Twenty years ago, the current new lease of life being given to psychedelic research and psychedelic-assisted therapy might have felt impossible. After years of stigmatisation and the pharmacological community scoffing at the idea, psychedelic substances such as psilocybin, MDMA and DMT (N, N-Dimethyltryptamine) are taking the spotlight for innovative treatments for mental disorders.
In December of 2020, pharmaceutical company Small Pharma and Imperial College London’s Centre for Psychedelic Research announced they would be conducting the world’s first clinical trials testing DMT’s effectiveness in treating major depressive disorders, that have been underserved by traditional SSRI (serotonin reuptake inhibitors) treatment.
The initial findings on the mechanistic effects of DMT by the Centre for Psychedelic Research have been very informative in terms of how DMT works. But what does this research uncover about the practicality of DMT assisted therapy? What does it indicate about the future potential of DMT as a therapeutic treatment?
We spoke to Dr Carol Routledge, Medical and Scientific Officer at Small Pharma about the initial process of choosing DMT for their research, the promising start made by their first clinical trial and on Small Pharma’s next steps.
Small Pharma and its history with psychedelic research
To start off our discussion, we asked Dr Routledge about how Imperial College London became their partner in the trials and about Small Pharma’s history with psychedelics as a treatment for mental disorders.
“I've been at Small Pharma for just under a year and a half now. And Small Pharma’s choice of DMT being the first psychedelic that they wanted to develop was made before I got here, but we can talk about the reasons for this selection later. Because of the experience that the Centre for Psychedelic Research has, not just with DMT, but all psychedelics and particularly in terms of the mechanistic studies they have conducted, it just made a lot of sense to partner with Imperial. So, they are advising on the study, both in terms of our better understanding of DMT, and then also in terms of the therapy protocol that is wrapped around the pharmaceutical.”
Dr Routledge also makes mention of researchers such as David Nutt, who as Routledge puts it “kept the flag flying” for the pharmacological potential of psychedelics.
On choosing DMT as their first development candidate in psychedelic-assisted therapy - the phrase ‘world’s first’ will always come with a lot of attention - we also spoke about Small Pharma’s history that led up to it.
“Small Pharma started off developing a metabolite of ketamine, 6-hydroxy-nor ketamine, which is still in our portfolio; this is where our introduction into psychedelic-assisted therapy started. I think Peter,” here speaking about Peter Rands, Small Pharma’s CEO and founder, “became interested in the research on psilocybin. Before selecting DMT, Small Pharma did thorough research into the psychedelic arena and selected DMT for, three different main reasons.”
“So first, it is a short acting psychedelic, but one that we think will have long-acting therapeutic benefit. Second, there's a reasonable amount of preclinical research that has been done on DMT. So, it shows activity in animal models of depression. Whilst animal models of depression are not so predictive, the models show that DMT has the same qualities as other antidepressant molecules in those models."
"Also, organizations like Imperial College London have done quite a lot of mechanistic research in humans. So, we have a good understanding of how we think that DMT works. They've used fMRI and EEG to really understand the change in neural connectedness and the increase in excitability to put together this hypothesis around brain plasticity and resetting of the brain. Thirdly, not many companies are working with DMT, they are developing other psychedelics but not really developing this one.”
Each psychedelic compound comes with its own limitations and unique qualities that lend it especially well to therapeutic benefits. We asked Dr Routledge what makes DMT so special, what is the DMT ‘unique selling point’, what makes it more marketable or accessible as a therapeutic solution?
“If you're a patient who's working, you don't really want to spend all day in a clinic which might be necessary with a psilocybin experience.”
“I do think because it’s a short, but more intense, psychedelic experience. So, when/if this drug reaches the market, people will be prescribed psychedelic-assisted therapy, and they will go to a clinic to have this treatment, I think that this treatment will always be given in clinic with a therapist present. But, If you're a patient who's working, you don't really want to spend all day in a clinic which might be necessary with a psilocybin experience. LSD has an even longer psychedelic experience, more like 10 hours, so again, there might be a need to spend all day in a clinic.”
“From a clinical flexibility point of view, then DMT should really help. It's akin to other in clinic treatments. A patient would go along to the treatment centre or the health clinic, they would have the preparation session, then the administration of DMT. The psychedelic experience would last 20 to 30 minutes, and then the patient would undergo integration therapy. Altogether, a full treatment session should be somewhere between an hour and a half and two hours and so a lot more clinically flexible.”
“In terms of how it affects the brain, based on data from academic research, the underlying mechanism appears to be very similar for both DMT and psilocybin. So based on that, we think that the greater intensity of DMT, even though the experience is shorter, elicits the same mechanism that you see for psilocybin. And this is one of the reasons that we do think DMT-assisted therapy should have antidepressant activity, at least the same as if not better than psilocybin.”
- See also: 'Psilocybin found to 'repair' neural connections in mammalian brain'
- See also: 'MDMA and its potential in unlocking the answer to trauma'
Focusing in on the psychedelic effects typical to a DMT experience, Dr Routledge commented humorously, “I haven't taken DMT, just so you know, so I can't tell you first hand,” but as Routledge mentioned above, there is a whole host of knowledge and understanding of the effects of a DMT experience.
She continued, “but, people will probably have visual hallucinations, which can be anywhere from just seeing geometric shapes to seeing balloon men or balloon animals and similar beings. So, depending on how sensitive that person is, they often hear auditory hallucinations, and they might lose a sense of time. You don't lose a sense of ‘you’, but you kind of perceive yourself in a slightly different way. And sometimes people will have discussions with themselves.” This is where DMT really lends itself to being paired with the “wraparound” therapy.
“So, they see that other self, and they have discussions back and forth. And this is supposed to be very therapeutically beneficial, because they can talk through a lot of the issues that they have.”
The search for a well-tolerated dose
DMT is one of the more intense psychedelics that we know of, as such we asked Dr Routledge about the challenges this might bring in terms of establishing a dose that would be well-tolerated in participants or patients.
“This is the reason that we conducted the first part of our study (the Phase I component) in psychedelically-naïve healthy subjects, then we will go on to dose participants in the second part of the study with the Phase IIa efficacy component. We wanted to understand how tolerable different doses of DMT are in the psychedelic naïve population,” psychedelic naïve here meaning people who have never taken or experienced psychedelics before, “because we think a lot of patients will be psychedelic naïve. So, we wanted to understand which doses of DMT elicited a breakthrough psychedelic experience in everybody but that were very well tolerated and safe.”
“You would always start at a low dose, in this case, we started at a pharmacological dose. This means we started at a dose that wouldn’t elicit a psychedelic experience, but they may feel different. And then you slowly increase dose levels in different subject groups. So, with your second group of healthy volunteers, and based on the levels of DMT in the bloodstream, you increase to a slightly higher dose. Again, you measure the psychedelic experience, if they have one, and measure safety and tolerability parameters. We also measured electroencerphaloram (EEG) changes to provide further data on the mechanisms of action of DMT.”
“Then, if this dose is safe and well tolerated, then again, you increase the dose a little bit more in group three, and then you increase the dose a little bit more in group four and so on. You don't necessarily want to go as high as you can get to, but you do want to feel that you've tested a reasonably high dose. We can then select the dose that gave everybody a psychedelic experience, but was safe and well tolerated to take to the second part of the study and this is what we were able to do.”
- See also: 'Psychedelics can open new doors for us, but can we walk through them alone?'
- See also: 'Could DMT be the answer for treatment resistant depression?'
Reflecting on the fact that all participants had a positive experience, Dr Routledge said, “I don't think I had expected any significant challenges but, I didn’t think all doses would be tolerated so well. But they were, in fact they all were. No one came back saying ‘I wish I hadn’t done it’ or ‘it was awful’. DMT was really safe and well tolerated in this study.”
“It may not sound like a particularly big thing, but the fact that we've been able to select a dose that elicits a psychedelic experience in all subjects and that it's incredibly well tolerated and safe, is great.”
Many of the additional details of this first phase of the trial are still what Dr Routledge called “blinded”, meaning the study’s findings, the data etc is still in need of reviewing and analysing, and so all additional data will come out later, once the Phase I component is “unblinded”.
The horizon for Small Pharma and psychedelic-assisted therapy
Finally, we discussed what might be on the horizon for Small Pharma with this drug, the clinical trials and possible future trials, as well as what Dr Routledge herself sees in the future for psychedelic research and psychedelic assisted therapy.
On Small Pharma’s plans for the future specifically, Dr Routledge said, “Too early to say, yes we do have other interests, but don’t quite know what they are yet. Also, we’ve chemically modified our DMT molecule, to give it a slightly different profile. One of the arguments around DMT is that it might be too short to treat some mental health disorders, in that a patient may not be able to go through their whole journey during the experience. So, we have found a way to potentially extend it. I’m not meaning extending to three hours, but just slightly. In addition, modifying DMT means you have the potential to administrate it via a different route. So, instead of intravenously it could be orally administered or inhaled. So that will be our next ‘watch this space’.”
On psychedelic-assisted therapy as a whole, and its potential Dr Routledge had lots to say, “Psychedelic-assisted therapy is a different way of treating people. So, we really have to understand how you take these molecules all the way to the market. How will each step of the process work? It is projected that patients will go to a clinic in order to be treated with this drug, there will be a therapist present during treatment who will provide the therapy."
"I think all of this is achievable. But for us, like a number of other companies, we also need to understand how often patients need to have these treatments. Do we only dose DMT once a year? Do we dose twice a year? So, we need to work out just how long the efficacy lasts, and when one needs to repeat the treatment and therapy.”
“I think if I had to be a betting man, or woman, I think most psychedelics will work across a number of these disorders.”
“So that includes depressive disorders, anxiety disorders, substance abuse, and it might be that different psychedelics work differently across various conditions, so DMT might work better for some, and psilocybin for others.”
“I've worked in the pharmaceutical industry for a long time. I have worked on SSRIs in the past. I do think SSRIs are effective, but clearly in a very different way to psychedelic-assisted therapy. But they are not effective in all patients.”
“And although effective, I don't really think SSRIs get to the root cause. Whereas I do believe that psychedelic assisted therapy potentially could.”
“So, it's not, ‘do I think psychedelic assisted therapy will remove all SSRIs from the market?’ No, I don't. And more importantly, that's not the aim. This just gives patients another choice and let's face it, the unmet need for mental health disorders is huge. There are so many people out there with various depressive disorders that are underserved by current treatments. So hopefully DMT assisted therapy will go a long way to serving some of those people.”