In our last post, we discussed how exercise plus the regular consumption of beetroot juice can strengthen healthy network-connection patterns in the brain. As we get older, the brain tends to develop odd patterns of activity that associate with loss of mobility and balance. Essentially, in older brains, the movement areas (somatomotor cortex) start connecting to other areas (insular cortex) to support the performance of physical activity. This is inefficient.

To create a crude analogy, it’s almost like someone with a weak leg using a cane to help them walk. Normally, you don’t need that extra support to perform the function, but when the limb is weak, you need the cane. That’s what these secondary brain connections are like when the normal functional patterns of neural activity become weak with age.

Strong connectivity of brain networks is vital to functions like movement, sensation, perception, and thought, and we now realize that when these networks go awry, function diminishes. Interestingly, altered brain connectivity is also present in mood disorders, like depression.

 

Depression and psilocybin

According to the latest estimates from the World Health Organization, more than 300 million people are now living with depression. This constitutes an increase of more than 18% between 2005 and 2015. It is now, in fact, the leading cause of disability worldwide.

Unfortunately, it is a problem that is hard to solve. More than half of patients fail to respond to treatment. But some very interesting recent research suggests that psilocybin – the psychoactive component of so-called “magic mushrooms” – may be uniquely effective for treating psychiatric conditions that have defied conventional therapies, particularly depression.

For instance, a couple of years ago, researchers affiliated with Imperial College London administered psilocybin in two oral doses, one week apart, to 12 men and women with treatment-resistant major depression. “Treatment-resistant” refers to individuals who have previously had two unsuccessful courses of antidepressants, lasting at least 6 weeks. In this study, psilocybin was well-tolerated, and relative to baseline, depressive symptoms were markedly improved one week after the second dose. But what was truly remarkable about this trial was that the improvements were sustained three months later for about half of participants. How can that be? What is responsible for these long-term improvements?

Fast forward a few years and we now have a new neuroimaging study, from the aforementioned research team from Imperial College London, which examined what is happening inside the human brain while in the psychedelic state. Let’s look at what they did.

 

Methods

In this newer study, the researchers recruited 19 patients who had been diagnosed with treatment-resistant depression. In order to assess changes in the condition at various points throughout the protocol, the patient filled out the Quick Inventory of Depressive Symptoms (QIDS-SR16), a validated 16-item questionnaire.

First, the patients underwent brain imaging via fMRI, measuring brain blood flow and network patterns in the rested state. Next, all subjects received a 10 mg dose of psilocybin and a week later, they received a second dose, this time with 25 mg. Both dosings were administered in a medical setting, accompanied by psychiatrists.

One day after the second dose (25mg), a second brain scan was administered to measure changes in brain blood flow and network connections vs baseline measurements. The researchers also compared changes in depressive symptoms from before and after the psilocybin treatment and also compared those clinical changes to the brain imaging changes. 

Quick aside here: it is pretty damn hard to blind participants when the experimental treatment is hallucinogenic mushrooms, so this was understandably an open-label trial, but a control group for the brain imaging would have been nice to see. 

Anyway. Here is what they found.

Results

Depressive Symptoms

Like the former study, treatment with psilocybin produced a rapid and lasting antidepressant effect. Of the 19 patients, all showed some decrease in depressive symptoms at the 1-week mark. At the 5-week post-treatment mark, 47% of subjects exhibited at least 50% reduction in their depression scores. Much like the previous study, there was a roughly 50/50 split in the sample between responders and non-responders with respect to long-term change. Note that that these improvements in depressive symptoms are very impressive when compared to those associated with common antidepressant therapies. So not only do we potentially have another form of therapy to treat depression, we also might have something that is much more effective than currently approved medications. 

Blood Flow

One day after treatment, there was a statistically significant decrease in blood flow to the temporal lobes and the left amygdala. Again, this decreased blood flow indicates reduced activity in these areas. 

Here’s why that matters: Previous research has suggested that increased blood flow in the amygdala is associated with major depression.

This makes a lot of sense – the amygdala is involved in processing stress and fear, and in triggering the fight-or-flight response. It is thought that the development of anxiety and depression may be part of a vicious cycle whereby exaggerated activity in the amygdala in response to stressful stimuli strengthens the processing of negative signals. And imaging studies conducted on subjects who have been administered psilocybin have indeed shown that it acutely modulates amygdala activity by suppressing the processing of negative emotions. This is almost certainly a major contributor to the mood-lifting effects attributed to psilocybin. Incidentally, it has been suggested that SSRIs may work in a somewhat similar manner, by dampening responsiveness of the amygdala to emotional stimuli.

Taking this into account, the researchers compared observed reductions in amygdala blood flow to self-reported reductions in depressive symptoms and found a statistically significant relationship: when blood flow to the amygdala decreased, so did depressive symptoms.

 

Network Stability

The researchers also observed that psilocybin changed the cross-talk between brain regions in the depressed patients. This brings us back to what I said at the beginning about brain interconnectivity. Let’s explore this further. 

The default mode network is a network of interacting brain regions. It’s also referred to as the ‘task-negative network’ because it’s active when we are not focused on something specific. For example, the default mode network is active when we daydream – in which our mind wanders to think about ourselves,  other people, the past, and the future. While the activity of this network is considered a part of normal healthy brain activity, depressed patients do show hyperconnectivity of the default mode network. This increased network activity has been related to the sort of pathological rumination that is characteristic of the depressed condition.

Curiously, the fMRI analyses in this study revealed increased stability in parts of the default mode network after treatment. Specifically, the “responders” who maintained improvement in depressive symptoms at the 5-week mark exhibited increased connectivity in two parts of the network (the ventromedial prefrontal cortex and inferior-lateral parietal cortex).

At first glance, this doesn’t seem to make sense. Earlier work showed psilocybin reduced the connectivity of the default mode network, which is thought to explain how it lifts depressed mood and combats depressive rumination.

What’s going on here? During exposure to psilocybin, the connectivity of the of the default mode temporarily disintegrates. Days after treatment, however, these brain circuits are remodeled, resetting the network and perhaps resulting in lasting improvement. This concept is further supported by comments from the patients, several of whom reported feeling as though their minds had been “rebooted,” or like a computer being defragged.

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Overall, this points to a therapeutic mechanism that is different than that of SSRIs, and may possibly lead to improvements in average clinical outcomes. SSRIs appear to suppress the amygdala response to negative emotional stimuli, but more recent analyses have suggested they may actually be exerting a broad muting influence on all emotionally salient stimuli. This would explain why many individuals report a blunting of positive emotions when taking SSRIs, and why this class of drugs hasn’t been very successful for resolving anhedonia – the inability to feel pleasure. In contrast, participants in the psilocybin trials report a feeling of catharsis and a greater resilience to emotional pain. Here’s an illustrative testimony from one of the trials:

 

[after psilocybin therapy] I have felt a sense of acceptance; more acceptance of agony, boredom, loneliness. [A] willingness to try to accept the negative times – but also an appreciation of the wonderful times.

 

Other resources

This blog is just scratching the surface on this topic. If you would like to know more about this research, I can point you to some other awesome resources in this area:

1. TED talk by Robin Carhart-Harris, lead author of the trial described above
2. Rhonda Patrick’s interview with Roland R. Griffiths, a pharmacologist at Johns Hopkins who has spent decades studying psilocybin and other mood-altering compounds (Dr. Griffiths and our CEO, Dan Pardi, have published together previously here)

Shows from our friend, Jesse Lawler at Smart Drug Smarts

1. #116: Psilocybin and the potential for “psychedelic therapies
2. #129: LSD with Dr. Robin Carhart-Harris
3. #155: Microdosing LSD with Dr. James Fadiman
4. #176: Breaking the psychedelic research logjam with Dr. David Nichols
5. #196: Psychedelics vs. inflammation with Dr. Charles Nichols

Finally, one quick caveat: this research is still in its infancy, and there is a lot we still don’t know about how or why this works, or longer-term effects (like beyond the three-month mark). The cliché “more research is needed,” though redundant, definitely applies here. Additionally, I think it’s worth noting that in these trials, the drug is administered in a controlled environment – rather unlike typical recreational use – to avoid potential adverse effects. Please note that self-medicating on your own might be tempting but is also quite risky.

Importantly, psilocybin is also illegal in the United States. Here is a quote from the website of the Department of Justice: “Psilocybin is a Schedule I substance under the Controlled Substances Act. Schedule I drugs, which include heroin and LSD, have a high potential for abuse and serve no legitimate medical purpose in the United States.”

I’m hopeful that science will continue to demonstrate the efficacy of psilocybin in the treatment of depression, and if it does, that this research will open up legal access to it for those suffering from this condition.