effects. But it is not always so. "If the tea is not properly prepared, or in the hands of an individual without the appropriate support, the consequences can be negative," says Grob. Even in the highly controlled lab setting it can trigger twitching, vomiting and diarrhoea. Useful if you are an Amazonian hunter wanting to rid your gut of parasites, perhaps, but not exactly convenient if you're not.

Ayahuasca, Neurogenesis and Depression

Ayahuasca, Neurogenesis and Depression

Daniel Mirante • May 4th, 2008 •

Recent scientific research suggests that neurogenesis – the growth of new brain cells – is a key to curing depression.
People suffering depression have an enlarged amygdala, a structure deep in the brain, which produces amongst other things stress hormones. An enlarged, overactive amygdala may produce too much cortizol, a fight-or-flight stress hormone. Too much cortizol can whittle away neural structures - especially in the hippocampus which is the cortizol shut off valve. In depressed people, this structure can be 15% smaller than the statistical average.
With the hippocampus function reduced and the amygdala enlarged and in overdrive, a damaging positive feedback loop gets established and eventually other neural structures such as the prefrontal cortex get damaged - the dentrites (the connections) get sheared away, leading to a tragic reduction of the full potential of a person.
Thus, depression is both a somatic and psychologically self-reinforcing cycle that requires intervention on several levels. The commonly persued course of action is via anti-depressants such as SSRI’s which increase serotonin.
The old theory for administering selective serotonin reuptake Inhibitors is that the brain is suffering from a lack of available serotonin, and that Prozac and other drugs in its class help by increasing the amount of serotonin circulating in the brain by reducing their uptake. However, it is well known such drugs take weeks to take effect, despite the fact that serotonin levels are boosted straight away.
Scientists are discovering that the mechanism is a lot more complicated than a simple lack of serotonin, but is rather enmeshed in the damage rendered by cortizol and related stress hormones, and impeded function of the hippocampus.
Serotonin can promote neurogenesis, the birth of new brain cells, and Prozac seems to work by promoting neurogenesis in the hippocampus. And not only SSRIs, but other antidepression treatments affect a type of protein that is involved in neurogenesis. It is established that SSRI’s help to increase levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. A neurotrophic factor is a protein, such as nerve growth factor, that promotes nerve cell growth and survival.
BDNF is a growth, sustainer and protector factor in the brain ; a neurogenesis hormone. Antidepressants apparently help keep hippocampal cells alive by boosting BDNF levels, inducing neurogenesis. Raising serotonin ups a protein known as CREB inside nerve cells, which also give rise to neurogenesis. This means that SSRI’s help to regenerate the hippocampus thus keeping the amygdala in balance.
This path of action restores the neurological balance which contributes (or else, determines) a healthy emotional life.
Banisteriopsis caapi, the Ayahuaca vine, is regarded by many that use it as an antidepressant. The mono-amine oxidase inhibiting beta-carbolines in the vine reduce the clearing of serotonin from the synaptic cleft : i.e MAOI is another angle from which serotonin can be boosted, which qualifies the use of MAOI in the treatment of depression back in the mid twentieth century.
It has been indicated that one of the constituents of the vine, THH, actually causes an increase in the density of platelet serotonin uptake sites in long-term users. It is likely that the increase of density of serotonin uptake sites in longterm users be an adaption to more monoamines in the system. . Increases in serotonin transporters could well be an adaptation to increased serotonin levels caused by MAO inhibition.
The additional power of Ayahuasca over commonly prescribed SSRI’s is that it allows people to experientially approach the early causal factors to their depression and work to symbolically resolve them, and cathart the primal pain and energies bound up in those repressed early experiences. After all, whilst we can address the run-away neurological consequences of deep trauma or chronic stress, the experiential gestalts themselves must be catharted and integrated. Ayahuasca allows conscious realization of how those experiences effect ones constitution and patterns of behaviour, giving beneficial insights into how the effects of the damaging influences on ones life can be greatly negated by changes of attitude and lifestyle.

Recommended Reading :

How Prozac Affects the Brainhttp://www.newscientist.com/article/dn9171-how-prozac-affects-the-brain.html

Repairing the Mindhttp://www.newscientist.com/article.ns?id=mg17924082.500

The Anatomy of Dispairhttp://www.newscientist.com/article.ns?id=mg18224455.700

Research on psychedelics moves into the mainstream

Research on psychedelics moves into the mainstream

Kelly Morris

The Lancet

Volume 371, Issue 9623, 3 May 2008-9 May 2008, Pages 1491-1492

The backlash against the recreational use of psychedelic drugs in the 1960s had a negative effect on research into their potential therapeutic benefit. But now attitudes are changing and work in this area is being revitalised, with several early-stage trials underway. Kelly Morris reports.

Some 50 years ago, substances called psychedelics were hailed as the new tools of psychiatry. After their use in diverse clinical contexts, not always with rigorous methods, and following widespread non-medical use, “research was quashed for misguided but understandable reasons”, explains Rick Doblin, president of the US Multidisciplinary Association for Psychedelic Studies (MAPS). Now, that scenario is rapidly changing, with several phase II trials underway worldwide, and many more studies ongoing or planned. “It's amazing how much is going on”, Doblin told The Lancet after the World Psychedelic Forum that took place in Basel, Switzerland at the end of March.

Part of this resurgence, say experts, is down to a more measured attitude of researchers towards the risks and the benefits of drugs like lysergide (LSD), psilocybin, and methylenedioxymethamfetamine (MDMA). “What we see now is the [US] FDA (Food and Drug Administration) making decisions based on data rather than politics, and major universities involved in research”, notes Tom Roberts, a professor of educational psychology from Northern Illinois University, IL, USA, and co-editor of the book Psychedelic Medicine. Clinical studies are the most appropriate context to start re-exploring the use of psychedelics, says Roberts, because of rigorous review processes and the step-by-step development of studies. The “Timothy Leary era” of informal or illegal explorations “caused a lot of problems”, he notes. Ben Sessa, a consultant psychiatrist based in the UK, agrees. “At the end of the 1960s these drugs were labelled as dangerous drugs of abuse in the wake of the explosion of recreational use by the general public. The resulting war on drugs has been only minimally effective at tackling recreational use but has been extremely damaging for any genuine medical research”, he says.

What the experience of the 1960s has shown is pointers to many possible therapeutic and non-medical uses. “The evidence so far suggests that the anxiety (neurotic) disorders tend to do well with psychedelics—that includes anxiety, post-traumatic stress disorder, and obsessive-compulsive disorder. This is because these drugs are particularly good at allowing the user to access otherwise repressed and painful memories and do some meaningful psychotherapeutic work under the influence of the drug”, says Sessa. Previous clinical experience, plus more recent informal use, has indicated other potential therapeutic uses for cluster headaches and addictions, among other conditions.

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The therapeutic benefit of MDMA is being tested in pilot studies for post-traumatic stress disorder

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Some of the first clinical trials have focused on MDMA, which is not a classic hallucinogen. Doblin was keen to develop protocols for formal phase II studies given the drug's reported capacity “to enhance people's ability to feel, accept, and integrate difficult emotions” within a psychotherapeutic context. Of MAPS' three pilot studies for post-traumatic stress disorder worldwide, the US study ends first, in July. Three further phase II studies are in planning. “What we need to do is to replicate the US findings”, says Doblin, who then hopes to see the development of phase III trials in Europe and the USA, which, if positive, could pave the way for MDMA to be available as a prescription medicine.

“We have shown that LSD [historically] and MDMA given in a psychotherapeutic context can be safe”, notes Doblin, but he emphasises that the therapeutic outcome seems highly dependent on the therapeutic context. Thus, as Roberts explains, “in psychotherapeutic sessions, psychedelics are best thought of as adjuncts to psychotherapy, not as whole treatments themselves”. Doblin concurs: “We are talking about reversing a lifetime of patterns, in some cases, so the magic bullet or single-dose miracle cure theory is out the window. Multiple doses are needed in the context of long-term psychotherapy.”

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Psychedelics might be of benefit in the treatment of cluster headaches

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Now, the first clinical trial of psilocybin in terminal cancer patients led by Charles Grob at the University of California is nearing completion, and others are recruiting or about to start further investigating psilocybin, MDMA, or LSD in similar situations. For example, a study led by Stephen Ross and Anthony Bossis from the New York University School of Medicine, NY, USA, is about to commence using psilocybin with psychological support, with endpoints that include reductions in anxiety, depression, pain, and increased acceptance of death. “I am interested in novel ways to relieve suffering for end-of-life cancer patients”, says Bossis. “We are looking to determine whether a mystical state can alleviate the psychosocial and existential anxiety associated with the end of life.” Roland Griffiths from Johns Hopkins University School of Medicine, Baltimore, MD, USA, is also researching the effect of psilocybin on anxiety surrounding cancer diagnosis; this trial is unique in that patients with and without disease progression will be eligible.

Amanda Neidpath, director of the UK Beckley Foundation, has been working for years to initiate new research on LSD, by collaborating with various groups worldwide. In addition to therapeutic research, she believes “we need to understand the mechanisms by which we get these changes of perception that may be beneficial…how these substances work, how they are helpful, and for whom”. Also, since psychedelics would not be efficacious in everyone, an understanding of mechanisms may point to non-psychedelic means to achieve the same therapeutic effects. Research on mechanisms might also help explore other potential uses for psychedelics. One such study about to commence will investigate the effects of LSD on brain connectivity and sensory processing, which might clarify previous suggestions about how psychedelics might enhance cognition and creativity.

“As our view of the human mind and nervous system expands, it is being recognised that different mind-body states, different from our waking state, are also useful”, says Roberts. One such state, which has been anecdotally linked with enhanced wellbeing and anti-addictive properties, is the group use of ayahuasca. This ancient compound is not pure, but a mixture of plants used mainly by indigenous and spiritual groups. Traditional mixtures vary, but all contain a source of the psychedelic dimethyltryptamine plus a compound to prevent its gastrointestinal breakdown.

Jordi Riba and a team led by Manel Barbanoj from the Hospital de Sant Pau in Barcelona, Spain have been studying ayahuasca in healthy volunteers for about 10 years. Using a freeze-dried preparation, administered at standard doses of the active alkaloids, the team have done tolerability and pharmacokinetic studies in addition to collecting data on neuroendocrine, immune, and subjective parameters. “During the acute phase [3–4 h], volunteers reported having gone through a deeply introspective and emotional experience with thoughts usually revolving around personal concerns”, notes Riba. “Most participants found this interesting and useful, and it is in this remarkable characteristic of ayahuasca where the potential for modifying self-destructive behaviours, such as drug abuse, could reside”, he speculates. EEG and SPECT studies have confirmed changes in brain electrical activity and blood flow consistent with these subjective effects, and now the team plans to assess the effect on long-term healthy users.

In learning lessons from the 1950s and 1960s, researchers in general remain cautious about the potential for psychedelics and how they are investigated. Roberts notes that except for a study on cluster headaches (which reviewed informal use), all studies presented at the recent Basel forum specify that psychedelics are taken in the presence of a trained professional, and programmes for educating and training professionals are starting to be developed. MAPS is planning to seek FDA approval for a training programme for psychotherapists or nurses to become psychedelic psychotherapists. Ross, with Jeffrey Guss, has developed a course on psychedelic medicine, taught earlier this year to a group including medical students, psychiatry residents, and post-doctoral addiction fellows at Bellevue Hospital department of psychiatry in New York, USA. The course focuses on use of psychedelics for addiction.

The development of education in parallel with research is essential to ensure an academic focus towards psychedelic medicine, Ross and others believe. “Often people hold very passionate and pseudo-scientific opinions about these drugs on both sides of the debate. As clinicians, we need to remain dispassionate and hold true to the principles of evidence-based medicine…we owe it to those patients who may benefit from this approach”, says Sessa.