Molecules who seem to have lost their way

9. November 2015

Lysergic acid diethylamide, psilocybin, and ketamine – if that only conjures up thoughts of illicit substances, you’re overlooking a crucial aspect: years of prohibition against their use that have done seriously harm to research. Many molecules show desirable effects in smaller studies.

Until 1967, things were still working properly: scientists could study the effects of lysergic acid diethylamide (LSD), psilocybin, and similar compounds without interference. But the US Controlled Substances Act brought an abrupt end their work. Many countries followed the American’s lead and classified such substances as “especially dangerous”. The consequence: research using these compounds was no longer possible without first going through the extensive hassle of obtaining special permits. At the same time, prices for pure substances in the chemicals trade climbed exorbitantly. To make matters worse, a United Nations resolution about these substances was passed in 1971. UN bodies declared that there was no benefit to be had from these psychotropic molecules.

“Politically, but not scientifically motivated”

This judgement was “politically, but not scientifically motivated,” writes James Rucker, London, in a commentary [paywall]. Until 1967, there were 1,000 scientific articles describing the medical uses of LSD alone. Then it all went dark, out of a fear of the risks. But unfairly: Rucker references the therapeutic index zoom as safety-relevant aspect. The value is calculated as the quotient of LD5 (dose that causes a lethal effect among 5 per cent of all test subjects) and ED95 (dose that results in the desired effect in 95 per cent of all test subjects). The larger the value, the safer the molecules. For LSD and psilocybin, Rucker names scores of 1000, while alcohol gets a score of 10 and cocaine 15. But that is not all: consumers of psychedelic substances interviewed as part of a survey showed lower suicide rates and fewer mental illnesses. Reason enough to take a closer look at these substances.

LSD: silver bullet of the flower children

As early as 1963, Aldous Huxley was injecting himself with 100 micrograms of LSD in the muscle. He was suffering from incurable cancer of the larynx and was tormented by anxiety disorders. Decades later, Peter Gasser, a Swiss psychiatrist and psychotherapist, looked at the matter again. In a study with twelve patients, he studied the effect of the controversial molecule. All participants were suffering from anxiety associated with life-threatening illnesses. On a randomized basis, they received either 200 micrograms of LSD or 20 micrograms with the ability to increase the dose to 200 mcg. They also received psychotherapeutic treatment. Under this protocol, they saw significant improvements in their anxiety, as measured by the State Trait Anxiety Inventory (STAI). Gasser’s advantage: Swiss authorities tolerate such experiments. Similarly liberal is the attitude of the Scandinavian countries. Pål-Ørjan Johansen at Trondheim investigated whether LSD could be used against alcohol addiction. For his meta-analysis he identified six suitable studies with a total of 536 participants. He reports statistically significant evidence that LSD has a positive effect on the treatment in a clinical setting. A single dose of the drug plus other programmes was able to reduce the abuse of alcohol.

Ketamine: more than just a knock-out drug

Scientifically, LSD is not an isolated case. Originally developed as an anaesthetic, then later misused as a dissociative drug, ketamine is also enjoying a revival of sorts. British psychiatrists working with Rupert McShane administered the drug to 28 patients with the most severe forms of treatment-resistant depression [paywall]. Eight (29%) experienced surprising effects, with the mental illness immediately disappearing or significantly improved. Ketamine was thus identified as an alternative to electroconvulsive therapy is according to the article. A disadvantage identified by McShane is that the treatment must be repeated regularly, at a median of every two months. The symptoms also improved for patients with bipolar disorder. In both cases, accidental discoveries led to further studies. Now, researchers in Freiburg have now succeeded in identifying the underlying mechanisms [paywall]. Ketamine immediately stimulates the Homer1a n the prefrontal cortex, while it takes imipramine, for examples, weeks to have an effect, which represents a decisive advantage. Drugs for the acute treatment of depression have yet to be identified. Homer1a has regulatory responsibilities in the transmission of impulses between nerve cells. When scientists blocked the Homer1A in animal studies, the effects did not occur.

Psilocybin: from mushroom to pill

New data is now also available for psilocybin. Charles S. Grob and George R. Greer report the results of a placebo-controlled pilot study. Twelve cancer patients with severe anxiety disorders were given the mushroom hallucinogen in relatively low doses, namely 0.2 milligrams per kilogram of body weight. This reduced psychosomatic complaints as measured by various scales. Rainer Kraehenmann at Zurich wanted to know which biochemical mechanisms were behind this effect [paywall]. Thanks to the functional magnetic resonance imaging, he was able to identify the effects in the amygdala, where our fear centres are located.

First analyse, then study

Despite the euphoria, many studies have their weaknesses. Some scientists are working with animal models and others are using a low number of test subjects. James Rucker is therefore calling for methodologically high-quality studies to investigate the therapeutic potential of LSD, etc. He wants to see the UN General Assembly Special Session on Drugs reclassify various molecules. The next meeting takes place next year.

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1 comment:

Dr Walter Serino
Dr Walter Serino

We continue to allow an uncultured, ignorant, insensitive, bigot and on the whole dangerous political class to handle clinical and scientific issues (even major ones).
How long we will continue to accept this without a strong reaction from anyone of us and our Scientific Societies?

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