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What do recent ketamine findings mean for depression treatment?

Psychiatrist Dr Tiago Reis Marques says that new research findings on ketamine’s mechanism of action could allow us to produce more, and eventually better antidepressants.

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Research suggests low addiction risk with medical ketamine use

Psychiatrist Dr Tiago Reis Marques discusses what new research findings on ketamine mean for treatment-resistant mental conditions such as major depressive disorder.

Ketamine is currently administered intravenously in clinical settings as a fast-acting antidepressant for treatment-resistant depression. Recent findings from researchers at Karolinska Institutet in Sweden uncovered the mechanisms behind ketamine’s antidepressant effects, demonstrating that ketamine directly stimulates AMPA receptors – part of the nerve cell that receives signals – leading to the increased release of adenosine (a neurotransmitter) which inhibits presynaptic glutamate release.

The researchers said the findings are new knowledge that can explain some of the rapid effects of the medicine and suggest that the “antidepressant action of ketamine can be regulated by a feedback mechanism.”

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Dr Tiago Reis Marques, psychiatrist and researcher with over 15 years of experience studying and treating psychiatric disorders, and CEO of Pasithea Therapeutics, which has ketamine clinics in the UK and Us to treat depression and post-traumatic stress disorder (PTSD), explains why these new findings provide hope for new treatment options for major depressive disorder in the future.

“It is a very interesting study because our understanding of how ketamine works from its basic action has been that ketamine works on the NMDA receptor which is a glutamatergic receptor, so, there is basically a rapid release of a neurotransmitter called glutamate.  

“This is why everyone thought that ketamine is a fast-acting antidepressant, it increases the levels of glutamate in the brain. This was a bit contradictory as the literature shows that in patients with depression, there was already an increase of glutamate levels. The question now was that, if patients already have an increase in glutamate levels, how can a drug that further increases this have an antidepressant property?

“Then research progressed which showed that ketamine also works on a receptor called AMPA, which is also a glutamatergic receptor. Research shows that blockage of the AMPA receptor was fundamental for ketamine’s antidepressant properties. 

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“What this new study shows is that, when ketamine blocks the AMPA receptor, it actually induced an increase of substance called adenosine which is a neurotransmitter – which then binds to adenosine receptors. There’s two types of adenosine receptor – A1 and A2. In this case, when it binds to the A1 receptor it causes a reduction in glutamate levels. So, basically, ketamine can bind to two glutamatergic receptors.

“Therefore, what the study shows is that ketamine has a complex mechanism of action with region-specific changes on glutamate levels in the brain.”

Dr Marques says the animal study is well designed, but that, as it is hard to conduct this type of experiment in humans, and because of the complexity of human psychiatric disorders, the findings need to be extrapolated from the animal study.

“As the study was done in rodents – in terms of its regional actions on the brain – a rat brain is very different from the human brain, but that is something that will be further explored in future studies. 

“The findings of this study will not change the way that ketamine is administered. But, they show the action through the AMPA receptor and that the A1 receptor is also involved. So, if we are trying to find future antidepressant drugs we might not look to other NMDA blockers but instead look for drugs that act on AMPA or on the downstream A1 receptor.

“By elucidating a method of action, it will allow us to produce more, and eventually better antidepressants and possibly, without the negative aspects of ketamine – such as the side effects and the potential for abuse. We are always trying to produce drugs with more efficacy and fewer side effects and we can only do that when we understand how these how drugs work, and what the mechanisms are that are involved in depression. So, the next step for this research will be to try to relate these findings into a human antidepressant effect.”

Marques highlights that the efficacy of ketamine treatment in patients with treatment-resistant depression is between 50 to 70 per cent.

“It is not a miracle drug but it is definitely a revolution in terms of having a new drug as a treatment for depression, as it has a completely different mechanism of action to other antidepressants. The study is another piece of the puzzle for what seems to be a very complex drug.”

What do recent ketamine findings mean for depression treatment?

Dr Marques, CEO at Pasithea

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The journey behind Heroic Hearts: psychedelic healing for military veterans

In part one of two, Heroic Hearts UK CEO discusses the journey to the organisation’s inception.

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The journey behind Heroic Hearts: psychedelic healing for military veterans

Heroic Hearts UK CEO Keith Abraham discusses his journey to setting up the organisation which aims to help veterans living with PTSD.

Heroic Hearts was founded in America in 2017 by Army Ranger veteran Jesse Gould and branched into Heroic Hearts UK by combat veteran Keith J. Abraham. The non-profit organisation connects military and emergency services veterans experiencing mental trauma to psychedelic therapy retreats around the world.

Part one of two.

A personal journey

Abraham was a member of the Parachute Regiment, serving for nine years, and fought in both Afghanistan and Iraq. He began experiencing symptoms of anxiety and depression towards the end of his service and explored treatment options from the NHS, which he says were unsuccessful. Instead, Abraham found healing through psychedelics, such as ayahuasca and psilocybin.

“I went to Peru in 2014 and had a couple of ayahuasca ceremonies which were profoundly transformative and healing. I came out of that jungle and I was healed. I went into that jungle when I was in a bad place. So, personally, I didn’t need any more evidence. But, of course, that’s anecdotal evidence, so it doesn’t really count too much.

“It wasn’t until 2019, which was roughly an eight-week period, where I was being told in one way or another that very nearly every day veterans were killing themselves. And that was not even through lockdown – this was before. It was very difficult to keep hearing this and it reached a point where I felt powerless because I knew I had the answer, which was ayahuasca and psilocybin.

“I said to myself, the first thing I’m going to do is find somewhere where I can take some veterans.”

Wanting to help veterans through psychedelic medicines, Abraham found a retreat centre that informed him of Heroic Hearts in the US. The orginsation had the same goal of helping veterans with these therapies, which led to Abraham setting up its UK branch.

“The problem is that the government does not differentiate suicides in terms of demographics. We’ve tried to petition the government to say it needs to be noted when it is a veteran. They do tend to have more extreme experiences but the vast minority of the military see combat experience, however, that doesn’t mean that other veterans in the military haven’t been traumatised by something.

“Within the veteran community and within serving members, depression is probably an epidemic as well as PTSD, which is probably more likely to be experienced by a higher percentage within the veteran community, but there is also plenty of civilians who have PTSD as well.

“For combat veterans, like myself, it can be very difficult. I had a really difficult time with my problems but since leaving the jungle I can talk about my problems, I can visualise them in my own mind, I can sit with my own emotions of any one of those desperately traumatic experiences. They are not traumatic anymore. They’re just experiences that I had.

“It’s not about just accepting that I actually had a difficult experience and that I just need to heal from that – that’s great and that’s a wonderful thing. If you can turn around and say that the experience was actually really valuable and I am better, or better equipped, or I am more because of that experience, instead of feeling that I am far less because of that experience – which is normally how you would feel about a traumatic experience which is debilitating.

“I saw lots of my friends dying in very traumatic situations. I am now empowered by those situations and that is the gold of psychedelics because it would take a great psychotherapist to get you to that point, and if they did, it would probably take 60 years.  Psychedelics will do that in a very short period of time, it might just be one or two doses.

Abraham says the team at Heroic Hearts, such as Grace Blest-Hopley, research director, and Mags Houston, marketing director, has helped to transform the organisation to be able to provide an expert service to veterans.

“We have got experts advising that actually are fundamental to the organisation’s structure itself. We are trying to keep people from killing themselves – however, people on these retreats are not suicidal – but we want to alleviate suffering, because these people are suffering.

“Is is so affirming to have other wonderful people working with us – it has been quite a journey. So, for me, on a personal level, it is special that we have gotten this far.”

Heroic Hearts will be launching a groundbreaking study at its retreats that will be exploring psychedelic medicines as a treatment for both TBI and PTSD in veterans.

“We’re in a very good place to launch these retreats and not just those ones – we are going to be in a good place to sustainably keep going. How many people do we help that way, how many families get resolution, how many husbands return to their wives and children, and how many wives return to their husbands and children?

“It is not just about the people that get the therapy. They go home and their relationships might be healed, and their children might see their dad or their mum with the life in their eyes again instead of – speaking from personal experiences – that vacancy that you can have sometimes, so children can grow up into healthy adults instead of adults that had a traumatised parent.

“We are changing the world by that ripple effect, and it’s a beautiful thing.”

Read part two:

Heroic Hearts: investigating psilocybin for brain trauma in veterans

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Psychedelic Health is a journalist-led news site. Any views expressed by interviewees or commentators do not reflect our own. We do not provide medical advice or promote the personal use of psychedelic compounds. Please seek professional medical advice if you are concerned about any of the issues raised.

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