Ketamine’s therapeutic glow-up is going from strength to strength. A Columbia University study, published in the scientific journal Cell Reports, has found that repeated use over an extended period leads to widespread structural changes in the brain’s dopamine system. Dopamine, in case you fell asleep in high school biology, is a neurotransmitter that affects things like how we feel pleasure and how we think.Biologists and biomedical engineers at Columbia used high-resolution imaging to map the brains of mice given doses of ketamine over one, five and 10 days. The structural changes were observed on the dopamine system after 10 days, and suggests future ketamine therapies could be produced to target specific parts of the brain rather than all of it. The news is further evidence that the medical anesthetic and party drug could have potentially wide-ranging medical benefits. The findings also could help explain why ketamine could potentially help those with eating disorders by increasing the number of dopamine neurons in the hypothalamus, which regulates your metabolism. It could also go some way to help scientists understand why extensive overuse can schizophrenia-like symptoms, possibly due to the way the drug negatively impacts the midbrain, which regulates mood. While it looks as though the future of the drug is bright in medical settings, what does it all mean for the recreational ket user who’s partial to a few keys at the weekend? We spoke to Raju Tomer, the senior author of the study, to find out more. VICE: What were the broad strokes finding of this study?
Raju Tomer: To our surprise, after 10 days we saw a broad impact, and the impact was diverging – it was different in different parts of the brain. In some [parts of the] brain, there was a positive impact, and it led to an increase in the number of dopamine neurons. In the hypothalamus area, we found an increase in the number of dopamine neurons, whereas in some regions like the midbrain – especially the dorsal raphe, which is involved in things like social isolation and social behaviour – we found there was a decrease in the number of dopamine neurons. So there was this diverging impact: The same drug was acting on the same class of neurons in different parts of the brain and affecting them differently. That supports the argument for developing methods where we target delivery to the brain, instead of generically washing the brain with the same drug, which could have different effects on different brain regions and might not solve the problem or have neural side effects.We also investigated how it's changing [brain] connectivity. The dopamine system connects throughout the brain, and we found differential changes. We found there was an increase in connections to the prefrontal cortex, which is involved in higher-order cognitive functions. There was a decrease in the sensory part of the brain, the sensory cortex, including visual and auditory. So that's kind of reflecting the dissociative effect of the drug – that it dissociates you from reality, right? You dissociate your senses from your cognitive abilities.So the findings suggest the need for some kind of ketamine treatment that just targets a specific part of the brain?
Right. So depending on the mental health problem, some regions might be more important to interact with or correct. Approaches are being developed now for targeted drug delivery, for example, by using ultrasound to open the blood-brain barriers in a localised region in the brain so that the drug can go through blood openings only on that part of the brain. There are [trials] still in the early phases. But in the future, we have to have these kinds of targeted drug delivery approaches where we target specific regions.What do the findings mean for a recreational user of ketamine, if you can speculate?
The study’s clearly showing that – at least in mice – when used over time and at higher doses, it's causing these very significant changes in the brain. They’re also significant [changes] from a functional perspective. It's detaching your senses from your cognitive capabilities. So I think if used over a long time, in high doses, ketamine can lead to these kinds of schizophrenic symptoms. There's a lot of possibilities in between, right? You could be using intermittently, like once a month, or once a year – I don't know how that's going to affect things. But one thing people need to be aware of that is it can cause these significant system changes in this very important system in the brain, which is modulating the entire brain, and it's affecting the sensory and associated pathways in a different way to lead to those cognitive problems.Could someone potentially self-medicate for depression with recreational ketamine? And what do you think about that?
Once in a while, the New York Times and other papers publish first-person accounts of people who have taken ketamine and it has really helped them recover. It's an important drug from that perspective, especially for treatment-resistant depression. It can help – it really helps. So there it makes a lot of sense, because you're kind of balancing out any side effects with the good effects you're getting. On the other hand, for recreational use, I think it doesn't have much addictive capacity. You don't get addicted to it in the same way as cocaine or opioids. But there are these long-term users who are kind of addicted to it. They have severe problems, severe behavioural problems, severe changes in the brain. So I mean, I would personally avoid it… Why do it?What if someone were to do ketamine every month? Would you expect to see any meaningful change in their brain or behaviour or mood?
That's something that needs to be explored more. But ketamine has a shorter half-life – the effects go away within days. So I would imagine if it’s let's say, once a month, then probably the effects are not cumulative [whereby] they're building up step by step. Given that its effect is short-lived, taking it once in a while is probably not leading to the same accumulated changes as opposed to if you take it every day, where you're hammering the brain with the same thing again and again.
Advertisement
Advertisement
Raju Tomer: To our surprise, after 10 days we saw a broad impact, and the impact was diverging – it was different in different parts of the brain. In some [parts of the] brain, there was a positive impact, and it led to an increase in the number of dopamine neurons. In the hypothalamus area, we found an increase in the number of dopamine neurons, whereas in some regions like the midbrain – especially the dorsal raphe, which is involved in things like social isolation and social behaviour – we found there was a decrease in the number of dopamine neurons. So there was this diverging impact: The same drug was acting on the same class of neurons in different parts of the brain and affecting them differently. That supports the argument for developing methods where we target delivery to the brain, instead of generically washing the brain with the same drug, which could have different effects on different brain regions and might not solve the problem or have neural side effects.We also investigated how it's changing [brain] connectivity. The dopamine system connects throughout the brain, and we found differential changes. We found there was an increase in connections to the prefrontal cortex, which is involved in higher-order cognitive functions. There was a decrease in the sensory part of the brain, the sensory cortex, including visual and auditory. So that's kind of reflecting the dissociative effect of the drug – that it dissociates you from reality, right? You dissociate your senses from your cognitive abilities.
Advertisement
Right. So depending on the mental health problem, some regions might be more important to interact with or correct. Approaches are being developed now for targeted drug delivery, for example, by using ultrasound to open the blood-brain barriers in a localised region in the brain so that the drug can go through blood openings only on that part of the brain. There are [trials] still in the early phases. But in the future, we have to have these kinds of targeted drug delivery approaches where we target specific regions.What do the findings mean for a recreational user of ketamine, if you can speculate?
The study’s clearly showing that – at least in mice – when used over time and at higher doses, it's causing these very significant changes in the brain. They’re also significant [changes] from a functional perspective. It's detaching your senses from your cognitive capabilities. So I think if used over a long time, in high doses, ketamine can lead to these kinds of schizophrenic symptoms. There's a lot of possibilities in between, right? You could be using intermittently, like once a month, or once a year – I don't know how that's going to affect things. But one thing people need to be aware of that is it can cause these significant system changes in this very important system in the brain, which is modulating the entire brain, and it's affecting the sensory and associated pathways in a different way to lead to those cognitive problems.Could someone potentially self-medicate for depression with recreational ketamine? And what do you think about that?
Once in a while, the New York Times and other papers publish first-person accounts of people who have taken ketamine and it has really helped them recover. It's an important drug from that perspective, especially for treatment-resistant depression. It can help – it really helps. So there it makes a lot of sense, because you're kind of balancing out any side effects with the good effects you're getting. On the other hand, for recreational use, I think it doesn't have much addictive capacity. You don't get addicted to it in the same way as cocaine or opioids. But there are these long-term users who are kind of addicted to it. They have severe problems, severe behavioural problems, severe changes in the brain. So I mean, I would personally avoid it… Why do it?What if someone were to do ketamine every month? Would you expect to see any meaningful change in their brain or behaviour or mood?
That's something that needs to be explored more. But ketamine has a shorter half-life – the effects go away within days. So I would imagine if it’s let's say, once a month, then probably the effects are not cumulative [whereby] they're building up step by step. Given that its effect is short-lived, taking it once in a while is probably not leading to the same accumulated changes as opposed to if you take it every day, where you're hammering the brain with the same thing again and again.