Ayahuasca and the depressed brain: Part 1

As ayahuasca, the South American plant medicine has become more popular in the west, we have heard ever more anecdotes of how this brew has transformed the lives of many. They state how there psychedelic journey on ayahuasca brings their life into focus, and helps them overcome problems such as anxiety, depression and addiction.

But what is this substance doing in the brain, and how is it it helping relieve issues like depression?

Research in the brain of depressed patients has shown that one common action of antidepressants is an increase in new brain cells – known as neurogenesis. Neurogenesis occurs in an area of the brain called the hippocampus. The hippocampus acts as the memory centre  – it is the place where memories are ‘stored’. In the simplest explanation, when there is an increase in neurogenesis in the hippocampus, there is an increase in the storage of new memories.

If depressed patients aren’t creating as many new memories, then what is their mind doing? There is a tendency for depressed patients to ruminate – remain stuck in negative patterns of thought which are difficult to get out of. They may continuously criticise their own behaviour around a overly simplistic, generalised theme, such as “I can’t succeed at anything I do”. They will then go in cycles of old memories, reinforcing this idea. By increasing new memories, depressed patients may be able to create new, more healthy ways of thinking about their life.

Many depressed patients who use ayahuasca report that they are able to break away from dysfunctional patterns of thinking, and come away looking at their life from a new perspective. Could increased neurogenesis help explain how ayahuasca helps alleviate depression?

What is Ayahuasca?

Ayahuasca  is made up of two plants – the caapi vine and the chacruna leaves. The chacruna leaves contain DMT and the caapi vine contain beta-carbolines, such as harmaline. If you ingest the DMT-containing leaves alone, you will not experience any psychedelic effects, as the DMT is broken down in the gut by the enzyme, monoamine oxidase (MAO). It just so happens that when harmaline enters the gut, it blocks, or inhibits MAO from doing its job and breaking down DMT. This enables DMT to enter the blood stream, and subsequently into the brain.

Inhibitors of MAO, or MAOIs are also a type of antidepressant. This led researchers to ponder whether the MAOIs of ayahuasca also have antidepressant effects. Two studies have shown that harmine exerts anti-depressant effects in animals, however, no studies have yet been done showing the effects of harmine in humans.

Harmine and neurogenesis

A recent study has shown that harmine is able to increase the proliferation of ‘neural progenitors’ from stem cells. Neural progenitors are stem cells that are half-way to becoming fully matured neurons. At the most optimal dose, they found that harmine increased the number of proliferated cells by 71.5%. This can been seen by the number of green cells in Figure A.

However, they are yet to show, that all of these cells mature fully into neurons – i.e. neurogenesis. In Figure C, some cells show protein markers of a different type of brain cell, a glial cell, which means that not all cells are becoming neurons.

dakic-2016-image-3

Thus, there is promise that harmine increases the life and production of new brain cells,  but we can not yet be sure this is neurogenesis.

Furthermore, these experiments are in cells in a dish. To confirm that harmine causes neurogenesis in humans, three further experiments are needed:

  1. we need to confirm harmine causes neurogenesis in a mammalian animal model. To do this protein markers of neurogenesis would need to be measured in the brain of these animals after they were dosed with harmine.
  2. We need to confirm that harmine crosses the blood brain barrier in humans. A previous study conducted has shown that harmine was present in the blood of humans who ingested ayahuasca. This indicates that harmine makes it into the blood, however, it is notoriously difficult to cross the blood-brain barrier, so further experiments are needed to show this.
  3. We need to show that the hippocampus size increases after treatment with harmine. Since we can not chop open the brain of a human and measure the amount of neurogenesis, we are left with imaging techniques. We can measure the density of the hippocampus using fMRI and if the previous two experiments show positive results, we can imply with confidence that this is due to increased neurogenesis. This is the same method that was employed with classical antidepressants.

So, currently we can not conclude whether or not harmine is causing increased neurogenesis similar to other classical MAOI antidepressants.

So, then, what is the other part of ayahuasca, DMT, doing to the depressed brain?
Answers to come in part 2…

World first clinical trial for Magic Mushrooms

Rolland Griffiths of Johns Hopkins University has led a world first full-scale clinical trial which shows that psilocybin, the active ingredient of magic mushrooms, is able to alleviate depression and anxiety in patients suffering from terminal cancer. The study was published in the Journal of Psychopharmacology.

Patients faced with the prospect of death very often suffer from  mood and anxiety disorders (around 40% of patients). Current therapies have not been very successful in treating these disorders. The exception to these are therapies which take an existential approach – a style of psychotherapy which deals with how patients develop meaning in their life, rather than treating dysfunctional cognitions or behaviours. This is where magic mushrooms come in, as they have be shown to inspire mystical experiences in patients.  These mystical experiences help patients establish meaning in their life whilst facing the the prospect of death, helping to alleviate their anxiety and mood disorders.

The Study

Unlike previous studies looking at psilocybin to treat depression or anxiety, this study is the first full-scale, placebo-controlled, double-blind clinical trial.

There were 52 participants, half the participants received a high-dose (22mg/70kg) of psilocybin while the control group received a low, non-active dose (1mg/70kg). Five weeks later, the groups were swapped.

Participants were measured for levels of anxiety, depression and other attributes, such as level of spirituality, positive behaviours, attitudes and moods. They were measured before therapy, after the first therapy session, after the second therapy session, and again six months later.

The Results

Five weeks after the first session, the patients who took the high dose had lower levels of depression and anxiety and higher rates of remission, than patients who took the non-active dose (see panel A and C of figure below). This effect was still present after 6 months!

If you now look to panel B and D, you will see the effects of the cross-over, i.e. the group who first took the low dose, now takes the high dose and undergoes therapy. It shows that after taking the high dose, this group also had remission rates equal to that of the first high dose group.

Six months after both treatments the remission rates remain low in both groups.

griffiths-2016-mushroom-depression-cancer-image

Interpretation of Results

What have we Learnt?

Earlier this year, an open-label pilot study appeared to show that psilocybin reduced depression in patients for up to three months after a single dose. However this study was lacking a control group and only had 12 participants – far too small a sample to generalise to the wider population.

The current study helps fill this gap and shows that psilocybin is able to decrease depression after a single dose. However, this was in cancer patients, so no matter how much we want to, we must not generalise this result to depression in general. It may be that the type of depression of a terminal patient is much different to that of the general population. This is supported by the fact that cancer patients with depression respond less favourably than other depressed patients to traditional cognitive and behavioural therapies – hence the need for an existential type therapy.

It also seems that a single dose of psilocybin sustains it therapeutic effects for up to six months. If this is the case, it is revolutionary! I mean pharmaceutical companies are going to hate it, because they make so much money from the chronic dosing of anti-depressant and anxiety medications, but, imagine the impact this would have on the quality of life of terminal cancer patients living with depression! They most likely are already suffering from considerable symptoms without having to add the extra side-effects associated with antidepressants and anxiolytic medication.

Flaws in the study

The current study has a pretty big flaw. For some reason they decided it was a good idea to do a cross-over design, meaning that every patient got a high dose of psilocybin. This means that there is no control group to properly assess if the long-term effects are actually due to psilocybin therapy. It seems logical that it is due to the therapy, but in science we cant afford to make such assumptions. It may be that these patients would have naturally got better over time, as is what happens with a lot of people with depression who undergo no therapy at all. It may be that the two therapy sessions on their own, without psilocybin were enough to create long-lasting change. Unfortunately the study design does not allow us to properly tease apart these variables, and alas, must be left for another study.

Other possible confounds including the impossibility of creating a true placebo due to the highly noticeable perceptual effects of psilocybin – i.e. the expectency effect. For example, when people notice they are tripping and their therapists face starts contorting into a devil-like creature, they may start inferring with confidence that they have been given psilocybin, and thus the placebo effect is stronger. For myself, I don’t consider this a placebo effect as it is inherent to the drug experience itself, but other purists disagree as they believe it is not due to the hypothesised mechanism of the drug – i.e. by inducing existential insight.

The final word

The acute effects that psilocybin has on both depression and anxiety are impressive, with remission rates around 60%, whilst normal therapies show remission rates around 30%. And this was after A SINGLE DOSE. This could have dramatic effects on the quality of life for terminal cancer patients, and if these effects generalise to all populations suffering from mood disorders, this could revolutionise psychiatry. We cant ignore the therapeutic potential of psychedelic drugs anymore – the next wave of psychedelic drugs as therapeutics is just around the corner.

Magic mushrooms: A magic cure for depression?

The last few weeks have seen magic mushrooms and their potential to treat depression spotlighted in the media.

This is just another of the latest instalments highlighting the changing perception of the media (and the public) on the valid use of psychedelic substances.

The study that birthed these news-bites was conducted at the Imperial College London, in the labs of the esteemed psychedelic scientist, David Nutt and was led by his protégé; Robin Carhart-Harris. This is the same team that brought you the equally publicised cardinal LSD imaging study earlier this year.

The study is titled “Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study” and was published in The Lancet Psychiatry, one of the most revered journals in psychiatry.

Over recent years, more and more psychedelic studies are being published in high-impact journals. The esteem of the journal can imply two things to a reader:

1)           The findings of the study are novel and exciting.
2)           The wider scientific community is starting to accept the use of psychedelic drugs as medicines

About time right?

So where do mushrooms fit on the societal landscape?

Magic Mushrooms – Public Policy and Other Dissociated Realities

Although it may seem irrational to ban a naturally occurring substance, magic mushrooms, and the active ingredient psilocybin, are recognised as a Schedule 1 substance as soon as they are picked from the earth.

Schedule 1 is home to substances that: 1) have a high potential for abuse, 2) are unsafe and 3) have no medical use.

The growing and established scientific evidence does not support the scheduling of psilocybin into this category.

Not only does psilocybin hold no potential for abuse or addiction, rather if you input  the search terms ‘psilocybin’ and ‘addiction’ into a journal database, what you are likely to find are a range of pilot studies and reviews like this, and this, describing the therapeutic potential of psilocybin in treating addiction.

We failed to find any scientific evidence of harms from psilocybin when used in a safe setting. In fact, a recent study has shown that use of psilocybin is associated with reduced risk of suicide. This may be because psilocybin is able to increase positive moods, whilst stimulating spiritual experiences.

In fact a study at Jon Hopkins has shown the magnitude of a spiritual experience on psilocybin to be directly proportional to the efficacy and duration of therapeutic effect.

Suggesting that the therapeutic effect is embedded within the psychedelic experience

The range of potential medical range from not only addiction, but also in alleviating near death anxiety, the treatment of autism and now, as described in this study, to alleviate treatment-resistant depression.

None of this coming as any surprise to experienced psychonauts.

The Hype

As always, even when the media gets it right the results are distilled with that thrilling ring of hyperbole.

This particular study has spurred many mainstream media articles to publish about this study, describing how “magic mushrooms beat severe depression”.

They go on to describe how 12 patients were given magic mushrooms.

With all 12 participants showing reductions in depression after 1 week!

With “the majority still showing effects after 3 months”.

However, even as psychonauts who have experienced the anxiolytic, mood enhancing effects of psilocybin we cannot allow ourselves to succumb to the all too easy pitfall of positive bias.

We have to be careful of the hype and learn to interpret the findings for what they are.

The Study

Participants of the study show a drop in depression measured after 1 week from a single therapeutic session under the influence of a strong dose of psilocybin (25mg; see figure below taken from Carhart-Harris et al, 2016).

However, do not mistake this for clinical significance, with 8 of the 12 participants in remission after one week.

This is still a great result, considering classic antidepressants (SSRIs, eg. Zoloft, Prozac) take 2-3 weeks to exhibit therapeutic effects.

Furthermore, these effects were seen in treatment-resistant patients, meaning they showed no response to at least 2 different prior treatments.

After 3 months, 5 of the 12 participants were in remission. This is approximately equal to the effect SSRIs being used daily over the same time period.

Psilocybin exerted its therapeutic effects from a single dose. In contrast, SSRIs are prescribed for a minimum of 3-6 months and very often for years, if not decades.

Additionally, SSRIs are known to cause many undesirable side-effects.

carhart-harris (2016) psilocybin depression image high res

Figure 1. Levels of depression over time. All participants show a drop in depression one week after being treated with psilocybin, with 8 out of 12 in remission. Three months after a single dose of psilocybin, 5 of 12 participants remain in remission.

 

The Limitations

We have to be careful of positive bias when talking about psychedelics… actually, any science.

Not all articles present an overly optimistic picture, such as this article from vice, because it notes the limitations of the study as well as the realistic positive effects. This is something i have noticed many other reports have left out of their assessment. I think to gain acceptance and respect from the wider community, we have to be honest about the results. Some limitations of the current study include:

1) Sample size – There are only 12 participants. This is not enough to determine if the therapeutic effect of psilocybin is likely to be “real”. Hence, why the study is categorised as a “proof-of-concept” trial.

2) Selection bias – Only one participant had not previously used psilocybin to treat their depression. Furthermore, most participants were self-referred. This indicates they had a belief that psilocybin was likely to be beneficial, either due to previous experience, or due to expectation. Previous positive experience with psilocybin is likely to lead to a positive selection bias of psilocybin, because people who did not have success with self-treatment are unlikely to volunteer to be in the study. Furthermore, those who seek to participate are likely to have some expectation of the effect of psilocybin, leading to a stronger placebo effect.

3) Placebo effects – There was no control group, and given psilocybin has such a noticeable effect on perception and cognition, this is likely to create a large placebo effect.

 

What does this mean?

 

Given this study is so small and the effects may be attributed to placebo or selection bias, we can not conclude on the clinical significance of psilocybin for treating depression. However, the strength of the effect after only one week is quite striking, and if these effects were to be real they could revolutionise the treatment of depression. Thus, this “proof-of-concept” trial is successful in providing a rationale for a larger, double-blind, randomized, placebo-controlled study. We are quietly excited about the results, but are yet to hold judgment on the use of psilocybin as an antidepressant.