Major depressive disorder (MDD) is a common and debilitating condition. In any given week 3 in 100 people will be diagnosed with depression in England.[i] You’d expect us to understand it, but we don’t; and our treatments vary massively in effectiveness between different people. A new treatment needs to be found. So why am I talking about psychedelics? Well for millennia people have used them in a healing way, and some studies in the 20th century found that people who used them were significantly less likely to have mental health difficulties. There’ve been some trials in the last 20 years that suggest that psychedelics (magic mushrooms, LSD etc) can improve depressive symptoms by a huge amount. The way they work is difficult to decipher- the brain is complicated; and we don’t even understand how it changes with depression. This review will give a quick overview of the evidence that they work, and a potential explanation of how they work.
What’s the evidence that they work?
There have been 4 recent trials that provide good, reproducible evidence that psychedelics could treat depression. They all follow the same formula. A participant volunteers, is assessed for baseline depression (using various ratings) and then given a single dose of a psychedelic. They then experience their “trip” in a quiet room, with a trained therapist present to discuss anything that the participant wants to talk about. The participants are then followed up over varying lengths of time (up to 6/7 months) and their depressive symptoms are re-assessed at intervals.
The studies have been done mostly for psilocybin, the active component of magic mushrooms, because this has a fairly small risk of causing harm, and these risks are well understood.
2 of these studies were done in 2016 and looked at the effect of psilocybin on depression associated with life threatening cancer. They both found a really impressive and significant reduction in depression ratings- in one[ii] around 70% of patients had a 50% of greater reduction in depression severity 6.5 months after the dose; and in the other[iii], the mean score on a well-known depression rating (HAMD17) decreased from 22.6 at baseline to 6.6, 6 months after the dose was given. For clarity, this 2nd finding means that the average rating of participant depression changed from “severe” to “in remission”. It should be noted that we don’t know whether we can generalise these findings in patients with life-threatening illness to the rest of the population; but they’re still very impressive.
The other 2 studies I will discuss were carried out with participants whose depression had not responded to traditional treatment[iv], or whose depression had recurred at least once[v]. The first investigated psilocybin and found a big mean reduction (slightly over one severity rating on a QIDS depression scale) in participant depression at 6 months. The reduction was even greater in the short term, with the maximum difference being at 2 weeks post-psilocybin. The latter study investigated a plant based hallucinogen, ayahuasca, and followed patients in the short term. Although only 6 patients took part, their depression ratings were reduced by up to 82% between the baseline and 3 weeks after the drug.
Should we all take psychedelics?
Before we get too carried away with these results, it is important to look at criticisms of these studies. In all of them, the people taking part volunteered, which means that a) they’re the type of people who are willing to try these drugs and b) they were probably expecting a good result. In depression treatments the placebo effect is really powerful and psychedelic drugs promote suggestibility, so its entirely possible that some of the improvement seen was due to anticipation bias and the placebo effect. Also the trials all involve the participant receiving some amount of high quality therapy; they all involved a pre-drug session, access to a therapist during the trip and at least 1 “debriefing” session. This might in itself be enough to help their depressive symptoms. The solution to both these problems might seem simple enough- use a control group, where the therapy is given but not the psychedelic. Some of the studies attempted this, but the issue is that the psychedelic experience is so unique that it is impossible to “blind the participants”- they will all know whether they received the psychedelic or not. This criticism doesn’t invalidate our results, you could say it just provides another aspect of patient treatment that could be exploited to help them, but it does call into question what the actual effects of the drugs are.
The main caveat to these findings is that not enough research has been done; the trials above involved a maximum of 51 patients each. For a drug to be licensed, you would need trials of hundreds of patients, so that you can be sure it works and that the side effects are acceptable. Also, its useful to know how a drug works before you approve it for general use- if you don’t, you’re more likely to find negative effects of it somewhere down the line.
How do these psychedelic drugs work?
We don’t have one unified model of how depression happens, but evidence suggests it involves an altered level of chemicals (monoamine neurotransmitters) in the brain, the brain’s plasticity and various psychological processes. More specifically, it involves reduced monoamine levels and reduced ability to make new connections and change the connections it already has. The psychological processes are things like negative affective bias- focusing on the negative, and maladaptive predictive processing- assuming everything will turn out badly. These processes seem to be things that happen in the depressed brain and help keep it in a depressed state[vi].
The way psychedelic drugs work during the “trip” is by acting on serotonin receptors in a specific cell type (layer 5 pyramidal ganglion cells). They make these cells more likely to fire, so more information flows through the brain in a much less constrained way than normal. The transmitter glutamate is released, which makes the brain more plastic (and able to make new connections) and the pyramidal cells firing affects the way in which your brain models and predicts the future. Ok so the brain can make new connections and predict the future differently, what does that mean?
The brain is constantly trying to predict the future, that’s how its designed. It does this based on 3 things: the information it’s getting at that moment, your prior experiences (memories) and any expectations or prejudices you might have. All these things interact, specifically your experiences and expectations may affect how you process the information. In depression generally, patients have more negative expectations and focus on negative experiences- meaning that the predictions the brain makes will tend to be negative. One basic example of this would be someone with depression wondering about going to an event. Even if the person has gone to many such events and they have gone well, the brain will focus excessively on the one that didn’t and make the prediction that going to the event will end badly for them. We pay a lot of attention to these prediction models, so the prediction made will occupy most of the person’s thoughts.
The way psychedelics affect this is basically making you rethink your predictions. The increased information flow means that the predictive models are going to have to work really hard- there’s a lot for them to respond to. The firing of the pyramidal cells means that we have less of a type of brainwave called alpha oscillations. This reduces the importance our brain places on our experiences and expectations. That means that the predictions will be made based largely on the information around you, rather than on what you expect to happen. The increased plasticity caused by glutamate release means that the way your brain works during this experience is likely to stick—the different patterns of firing will be maintained to an extent even after the drug has left your system[vii].
The rethinking of predictions and changes in the way you think that I’ve described are actually how cognitive behavioural therapy works- it targets the depressive thought processes of patients. Researchers have asked patients whether the way they think changes, and it does[viii]! This model is also supported by brain scanning studies and changes in brain wave patterns during the psychedelic trip.
Author; Helen Clay, St Anne's College, Medicine
References [i] McManus S, Bebbington P, Jenkins R, Brugha T. (eds.) (2016). Mental health and wellbeing in England: Adult psychiatric morbidity survey 2014. [ii] Ross, S. et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. J. Psychopharmacol. (2016) doi:10.1177/0269881116675512. [iii] Griffiths, R. R. et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J. Psychopharmacol. (2016) doi:10.1177/0269881116675513 [iv] Carhart-Harris, R. L. et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry (2016) doi:10.1016/S2215- 0366(16)30065-7 [v] Osório, F., Sanches, R., Macedo, L., dos Santos, R., Maia-de-Oliveira, J., Wichert-Ana, L., de Araujo, D., Riba, J., Crippa, J. and Hallak, J., 2015. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Revista Brasileira de Psiquiatria, 37(1), pp.13-20 [vi] Madsen, M. K. et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology (2019) doi:10.1038/s41386- 019-0324-9 [vii] Carhart-Harris, R. L. & Friston, K. J. REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacol. Rev. (2019) doi:10.1124/pr.118.017160 [viii] Watts, R., Day, C., Krzanowski, J., Nutt, D. & Carhart-Harris, R. Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression. J. Humanist. Psychol. (2017) doi:10.1177/0022167817709585
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