Jump to content
The Corroboree
Alchemica

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles.

Recommended Posts

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles.

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

doi:10.1177/2045125314527985

While I can't endorse their use for depression in many set and settings, it's pleasing to see the research.

  • Like 1

Share this post


Link to post
Share on other sites

Magic mushrooms trial for depression delayed by red tape

by Sam Wong

08 April 2013


main_image_shd.png

Professor David Nutt says drug laws hinder research on clinical applications

The UK's first clinical trial using the hallucinogenic ingredient in magic mushrooms for treating depression is being delayed due to UK and EU rules on the use of illegal drugs in research.

Professor David Nutt, president of the British Neuroscience Association (BNA) and Edmond J Safra Professor of Neuropsychopharmacology at Imperial College London, told BNA’s Festival of Neuroscience yesterday that although the Medical Research Council has awarded a grant for the study, Government regulations controlling the licensing of illegal drugs in research and EU guidelines on Good Manufacturing Practice (GMP) have stalled the start of the trial, which was expected to start this year. He is calling for a change to the regulations.

Professor Nutt’s research has shown that psilocybin, the psychedelic ingredient in magic mushrooms, may have the potential to alleviate severe forms of depression in people who have failed to respond fully to other anti-depressant treatments. However, psilocybin is illegal in the UK. The United Nations 1971 Convention on Psychotropic Substances classifies it as a Schedule 1 drug, one that has a high potential for abuse with no recognised medical use, and the UK has classified it as a Class A drug, the classification used for the most dangerous drugs. This means that a special licence has to be obtained to use magic mushrooms in research in the UK, and the manufacture of a synthetic form of psilocybin for use in patients is tightly controlled by EU regulations.

The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients.

– Professor David Nutt

Department of Medicine

Professor Nutt said: “The law for the control of drugs like psilocybin as a Schedule 1 Class A drug makes it almost impossible to use them for research. The reason we haven’t started the study is because finding companies who could manufacture the drug and who are prepared to go through the regulatory hoops to get the licence, which can take up to a year and triple the price, is proving very difficult. The whole situation is bedevilled by this primitive, old-fashioned attitude that Schedule 1 drugs could never have therapeutic potential, and so they have to be made impossible to access.

“The knock-on effect is this profound impairment of research. We are the first people ever to have done a psilocybin study in the UK, but we are still hunting for a company that can manufacture the drug to GMP standards for the clinical trial, even though we’ve been trying for a year to find one. We live in a world of insanity in terms of regulating drugs at present. The whole field is so bogged down by these intransient regulations, so that even if you have a good idea, you may never get it into the clinic.”

He said that the regulations need to be changed. “Even if I do this study and I show it’s a really useful treatment for some people with depression, there’s only four hospitals in this country that have a licence to hold this drug, so you couldn’t roll out the treatment if it worked because the regulations would make it difficult to use,” he said.

Professor Nutt and his team at Imperial have shown that when healthy volunteers are injected with psilocybin, the drug switches off a front part of the brain called the anterior cingulate cortex, which is known from previous imaging studies to be overactive in depression. “We found that, even in normal people, the more that part of the brain was switched off under the influence of the drug, the better they felt two weeks later. So there was a relationship between that transient switching off of the brain circuit and their subsequent mood,” he said. “This is the basis on which we want to run the trial, because this is what you want to do in depression: you want to switch off that over-active part of the brain.

“The other thing we discovered is that the major site of action of magic mushrooms is to turn down a circuit in the brain called the ‘default mode network’, which the anterior cingulate cortex is part of. The default mode network is a part of the brain between the front and back. It is active when you are thinking about you; it coordinates the thinking and emotional aspects of you.”

The researchers discovered that the ‘default mode network’ had the highest density of 5HT2A receptors in the brain. These are known to be involved in depression and are the targets for a number of existing anti-depressive drugs that aim to improve levels of serotonin – a brain chemical that gives people a sense of well-being and happiness. Psilocybin also acts on these receptors.

“We have found that people with depression have overactive default mode networks, and they are continually locked into a mode of thinking about themselves. So they ruminate on themselves, on their incompetencies, on their badness, that they’re worthless, that they’ve failed; these things are not true, and sometimes they reach delusional levels. This negative rumination may be due to a lack of serotonin and what psilocybin is doing is going in and rapidly replacing the missing serotonin, switching them back into a mind state where they are less ruminating and less depressed,” Professor Nutt said.

The proposed trial will be for patients with depression who have failed two previous treatments for the condition. Thirty patients will be given a synthetic form of psilocybin and 30 patients will be given a placebo. The drug (or placebo) will be given during two, possibly three, carefully controlled and prepared 30-60 minute sessions. The first session will be a low dose to check there are no adverse responses, the second session will give a higher, therapeutic dose, and then patients can have a third, booster dose in a later session if it’s considered necessary. While they are under the influence of the drug, the patients will have guided talking therapy to enable them to explore their negative thinking and issues that are troubling them. The doctors will follow up the patients for at least a year.

“What we are trying to do is to tap into the reservoir of under-researched ‘illegal’ drugs to see if we can find new and beneficial uses for them in people whose lives are often severely affected by illnesses such as depression. The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients.”

Ethical approval for the trial was granted in March and Professor Nutt says he hopes to be able to start the trial within the next six months – so long as he can find a manufacturer for the drug.

Professor Nutt’s research also receives funding from the Beckley Foundation.

Adapted from on a news release from the British Neuroscience Association.

------------------------------------------------------------------------

http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_24-1-2012-10-39-58

Edited by ☽Ţ ҉ĥϋηϠ₡яღ☯ॐ€ðяئॐ♡Pϟiℓℴϟℴ

Share this post


Link to post
Share on other sites

I just spent 3 hours going through wikipedia trying to understand the anterior cingulate cortex. The magnesium, restless leg syndrome (dopamine deficiency also parkinsons), own will, hallucinogens, sunshine, etc etc... man it just amazes me how intricate and inter-relative the human organism is.

I have restless legs, also some apparently tiny cysts picked up via MRI in some part of my brain within the limbic system but I can't remember where...

now to continue reading....

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×