A Mental Health-Focused Guide to Psilocybin
For months now, we've been knee-deep in NIH research on anxiety pathways with CBD.
It's been a deep dive across common elements (neuroinflammation, basic mechanisms, etc) and even more obscure ones (BDNF, PF55, etc).
Along the way towards 150,000 words on CBD and anxiety, we keep coming across another actor.
Psilocybin. The chemical that gives magic mushrooms (as they're called colloquially) their distinct attribute.
To be upfront, mushrooms and their synthetic cousin LSD are schedule 1 drugs at the time of this writing.
But there are murmurs. Rumblings.
- Denver made personal possession of the mushrooms legal
- Oakland just did the same
- John Hopkins is creating a new $17 million facility to study psychedelics on depression and Alzheimers
- The FDA has given fast track status to studying psilocybin for depression
A watershed moment was really the New York Best Seller, How to Change Your Mind by Michael Pollan and the Neflix show by the same name following Fantastic Fungi (both great intros).
The original book was an interesting read.
Much more interesting to us is the research.
Lots of new research. Fascinating research. We're going to look at all (or almost) all of it.
As with CBD, we are really about cutting through the noise to find research on safety and function.
How is something actually working and is there a downside?
It may be much more attuned with the needs of a 50-year-old's brain (albeit with some magnesium for support...we'll explain later).
These are the areas we'll cover:
- What is psilocybin
- What are the effects of psilocybin on the brain
- Psilocybin's primary result - neurogenesis
- Psilocybin and serotonin (5ht)
- Psilocybin and BDNF
- Psilocybin and depression
- A brief discursion - Psilocybin and Default Mode Reset
- Psilocybin and anxiety
- Psilocybin and addiction
- Psilocybin and OCD
- Psilocybin and Alzheimer's or Dementia
- Is Psilocybin safe
- Is Psilocybin legal
- Microdosing psilocybin
Let's get started.
What is psilocybin
Psilocybin is a naturally occurring chemical in a certain class of mushrooms.
The amount can vary by species.
It's know to create psychedelic experiences at higher levels including:
- Visual and mental hallucinations
- Changes in perception
- Distortions in time
- Spiritual experiences
- Panic attacks
These are usually associated with a high enough amount to elicit a "trip".
However, a new movement (Silicon Valley might be ground zero) is focused on "microdosing" psilocybin.
This means that low enough levels are taken to avoid these psychedelic effects.
Essentially, to stretch the typical "trip" dosage or a longer period of time.
We'll look at that later.
So what's all the fuss. Besides the trip (think of THC's role in "recreational" cannabis), are there any benefits to psilocybin (think of CBD's health benefits in medical cannabis)?
This is where it gets really exciting.
Let's head to the brain (nervous system really amd immune system actually).
What are the effects of psilocybin on the brain
We now have fMRI scans of brains after psilocybin with very good research on what's happening as a result.
The "trip" may just be a temporary overload along this pathway but the long term results are impressive.
After combing the research on anxiety (see CBD and anxiety research here), one thing becomes apparent.
Newer studies are pointing to either a loss of integration or reduced/off-balance activity across the brain as a signature of many mental illnesses.
This can result in both sides:
- Insults such as inflammation, early exposure to viruses, overactive immune response, trauma, etc
- Poor repair and support mechanisms due to low serotonin, low BDNF, or other genetic "lapses"
So...why all the buzz on psilocybin.
It's almost like a turbo-boost for the repair side of the equation.
If one word were to capture this entire article it would be…
A fancy way to say the brain's ability to build and rebuild nerves and all their surrounding components.
Keep in mind that our brain is dynamic.
It's changing at the time.
Just by reading this sentence, you are building new pathways.
If you never think of it again, that connection will start to wither away to make room for obviously more pressing new learning (how dare you!).
Time and neglect are not the only things to destroy nerves.
- Overactive immune systems
- Inflammation (especially chronic)
- Too much glutamate (gas pedal) or histamine (thank you allergies)...not enough GABA (brake pedal)
- Alcohol and Drugs
We have a massive review on psilocybin/CBD and early trauma.
There's a careful balance between destruction and growth since after all, there's limited real estate in our small skull.
The problem that researchers are finding is that the "loss" side is accumulating wins.
Don't take our word for it:
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders.
In the fMRI scans after psilocybin, it's like spring just came to our brains.
Just look at this image here:
You can literally see an explosion of growth in the dendrites or spines off of nerves.
It's akin to what's happening in a young brain when the mind is in rapid growth mode.
Remember what that feels like?
Everything is new and interesting. The brain is literally hungry for new experiences.
That's also why it's so much easier to learn a new language before a certain age when the brain starts to "congeal" and become a little more intransigent.
As we said...psilocybin is wasted on the young.
The net effect is this:
Psychedelics Promote Structural and Functional Neural Plasticity
Let's look closer at the neurogenesis side of things.
Psilocybin's impressive result - neurogenesis
So we have an arm's race between the insults on our brain and our brain's ability to compensate with new growth/repair.
That latter half is called neurogenesis.
This appears to be a primary effect of psilocybin.
Let's look at the hippocampus, our seat of memory and mood modulation.
This is one of the most dynamic areas of our brain since it's constantly written and re-written (think memory).
It is also is impacted greatly by the insults mentioned above such as chronic stress.
Many mental illnesses show defects here and even loss of brain mass.
In fact just today, a big study on schizophrenia points to lack of connectivity between neurons:
Synaptic density marker SV2A is reduced in schizophrenia patients.
As for the hippocampus…
This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders.
Atrophy just means withering away. Reducing volume.
In fact, when you really drill down to how SSRI's work, it's via neurogenesis.
Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers.
This explains why it can take a few weeks for SSRIs and antidepressants to start working until tolerance builds up (if they do - see CBD versus antidepressants here).
We actually drilled directly into why SSRI can cause anxiety and depression in the first 2 weeks.
All the new research is converging on a powerful neurogenesis effect of psilocybin along similar pathways.
For example, in studies of fear extinction (important to PTSD, anxiety, panic attack, and more):
At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased but rather tended toward an increase.
That was at low doses and we'll reevaluate the effects to reduce reactions to fear and negative thoughts below.
So...how does psilocybin cause this increase in brain connectivity and neurogenesis?
Let's follow the path downstream.
Psilocybin and serotonin (5ht)
We can use SSRI's as a way to look at this process.
We'll hopefully skip their side effects, low effectiveness (estimated at about 30%), ability to normalize (effects go away), and nasty nasty withdrawal effects (just don't call them withdrawal - serotonin discontinuation syndrome).
Also, we want to avoid ripping choline which is a direct risk for dementia.
At the heart of how SSRI's work is a boost in serotonin.
Serotonin is a fascinating player on our brain's (and gut's) stage.
It's commonly called our "feel good" neurotransmitter but that's a bit of a misnomer.
Really, it's more about feeling bad when it's too high or too low. The manager of ALL human behavior.
Its footprint is all over mood and mental health.
We just did an extensive article on tryptophan (serotonin's precursor) and how it drives confidence in social situations (see CBD and social anxiety).
Serotonin has very powerful effects across the brain:
- Rises and fall with social status and confidence - especially in men
- Tied to positive moods or irritability/depression when low
- Estradiol (our main estrogen) and Testosterone are critical boosters for this pathway
- Works as a stress buffer or responder (remember how insults can actually attack the brain??)
- Is intimately tied to dopamine and works as master control across the neurotransmitter landscape
- Promotes neurogenesis via BDNF
Wait a minute...did you catch the last one?
In fact, when you pull back the curtains, there may be some modulation of gut bacteria but the real lever that SSRI's push on for depression is neurogenesis.
New insights into how selective serotonin reuptake inhibitors work suggest they reverse inhibited nerve regeneration and connectivity that may underlie depression.
This is pretty well established now.
It's really shaken up how we look at issues like depression and anxiety as well as the more complicated diseases like schizophrenia and bipolar.
Especially in light of the fact that early exposure to viruses and trauma can come back later in life as a mental illness.
Even a subset of OCD has a strange tie to certain viral infections (called PANDA).
See OCD review for more.
The new culprit, therefore, is our immune system overreacting and attacking brain tissue as well.
Ahhhh...the telltale sign of autoimmune!
Your nerves instead of joints or islet cells (diabetes).
One interesting note on the serotonin effect...it turns out that this is all mediated via our endocannabinoid system (where CBD operates).
Yes, when they block this system, the neurogenesis from SSRI's stop!
Genetic or pharmacological manipulations of cannabinoid receptors (CB1 and CB2) or enzymes responsible for endocannabinoid-metabolism have also been shown to control proliferation and neurogenesis in the hippocampus.
We look at this in detail in our CBD and hippocampus neurogenesis article.
What about psilocybin and serotonin?
First, psilocybin directly works via the 5HT (serotonin) pathway across multiple receptors:
It has a high affinity for several serotonin receptors, including 5-HT1A, 5-HT2A, and 5-HT2C, located in numerous areas of the brain, including the cerebral cortex and thalamus.
In fact, a study administered psilocybin and two different 5HT blockers to test response to fear-based events in mice.
Psilocybin led to a greater fear extinction result (less fearful or anxious to the stimulus used) and more neurons on the hippocampus.
The two serotonin blockers administered with psilocybin unwound the reduction in fear and resulted in fewer new neurons.
This really points to serotonin pathways as the heart of psilocybin's effect on fear reduction and neurogenesis.
Let's follow the rabbit hole further down.
One more curtain and we find the real star of the show is less-well-known.
Psilocybin and BDNF
BDNF is our brain's fertilizer. Our nervous system's really with implications on pain syndromes in your feet and elsewhere.
We covered it extensively at our CBD and BDNF article because there's a billion-dollar market (SSRI's) resting on it.
Simply put, BDNF is a growth factor for nerves.
Any neurogenesis is going to have to go through its office.
Again...just to remind us why neurogenesis is important:
Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases.
And where does BDNF operate?
Brain-derived neurotrophic factor (BDNF) is highly expressed in the brain, including hippocampal and cortical regions, and has pivotal roles in the maintenance of neurons in the central nervous system (CNS).
Goodness...there's that hippocampus again and "maintenance" of brain material and structure seems pretty important.
Studies have blocked a key BDNF pathway (called TrkB) and guess what happens to SSRI's?
They stop working!
Moreover, the behavioral actions of typical antidepressants in animal models are blocked by the deletion of BDNF, and infusion of BDNF into the prefrontal cortex or hippocampus is sufficient to produce antidepressant effects.
Keep in mind that BDNF is solely about the repair/rebuild side of our equation with neurogenesis.
By the way...serotonin directly boosts BDNF activity.
All this time, we have been calling them serotonin medications but really it was about BDNF.
Is may also be psilocybin's real lever.
The whole class of hallucinogenics causes a massive explosion of BDNF at "tripping" doses.
We'll look at the microdosing effects later.
In fact, when researchers blocked that same TrkB pathway to process BDNF, look at what happens:
When cortical cultures were co-treated with ANA-12 (Cazorla et al., 2011), a selective antagonist of BDNF’s high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked.
Interestingly, BDNF is not the sole determining factor for depression.
Meaning, you can't show low BDNF function in all people with depression.
This makes sense based on the insult-repair description above.
Some people may have sufficient repair mechanisms (serotonin and BDNF) but higher insults (trauma, infection, chronic stress, etc).
Having both might be the key to serious mental health issues.
For example, we looked at the SERT serotonin gene and schizophrenia risk at our comprehensive CBD and schizophrenia guide.
One interesting note...new research is showing that psilocybin might partially cut out the middleman and directly stimulate the TrkB activity.
Just a geeky note.
The next effect of this activity:
These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology.
The BDNF effect as a result of serotonin stimulation.
By the way, another serotonin receptor is responsible for the psychedelic effects.
Again, serotonin has its hands in many pies!
We looked at serotonin (5HT) and BDNF (including TrkB) pathways with Psilocybin.
There's one more.
The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds.
Let's look at mTOR. Further down the rabbit hole (but almost here).
Psilocybin and mTOR
Really fascinating new research is pointing to powerful effects of fisetin and they result primarily from interactions with mTOR.
mTOR stands for the mammalian target of rapamycin.
Many people have heard of rapamycin from the effects on aging.
mTOR is a master controller of cell growth and death in the body and brain.
Of course, it will be front and center in the neurogenesis process.
If BDNF is the fertilizer (construction crew) for nerves, mTOR is our architect.
This gets to the heart of "brain plasticity" or the ability to constantly change and adapt.
This also speaks to the rigidity of the brain.
Think of how this plays out:
- Depression - retrenching connectivity - especially with aging
- Anxiety - maladaptive connectivity between the fear center (Amygdala) and prefrontal cortex or hippocampus loss of connectivity (see CBD and mechanisms of anxiety)
- Schizophrenia - a new study just yesterday pointed to lack of connectivity as a key attribute
- OCD - too rigid - reduced ability to change
- PTSD - too rigid - inability to re-wire after traumatic events
- Autism - many studies point to plasticity issues
mTOR governs this ability to constantly "re-map" and change.
It's kept busy these days as chronic stress alone can tax its ability to repair:
Exposure of rats to 6 weeks of unpredictable chronic mild stress (CMS; pink) induces depressive-like behaviors (e.g., anhedonia, learned helplessness) and multiple detrimental effects in the hippocampus and medial prefrontal cortex (mPFC), including decreases in neurogenesis, dendritic length, and synaptic density, as compared with control conditions.
Goodness….that statement just combined all the elements we're looking at:
- The insult - chronic stress (can also be acute as in trauma or infection)
- The result - depression
- The driver - loss of neurons in hippocampus and plasticity via dendrites, synapses, and "plumbing" of the brain
It's all right there.
mTOR is more involved with the "plumbing" part.
Like ketamine, these compounds stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR).
So like a giant Public works project, there's an injection of funds and activity to support nerve growth and repair.
Again, this mTOR pathway which piggybacks TrkB (BDNF) action may be the key.
When the researchers experimented by inhibiting mTOR, it also completely blocked the psychedelics' ability to promote neurite growth.
Just to take a step back...why would nature do all this with mushrooms?
The current theory for the hallucinogens is that it's a defense mechanisms against insects.
The psychedelic effects would be a warning to any potential feeders.
This occurs via the 5HT2 receptor (one of the serotonin receptors).
Of course, serotonin does many other things and the knock-on effect for us mammals is neurogenesis and increased brain plasticity.
Thank you insects!
That's the view from 30,000 feet up.
Let's turn to actual results on the ground.
Psilocybin and depression studies
This has probably garnered the most attention and interest.
We've looked at CBD and perimenopause depression in detail here.
It follows the same insult/repair mismatch we described above.
All the usual suspects are at the table.
- There can be ties to early viral exposure or trauma (really check out the CBD and neuroinflammation article - a fascinating new look at our immune role in all this)
- A loss of connectivity and brain mass in key areas
- Of course, SSRI are the go-to course of treatment despite the issues (see CBD versus SSRI for serotonin)
New studies are pointing to a general "dis-integration" of the brain with depression.
What about psilocybin and depression?
Let's go there.
A great deal of buzz started with a study after a single dose of psilocybin and its effect on the sense of well-being (for lack of a better word).
The results for these 36 participants who had never tried psychedelics:
At the 14-month follow-up, 58% and 67%, respectively, of volunteers rated the psilocybin-occasioned experience as being among the five most personally meaningful and among the five most spiritually significant experiences of their lives; 64% indicated that the experience increased well-being or life satisfaction; 58% met criteria for having had a 'complete' mystical experience.
That was 14 months later which speaks to the "transformative" effect.
Keep in mind that SSRI's take a few weeks to even start to work (assuming your part of the 30% that actually has low serotonin and gets a benefit) ...till the brain counteracts this outside interference by drawing down your baseline serotonin function).
That was a higher dose of 30 or 70 mg. But 14 months later??
Another researcher looked at a large group in terms of depressive symptoms and suicidality:
- Used psilocybin in past only
- Used psilocybin with other psychedelics
- Used other psychedelics (but not psilocybin)
- Never used any psychedelics
They then looked at odds of suicidal thinking, planning, or actions.
The odds of all of the outcomes were reduced in the psilocybin-only group compared to the no psychedelic use group.
There were other aspects positively affects (emotional distress, etc).
It's sad but psilocybin is usually relegated to the most extreme and last-ditch efforts due to its current Schedule 1 status.
But even there….
John Hopkin's study looked at depression/anxiety as a result of life-threatening cancer.
High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety.
Here's the fascinating piece:
At a 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety.
Both are generally transient with the latter being extremely addictive.
Another study looked at moderate dose levels (we'll cover dosage later) and found similar results:
The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 months.
There may be more at play than just the neurogenesis effect here as new studies are pointing to a "reset" of brain activity.
This speaks to synaptogenesis, or the growth of new pathways.
What does this structural effect have on depression?
The idea that depression stems from imbalanced brain chemistry remains popular, but recent studies have revealed evidence that depression manifests as structural changes in brain circuits or atrophy in parts of the brain.
There's that word "atrophy" again. To wither.
Specific areas are coming to light.
"One of the hallmarks of depression is that the neurites in the prefrontal cortex -- a key brain region that regulates emotion, mood, and anxiety -- those neurites tend to shrivel up," says Olson.
This also shows anxiety, PTSD, schizophrenia, and addiction.
There's a great personal run-through from a patient with stage 4 cancer and psilocybin here.
I dare you not be moved (and maybe a tad bit envious parodoxically).
Then, there's the treatment-resistance depression.
This is a very severe disease where none of the first (and even second) line treatments are working.
Again, relegated to the unwinnable.
So is it?
Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks.
They took fMRI scans of the brains before and after and found significant changes.
Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms.
CBF is short for cerebral blood flow and equates with activity in a given pathway.
Why does the amygdala decrease matter?
This is part of the anxiety circuit we covered in detail at our CBD benefits for anxiety.
It's in a constant cross-check with the prefrontal cortex (the area that shows reduced brain activity from above).
The imbalance between these two players is key to both anxiety and depression.
Here's where it gets interesting...the game behind the game.
Enter the Default Mode.
Psilocybin and Default Mode Reset
Think of this as a traffic pattern of brain activity.
You have different traffic patterns depending on whether you are focusing on a task or daydreaming.
The default mode is a pattern of activity they can actually see in scans.
It corresponds with daydreaming, zoning out, or thinking about the future/past.
Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment.
Let's decipher that a bit.
Basically, they found increased connectivity in this "resting state" of brain activity after treatment.
This is revolutionary.
It's like a "reset" button. First, a scrambling of the patterns and then a more cohesive one emerges.
It's one thing to boost serotonin (exercise, meditation, and social status will do that).
It's another thing to suddenly re-direct the brain's traffic in a primordial, system-level way.
It's like when your computer would freeze up and you had to reboot. (Goodness, I'm old now.).
This resting-state connectivity caused by psilocybin directly correlated with positive effects later:
Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC.
Literally resetting the connectivity between key brain areas we've mentioned above.
We can't put it better than they did:
A ‘reset’ therapeutic mechanism is proposed.
Okay...why does this matter?
New research is pointing to an inability to shift modes as needed (daydreaming to problem-solving).
This manifests itself as rumination or negative thoughts as emotional signals get "stuck" in this wandering mind mode. (see CBD and negative thoughts).
PTSD is the best example as the original trauma is "etched" into the default mode...which is why it can feel so vivid and "current".
Anxiety is obvious here but the mental exhaustion that comes with mitigating the imbalance is...depressing.
Brooding is a key attribute of depression.
In mentally healthy people, sad thoughts pass quite quickly but in people who suffer from depression they don't.
That's the default mode lingering in our processing.
Researchers go into further here:
Unfortunately, a different sequence plays out in depression. Emotional information from sgACC—presumably, conveying feelings of sadness, dejection, and anxiety—short circuits, with the DMN becoming a subject for rumination.
I'm sorry but how cool is this? That we know this? That we're starting to unpeel the union.
This speaks to why mindful meditation can have a positive effect on depression (by default, it forces us out of default mode).
And psilocybin causes a massive reshift of this stuck gear.
Goodness...this may be the most important thing you read in this whole article.
Of course, negative thoughts, worry, and rumination remind us of another mental illness...the most common today and one close to our heart.
Up next...depression's worrisome cousin.
Psilocybin and anxiety
We've covered this topic in-depth. You can access all the various articles.
There are some key similarities with depression, especially on the insulting side (chronic stress, trauma, infection, inflammation, etc).
The main pathway is GABA/Glutamate (our brake and gas pedal) as opposed to serotonin.
This is one reason why SSRI's are not as effective for anxiety as depression.
The whole default mode reset piece though is very relevant to anxiety.
You can read relevant article with in-depth information on relevant topics here:
- CBD versus SSRIs for Anxiety
- CBD and BDNF for anxiety
- CBD and GABA for anxiety
- CBD and serotonin for anxiety
- CBD and neurogenesis for anxiety
- CBD and negative thoughts or ruminations
That's the last one that is really intriguing with psilocybin.
Let's look at psilocybin research with anxiety first.
Of course, anxiety was a big piece of the John Hopkin's study on terminal cancer patients that really sparked the 2nd wave of legitimacy for psilocybin.
The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment.
Even more fascinating is research showing that the results persisted for up to 6 months following a single session:
Grob and colleagues showed that a low-moderate dose of psilocybin (14 mg/70 kg) decreased a measure of trait anxiety at 1 and 3 months and depressed mood at a 6-month follow-up.
Let's really break down the effects of anxiety.
We'll start with the HAM-A test, a well-recognized test for anxiety.
Here's the scoring:
Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0–56, where <17 indicates mild severity, 18–24 mild to moderate severity and 25–30 moderate to severe.
In the Psilocybin study, the participants started at about 25 (just over the moderate/severe line).
They tested these people at 1, 3, and 6 months.
The average numbers dropped to around 8 by 3 months and slightly lower by 6 months.
From 25 to 8. That's 3 fold!
This is a huge deal.
A study on common benzo (lorazepam - Ativan) showed a drop of 11.3 points from a baseline of 25.
Of course, without the nasty side effects like crushing addiction and withdrawal (see how I used CBD to wean off benzos).
It's harder to get straight HAM-A scoring on SSRI's since they are generally prescribed for depression (HAM-D test).
Benzo's generally show a stronger effect on HAM-A and psilocybin lapped them (25 to 8 versus 25 to 14).
Of course, the benzos will normalize which means that the effects lessens with use till eventually, your anxiety profile is even worse than when you started (see CBD versus benzos for anxiety).
Those initial studies really focus on teh 5HT2a changes from psilocybin.
Let's look at the default mode effect for anxiety.
This partially speaks to why anxiety and depression can go hand in hand.
Chronic anxiety can exhaust our brain's structure and function.
Pathological anxiety and chronic stress are associated with structural degeneration and impaired functioning of the hippocampus and the prefrontal cortex (PFC), which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia.
Remember how negative thoughts, worries, and doubts can get entangled with our default mode activity (daydreaming)?
A constant barrage of emotionally charged negativity that the brain can't actively manage (because it hiding in the background noise of default mode).
Here's maybe the most exciting piece of information that originally caught our attention (and led to the 1000's of words on this page).
Go through this slowly because it's critical.
First, a quick introduction to your amygdala.
The amygdala is part of the so-called reptilian brain...our oldest part we share with most animals.
It's the seat of emotional processing including very primal responses like fear, sadness, and anger.
We need those but what if they're too pronounced or not "neutralized" by our more evolved (newest addition) part of the brain, the prefrontal cortex.
So the amygdala is constantly sending out warning signals to be interpreted by the rational gatekeeper in the prefrontal cortex.
Is that rattle in the bush a tiger???
No, it's just a mouse. Stand down.
What happens when this cross-talk is lopsided?
Elevated activity of the amygdala in response to stimuli leads to the neurons strengthening negative signals and weakening the processing of positive ones. This mechanism plays an important role in the development of depression and anxiety disorders.
Watch what happens…
Even a moderate dose of psilocybin weakens the processing of negative stimuli by modifying amygdala activity in the limbic system as well as in other associated brain regions
Ding ding ding.
We have a winner. Drop mic.
Basically, psilocybin causes a long term (since effects go on after dosage as opposed to benzo or SSRI, etc) change in this communication.
It BLUNTS the effect of negative emotional signals!!!
They could see this right on fMRI scans.
Interestingly, for depressed people (low emotional response or tone), psilocybin INCREASED response to emotional faces (different from SSRI response).
The results in people with depression:
Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect on previous findings with SSRIs.
This really reminds of CBD where the effect depends on the state of the system.
Check out CBD and negative thoughts for more guidance on this "fixed" mental state.
In a study of treatment-resistant depression, researchers looked at all the surrounding aspects of these negative thoughts...essentially pessimism about the future.
Importantly, post-treatment, patients became significantly more accurate at predicting the occurrence of future life events.
That article does a good job of tying it all together and this statement neatly folds the edges:
Moreover, the key receptor associated with the action of psychedelics, the serotonin 2A receptor [5-HT2AR (Glennon et al., 1984), has its highest expression in DMN regions (Beliveau et al., 2017) – and 5-HT2AR binding has been reliably linked with trait pessimism.
- Serotonin 2a receptor is highly involved in the default mode processing
- It's also linked to negative thoughts (be it pessimistic or worried)
- Psilocybin normalized this activity
This weakening of negative emotions is pretty fascinating. Usually, everything gets blunted (hello SSRI's).
Speaking of getting stuck.
Psilocybin and PTSD
The ability to blunt negative thoughts and rewire brain activity may be most pressing with PTSD.
Let's look at psilocybin research specifically.
The real interest starts with a fascinating study on the fear response we mentioned above.
They took three groups of mice who were conditioned to fear a specific tone as it has been associated with the following shock.
This is a subconscious remembering and reaction to embedded fear from prior events.
- One group received low dose psilocybin
- One group received high dose psilocybin
- The third group received a salt solution
Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice.
Interestingly, the low dose group fared the best.
The same researchers measured neurogenesis and found the highest number of new neurons in the hippocampus as a result of this low dose treatment.
Remember, the brain can't "unlearn" or learn new tricks without neurogenesis.
Imagine a road or traffic being routed through a real bad town (the traumatic event marbleized in memory and brain architecture).
You need construction crews to build around it or to demolish the town and rebuild it! Huge implications for addiction.
Back to the other study of scary faces.
Here's the summary line from the study:
Psilocybin enhanced positive mood and attenuated recognition of negative facial expression.
Maybe more interesting was that the treatment with psilocybin was this:
Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component.
Let's break this down. It's really fascinating.
They used a game called go/no go which measures a person's action based on cues (positive, negative, neutral).
With psilocybin, participants were more likely to respond to the positive than the negative.
This speaks to optimism/pessimism bias which is very important.
Equally interesting, they blocked the serotonin pathway in one group and the effects went away.
What about the whole default mode issue and PTSD?
Disruption in the default mode network (DMN) has been implicated in numerous neuropsychiatric disorders, including posttraumatic stress disorder (PTSD).
The default mode is intimately tied to thinking about the future or re-engaging the past.
Even the traumatic past.
Not to get too far afoot but studies on psilocybin itself are showing that the default mode network may be the residence of the classical "ego" concept.
This is why with higher doses of psilocybin there are subjective reports of a "disintegration of self".
Perhaps trauma can disrupt or injure this mental map of our identity.
We found decreased DMN functional connectivity strength to be associated with increased PTSD symptom severity.
As we saw above, psilocybin appears to act as a "reset" button on the default mode.
It may be its greatest and most profound attribute.
Also, check out CBD and panic attacks as there are interesting studies there as well.
The anecdotal reports on psilocybin and PTSD from sufferers are nothing short of jaw-dropping but we look forward to clinical studies now that FDA is finally fast-tracking status.
Let's look at another promising area which is front-page news these days.
Psilocybin and addiction
A study just came out with pretty ridiculous results for heavy alcohol use:
Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0–24.7; F1,86 = 6.43; P = .01).
An 88% reduction! Interesting the 2nd control was an anti-histamine (part of the immune system) and it showed some positive effects.
Research is showing certain neural similarities between PTSD and addiction.
In fact, they usually travel together, unfortunately (co-morbid is the term).
Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry (Arnsten, 2009; Russo et al., 2009; Peters et al., 2010; Russo and Nestler, 2013) and have high comorbidity.
Before studies were ripped from the scene with schedule 1 status in the early '70s, there was actually some pretty interesting research for psilocybin and addiction.
For example, an initial study of people diagnosed with alcohol addiction:
Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin) but increased significantly following psilocybin administration.
Percentage of drinking days during weeks 5 through 12 decreased by 27.2%
The gains were largely kept at the 36-week marker which speaks to the structural change component.
Another pilot study on psilocybin and tobacco found similar results.
The key is to get to 6 months of not smoking.
The study looked at people with long term smoking habits who had been unsuccessful quitting before.
We're talking a minimum of 19 cigarettes a day and an average of 31 years of use.
Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up.
This is way above what's found with other cessation options. Nicotine is notoriously depressing in terms of success in quitting.
Let's bring up the gorilla in the room...opioid addiction (soon to be followed by benzo addiction).
What about studies there?
Researchers are just starting to look at psilocybin and opioid addiction.
Here's what we do know.
Use of psychedelics like psilocybin is associated with a reduced risk of opioid addiction later on:
Among respondents with a history of illicit opioid use, psychedelic drug use is associated with 27% reduced risk of past-year opioid dependence (weighted risk ratio = 0.73 (0.60–0.89) p = 0.002) and 40% reduced risk of past-year opioid abuse.
The only other drug which reduced risk for later opioid addiction was cannabis.
All other drugs are associated with a higher risk of later opioid abuse.
This is how sad our current situation is in terms of FDA oversight.
We have to go back to a 1973 study on psychedelics for heroin addiction.
Comparative verified abstinence data throughout the first posttreatment year were significantly in favor of the treatment group.
Really? We're handing out needles and giving methadone, a drug with a ridiculously long half-life (which makes it almost impossible to ever get over the withdrawal) and the above study is never followed up on?
There are studies underway on the different doses of psilocybin with opioid addiction and we expect more of the same (breathtaking results) as we've seen with nicotine and alcohol.
After all, nicotine is one of the most intractable addictions out there.
California actually is in stage 2 of trials for psilocybin for addiction now.
Current research is mainly pointing to 5HT2a receptors in terms of addiction.
And the default network is also coming into focus with addiction.
Negative thoughts can come in the flavor of cravings.
A steady barrage of them. As researchers put it:
During illnesses like depression or addiction, the default mode network in the brain becomes over-engaged with negative thoughts or cravings.
The net effect:
Psilocybin decreases activity in the parts of the brain that are overactive in depression, addiction, and ingrained behaviors.
Psilocybin appears to "deactivate" cravings.
Not to be overly conspiratorial but when the studies in the '60s and '70s saw such profound effects for just alcohol and nicotine alone…
Then it's suddenly slammed with Schedule 1 status...who benefits from that?
Definitely not the addicts.
Remember...for Schedule 1 status, it must have negatives and no medical use.
As a comparison, cocaine and methamphetamine enjoy the less restrictive Schedule 2 classification. Go figure.
The vast majority of cigarettes and alcohol are probably consumed by a smaller percentage of the population that chronically uses.
This is especially true for cigarettes.
Sure would hate to see half your market disappear from a mushroom.
If we were jaded over here.
The book Never Enough is an amazing look at how the brain responds to drugs. Very fascinating.
Of course, CBD and addiction.
Speaking of "ingrained behaviors" and inflexibility.
Psilocybin and OCD
We covered OCD's mechanism in more detail at our CBD and OCD.
Let's look at psilocybin.
There are two studies which drew attention to psilocybin for OCD although they are small scale (because psilocybin was made illegal).
First, a study on a man with treatment-resistant (benzo, SSRI's, etc) intense OCD.
We're talking the very severe end of the spectrum with intrusive thoughts 100's of times a day.
He determined that every time he ingested approximately 2 g of psilocybin mushrooms, his OCD symptoms would be reduced for the following 3 weeks.
No adverse effects were reported.
Another study looked to expand on this with 9 patients with an established OCD diagnosis.
88.9% of patients showed a greater than or equal to 25% decrease in symptoms per the Yale-Brown Obsessive-Compulsive Scale (YBOCS) at the 24-hour mark, and 66.7% maintained a greater than or equal to 50% decrease in YBOCS scores at 24 hours post 1 of their testing doses.
Two important pieces from this.
Reduction of symptoms was up to 100% in at least one participant
The dose amount did not matter (4 different doses were used).
We look forward to more expanded studies since as one of the studies pointed out, our current approach will literally look at brain surgery before psilocybin for treatment-resistant OCD.
Let's look at two areas of significant brain loss (the opposite of neurogenesis).
Psilocybin and Alzheimer's or Dementia
Check out CBD for dementia and Alzheimer's here to learn more about the mechanism.
And for goodness sake, investigate choline supplementation and the importance of estradiol (for my perimenopausal ladies), our main estrogen. Testosterone does the same thing via conversion to Estrogen in the brain.
Newer research is really pointing at choline (which feeds acetylcholine) as being a key player.
What about psilocybin?
We know there's a powerful neurogenesis effect from psilocybin. That's literally the opposite direction what the brain loss associated with dementia.
We don't have much research on this, however.
There is some research on the depression and anxiety that accompanies dementia but not on the cognitive side.
There are studies on psilocybin's effect on cognitive function or "thinking" for lack of a better word.
We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected.
John Hopkins is taking the lead with a new $17 million dollar facility to study psychedelics for Alzheimer's and Depression.
More on that endeavor here:
We're starting to get some tantalizing results.
For example, one study found that ayahuasca (a sister psychedelic to psilocybin) affected a gene that's overexpressed in Alzheimer's:
Moreover, the observation that harmine inhibits DYRK1A in neural cells allows us to speculate about future studies to test its potential therapeutic role over cognitive deficits observed in Down syndrome and neurodegenerative diseases.
It did this by….neurogenesis!
Promoting the growth of neural cells that blocked DYRK1A to be exact.
Let's reverse this a bit until the research comes out.
Is there a tie between neurogenesis and dementia or Alzheimer's (AD)?
Analysis of AD brains at various stages of the disease revealed a progressive decline in neurogenesis as the disease advanced.
Interestingly, the slowdown in this process shows before the symptoms:
Let's drill down further along the pathway most affected by psilocybin.
BDNF...our brain's fertilizer.
Each standard-deviation increment in BDNF was associated with a 33 percent lower risk for developing Alzheimer’s or another dementia.
Put a different way, the more BDNF activity, the lower the risk of dementia.
This all speaks to the repair side of things. The insult side may very well lie in the evergrowing autoimmune category (with genes and environment thrown in of course).
Check out CBD and dementia here to look at that.
Next, let's look at another mental health issue intimately tied to psychedelics on two fronts.
Psilocybin and schizophrenia
First, we need to address if psilocybin use increases the risk of schizophrenia since that's floated around our shared mind space for decades.
After all, the psychedelic "trip" (heavier doses) is used to study symptoms of schizophrenia.
A large study looked at prior use of psychedelics including psilocybin and found no increased risk for any mental health issues including schizophrenia:
The researchers found that individuals in this group were not at increased risk of developing 11 indicators of mental health problems such as schizophrenia, psychosis, depression, anxiety disorders, and suicide attempts.
In fact, they found a reduction in certain mental health issues (as should be apparent from the 7000+ words above).
They made sure to show a distinction with MDMA and PCP which can be habit-forming and/or have serious health concerns.
More importantly, they don't act via the serotonin system we described above.
Another large study mirrored this same result. (first was Norwegian and second was John Hopkins).
What about HPPD (hallucinogen persisting perception disorder)?
This is where a trip causes flashbacks and is estimated at about 1 in 50,000 regular users.
Visual snow is such an example.
First, HPPD exists outside of psychedelic use and LSD is 40-100 times more powerful than psilocybin.
More importantly...HPPD is primarily tied to LSD (when it can be definitively tied at all).
There's one documented case with psilocybin.
New research is looking at too much serotonin activity at the 5ht2 and GABA pathways:
The available evidence suggests that HPPD symptoms may be a result of a misbalance of inhibitory-excitatory activity in low-level visual processing and GABA-releasing inhibitory interneurons may be involved.
One note…CBD is gaining popularity as a way to normalize the activity of HPPD and snow vision although it's poorly studied.
This is about normalizing the serotonin system (see CBD and serotonin here) and GABA/Glutamate (key to its initial discovery with seizures).
Of course, our goal is microdosing and avoiding the level of a trip altogether.
After all, we're after the potential health benefits and not the recreational side.
More along the lines of self-hacking than a crazy Friday night.
There's an impressive review of the relative risks here:
He's the same author behind How to Change Your Brain.
What about the other side...can psilocybin help with schizophrenia?
We don't have good research on this, unfortunately.
If you've noticed, many of the issues listed above deal with entrenched brain pathways...where we're stuck or rigid.
This can be:
- Depression (negative thoughts and rumination)
- Anxiety (fears and worries)
- OCD - reoccurring and habitual thoughts
Psilocybin at the microdosing level is a boost to the system...a gentle shake of the apple cart when it's not budging the way it should.
Schizophrenia and Bipolar (the mania side) already have a wobbly apple cart.
Definitely, "tripping" may be suspect in this case.
As for microdosing, we don't have good research yet. Even good anecdotes (one example here).
Schizophrenia is such a multi-faceted disease (see the guide on CBD and schizophrenia).
Until research comes out, let's investigate possible pathways of interest.
Neurogenesis and Schizophrenia
There are known elements of disease pointing to a loss of brain activity/matter in certain areas.
Several recent research findings indicate that schizophrenia (SCZ) may begin with abnormal neurogenesis from embryonic Neural Stem Cells (NSCs) and that this process may be particularly vulnerable to a number of genetic and/or environmental disturbances of early brain development.
People...we've spent the better part of this article discussing "neural stem cells".
That's the neurogenesis piece!
The process of neurogenesis involves a proliferation of neural stem/progenitor cells and their differentiation into mature neurons, followed by integration into hippocampal circuitry.
The very thing that psilocybin jumpstarts in the brain.
And our good friend BDNF...the heavy lifter in this process?
Neurodevelopmental models suggest reduced concentrations of BDNF modify synaptic efficiency and connectivity, which alters neurotransmission and results in signs and symptoms consistent with schizophrenia.
This is tantalizing information upon which to proceed.
Either way, CBD would be a powerful adjunct or safety measure with any use due to its powerful effects on psychosis (see CBD versus THC as an example).
Pregnenolone is also used by the brain to offset the psychosis effects of THC (see our review on pregnenolone).
Let's look at a different area.
Psilocybin and brain damage
Can Psilocybin help following a brain injury? After all, neurogenesis and BDNF carry out the heavy lifting in repair.
Traumatic brain injury is a good proxy for this study.
Of course, BDNF comes into play:
Current therapeutic strategies primarily target secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has a significant effect on both aspects, promoting neuronal survival, synaptic plasticity, and neurogenesis.
This is true following stroke as well (see magnesium connection below in safety).
BDNF has emerged as a key facilitator of neuroplasticity to improve motor learning and rehabilitation after stroke.
This is why exercise and mindful meditation are so important.
Just a reminder:
In fact, the plasticity-promoting properties of psychedelics and entactogens rivaled that of BDNF
Let's look at some more practical questions finally.
Is Psilocybin safe
We're going to focus on microdosing….dosages below the trip level.
Most of the research out there is for tripping levels which are higher.
An extensive study of psilocybin use was carried out (beyond the study above on mental health risk from 100's of 1000's of participants).
Short- and long-term safety was evaluated, and there was no indication of increased drug abuse, persisting perception disorders, prolonged psychosis, or other long-term deficits in functioning
Again...the dosage impact:
The number of adverse reactions from psilocybin was few in number, resolved quickly, and was mostly associated with the highest doses of psilocybin.
Also with higher doses:
Psilocybin has been found to have mild, pleasurable and non-threatening effects in 110 healthy individuals in a pooled analysis of eight double-blind placebo-controlled experimental studies.
As for the original John Hopkins study on cancer patients:
There were no clinically significant adverse events with psilocybin.
Here's the fascinating piece.
Alcohol is a multi-billion dollar industry. Nicotine is not far behind and cannabis is quickly catching up.
There was a large study that looked at the risk and dangers of many drugs and psilocybin (magic mushrooms) came out as the safest!
As for safety, studies show it frequently falls at the end of the scales with the least harm to users and society, say the researchers. Psilocybin also is lowest in the potential for lethal overdose as there is no known overdose level.
That's from John Hopkins medical.
The chart of the drugs are here:
One note...magnesium glycinate might be a powerful ally with any psilocybin use to help mitigate issues with higher dosages.
After all, there's construction going on and mag is a powerful support system. A methylated B complex is also advisable.
I personally take 3 magnesiums a day for migraine prevention and stress response anyway!
Both are listed here for supplements with psilocybin:
Again...this is all for "tripping" doses. We're more interested in microdosing which avoids the few pitfalls out there.
Let's look at that now.
The vanguards in Silicon Valley really pushed this where any edge in that extremely competitive stew is fair game.
Way up top, one study looked at the effect of four different doses on OCD and found no difference in their benefit.
The study above on fear processing actually showed better effects from low dose.
The powerful anxiety and depression study (cancer patients) was based on a low dose amount.
Neurogenesis was shown to increase with a low dose as well.
Microdosing involves taking roughly 1/10th of the amount of a trip dose. That's about .33 grams of mushrooms. .1 to .4 grams is the standard range.
Researchers in the Nederlands looked to test the actual effects of microdosing.
“Performance was significantly higher” on tests of convergent and divergent thinking, said psychologist Bernhard Hommel of Leiden University in the Netherlands, who led the study.
We're finally getting new studies (we're talking 2019!!!...the latter half of 2019!)
Such as this one:
Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = - 0.92) and negative emotionality (p = 0.009, r = - 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls.
Microdosing, on the other hand, is not experientially intense and has not been reported to result in negative health reactions in anyone.
That link has some good feedback on how microdosers go about this activity (how often, how much, for how long, etc).
It's one of the more pragmatic and helpful guides we've seen online for practical questions on microdosing.
More guidance is here.
Again, we understand the research on higher levels but our personal goal is to get the benefits (anxiety, depression, neurogenesis, etc) and minimize any risks (however small).
Some practical steps for when it's available:
- get an .1 spoon on amazon (about the size of a bb)
- .1-.5 grams (1-5 scoops of the above spoon) every 3rd day
- magnesium glycinate, CBD isolate, B complex with dose
Test .1g first. You may "feel" .5 initially.
What about legality?
Is Psilocybin legal
Right now, mushrooms are only decrimimilized in Denver and Oakland for personal use. SF just passed a rule to decrimilize personal use as well!
Chicago is considering legalization as well.
Make sure to check out the status where you live.
At the Federal level, it's still a schedule 1 drug (which John Hopkins is vehemently fighting).
We expect it will go the way of cannabis with a 5-7 year trailing period.
Interestingly, the spores of magic mushrooms are legal (except for a few states).
A company in Oregon is looking at a nasal delivery device and again, venture capitalists in Silicon Valley are aggressively preparing.
The data is just too compelling for it to remain in this limbo status.
Unless of course, Big Pharma, Alcohol and Tobacco have their way with our legislators.
The reason we're such big fans of CBD is that it operates on the same pathways (calming insults and boosting repair) if you're not quite ready for psilocybin.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.