We are Dr. Josh Woolley, and Ryan Moss - Experts in psychedelic research and drug development. To mark World Mental Health Day on Oct 10th, we want to share our knowledge around magic mushrooms, and other psychedelic plant/fungi for the treatment ...

Can you provide any insight or information into a psychoactive truffle known as a philosopher stone?

I encountered it once about 15 years ago, and have not yet met another person familiar with them. They kind of look like pebbles, dark greenish and dark brownish in color, ranged in size from half a pea, to a clove of garlic, and had the consistency of a walnut. They had a bitter taste and an almost immediate effect (10 mins) which lasted at least 1/3 of a day.

Ryan: "Truffles" are actually very similar to your regular magic mushroom fruiting bodies, in that they derive from the same genus Psilocybe. The difference is that the truffle (in this case Psilocybe tampanensis) grows underground and forms a sclerotia, which contains a not-insignificant amount of both psilocybin and psilocin.

The question is whether this truffle actually creates a different experience than ingesting regular magic mushrooms. Chemically they are quite similiar, but may have minor differences in their chemical fingerprints. This is something we are growing and researching in my Lab. I hope to be able to provide you definite answers to this question and more in the coming months!

Truffles you say? Maybe your guys should reach out to Todd Sharpio over at Red Light Holland. If anyone knows truffles it’s these guys….they just finished growing 1 million grams. Personally I haven’t tried truffles, only because I lack access. I regularly take psilocybin from fruiting bodies I source on the gray market or grow myself.

It's important to note that taking the raw substance (either truffles or fruiting bodies) can vary widely in psilocybin content. Regardless of the same strain, batch etc. We have seen in lab trials as much as a 4X difference mushroom to mushroom, truffle to truffle.

The goal in this field is to create standardized dosing of the naturally occuring psychedelic.

Happy exploring!

After a recent shrooms trip, which went well for me, I experienced a significant headache which continued for the rest of the day and into the next. Looking into it, I found that this is a common side effect for others, as well. I also learned that the inventor of LSD had actually been trying to find a cure for migraine headaches, but both shrooms and LSD actually commonly cause headaches. Since the brain itself obviously doesn't have pain sensors, can you elaborate on why psychedelics might frequently induce headaches as a side effect?

Jake: There are several hypotheses for why people can experience headaches during the end of psychedelic experiences or the next day. It is a fairly common phenomena even when administered in clinical settings. The short answer is that we don’t know for sure why it happens. Some think it could be related to the acute effects of psychedelics on blood pressure, vasoconstriction, or other direct central mechanisms. Others have noted that any type of experience that is highly emotional and exhausting can be followed by headaches. Lastly, it should be noted that people can become fairly disoriented during psychedelic states and may not be drinking enough water! Ironically, psilocybin is also being examined as a treatment for migraines.

Do you think it’s likely that psychedelic compounds can be changed such that they are more suitable to being taken as an everyday pill for the treatment of depression like today’s SSRI’s are?

Or do you think the treatment modality will be completely different (e.g. coming in once per quarter for a series of guided sessions)?

Jake: Some individuals take “microdoses” (i.e. doses so small that they are non-hallucinogenic) of psychedelics several times a week to manage depression, enhance cognition, and improve overall wellbeing, but there has been very little rigorous research testing this so far. Most of the studies have been surveys of recreational microdosers rather than controlled clinical trials. The most rigorous study to date evaluating the potential benefits of microdosing found that the benefits could mostly be attributed to positive expectations about microdosing (i.e. it was a placebo effect; https://elifesciences.org/articles/62878). More studies are needed to test if the benefits are solely attributable to “hype” or if there is an actual direct treatment effect. Part of the issue is that it is still unclear what the exact mechanisms are that make psychedelics beneficial. It is possible that there is a direct pharmacological effect, in which case microdosing may be useful, but others argue that it is the transcendent experience induced by psychedelics that leads to healing. If this is the case, a limited number of high dose sessions may be what it is needed.

Some researchers are currently trying to engineer psychedelics that do not have hallucinogenic effects so that they can be taken more regularly. The Olson Lab at UC Davis has published some work in animal models showing that a non-hallucinogenic psychedelic analog has antidepressive effects, but there are many challenges to translating animal research to human clinical use.

Have you found any major differences in how humans react to naturally occurring psychedelic molecules vs. synthetically developed molecules? What is your take on so many psychedelics companies now entering the market and trying to patent every little thing, will that encourage mental health treatment innovations or limit the broader societal benefits?

Ryan: I think it’s important to make the distinction that chemically, synthetic versions of molecules that occur in nature ARE naturally occurring molecules. But I think for me personally, an interesting question is whether there is a difference between molecules derived from a natural source vs. synthetic versions of the same molecules. And the answer is: we don’t know, yet. In conjunction with Dr. Woolley and his team at UCSF, Filament Health is engaged in starting our first phase I and phase II clinical trials using our completely naturally derived mushrooms extracts. From these trials, we hope to be able to gain some resolution on this question, as well as some clarity on some of the other molecules that are co-biosynthesized along with the major psychedelics like psilocybin.

You’re right there are a lot of new psychedelic companies entering the market, and I think that it is a side-effect of how truly-promising much of the new research is with these compounds. With any new industry there is the risk of shady players entering the game, and I think that this industry isn’t any different. It’s important to remember that there are real, genuine companies in this space that are in it for the right reasons, and I think that they will ultimately rise above a lot of the “smoke and mirrors” type businesses.

To add to this great question, may I ask if any trials or research is being conducted to explore how the complex arrangement of chemicals may be useful vs isolating certain ones such is psilocybin?

Stay tuned, This is exactly what my team and I are doing on a daily basis. But also note that finding a definitive answer, free of bias is a long road and typically involves laborious clinical trials.

Aside from anecdote, is there any evidence of mushrooms being contraindicated with any other medications?

Josh and Jake: This is a complex issue and we lack good clinical trial data in this space. One recent study collated reports from Reddit and found high numbers of people reported having adverse outcomes including seizures after combining psychedelics in general (not specifically mushrooms) with lithium so I would not combine those two (https://psyarxiv.com/r726d/). There is also a theoretical risk of developing something called serotonin syndrome when combining mushrooms with SSRI’s but there is not good data to tell us whether this happens or not (https://link.springer.com/article/10.1007/s00213-021-05876-x). Finally, there are a fair number of reports of taking SSRI’s decreasing the subjective intensity of hallucinogenic mushrooms. Antipsychotics likely quench the psychedelic experience. There are also concerns about medications that cause high blood pressure because psilocybin can do this as well. Finally, there just have been so few clinical trials and most research participants are not allowed to be on any other psychotropic meds so we don’t have good data on any of these potential interactions. I would be be very cautious in combining psychedelic mushrooms with psychotropics medications.

How has this space changed during the course of your career. Where do you see it going in the next 5? Thanks for doing this!

Josh: Well, my research career has been about 8 years. When I started, it was a fringe idea in biomedical research and seemed pretty farfetched. One of my mentors strongly encouraged me not to do it lest I become “that guy”. Now, however, psychedelic research is blowing up and more mainstream actors are getting involved. It is an exciting time.

Another way to think about it is that when I started, the only way to obtain funding to do psychedelic research was from open-minded philanthropists. More recently, nonprofit and for profit pharmaceutical companies have gotten into the space and have been able to raise investments to support critical clinical trials to move the field forward. In the last 2 weeks, the US government, through the NIH, has funded their first clinical trial of psilocybin I think ever, which is a big deal. So this shows the research becoming more mainstream. However, we still mostly depend on philanthropic support.

Jake: In the next five years, we anticipate the field to continue growing substantially. Psychedelics are now a multibillion dollar industry in healthcare and the federal government is increasingly opening up to the research. The National Institute on Drug Abuse (NIDA) recently granted the first federal grant to study psychedelics since the 1970s (funding for the research to date has come largely from private donors). Federal approval for MDMA-assisted psychotherapy for PTSD is targeted in the US and Canada within the next few years as the Multidisciplinary Association for Psychedelic Studies is currently completing Phase III trials.

Is there any evidence of psychedelics helping PTSD or long term depression? So many people with these disorders feel so hopeless.

Josh and Jake: Regarding PTSD, yes! Although there has not been as much evidence as there is for MDMA as a treatment for PTSD (see the trials sponsored by MAPS). With classic psychedelics, there have not been any trials specifically focused on PTSD. Our paper though, published in 2020 (https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30282-0/fulltext) included people with high PTSD symptoms and they benefited from the treatment. There have also been some open-label studies using 5-MeO-DMT (another psychedelic tryptamine found in several plants and certain desert toads) and ibogaine to treat PTSD in combat veterans (N=65) (Davis et al. 2020) with positive effects. A survey study of people using ayahuasca found that 21% reported having PTSD and of those, 79% reported symptom improvement (18% no change, 3% worsening) (Davis et al. 2019). Similarly, a survey of people using mescaline found improvements in PTSD symptoms (Agin-Liebes et al. 2021). At this point, I think the data is highly suggestive of positive effects in PTSD. However, more trials are needed. We are very interested in doing these studies and there are some companies also interested in this space.

In regards to long term depression, there is promising preliminary evidence that psychedelic-assisted psychotherapy can have beneficials effects. In the initial psilocybin/depression studies conducted by Robin Carhart-Harris and his colleagues at Imperial College London, the patients had depression on average for almost 20 years. These patients would be considered “treatment-resistant”. Their study found that the patients’ symptoms improved substantially after the treatment, and although depression levels rebounded somewhat over time, they remained below baseline levels.

A recent systematic review found that 8/9 studies examining changes in depression after psychedelic-assisted therapy found reductions (Aday et al. 2020: https://www.sciencedirect.com/science/article/abs/pii/S0149763419310413). In follow-up qualitative interviews from one study (Watts et al. 2017), participants reported post-treatment shifts from avoiding traumatic memories and painful emotions to confronting and accepting them, increased understanding and compassion for past abusers, access to a fuller range of autobiographical material, and a sense of reconnection with self, others, and the world.

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Jake: To some degree, they already are being legalized! Oregon voted to legalize psilocybin therapy in 2020 and the state is currently working to set up a system for psilocybin to be administered in controlled settings. This does not mean that psilocybin is completely legalized there or that people will be able to buy mushrooms in a way akin to cannabis, but that it will be able to be administered in a regulated context. The exact parameters of who will be able to administer psilocybin are still being negotiated. In about a dozen other cities in the US, naturally-occuring psychedelics (e.g. mushrooms, ayahuasca, peyote) have been decriminalized and there has been an increasing number of prominent politicians (e.g. Alexandria Ocasio-Cortez, Andrew Yang) coming out in favor of increasing research into psychedelics. Therefore, it seems there is rapidly growing momentum for regulatory changes, particularly in the US and Canada.

What do you think is the best treatment program for ptsd/ cptsd? My cptsd is very treatment resistant. I have cptsd, adhd and auditory processing disorder.

I've been coming bsodering saving for psilocybin treatment in the Netherlands

Josh: I assume your question was what is the best psychedelic treatment for cPTSD? I can’t really answer that because there have been no studies of psychedelics for cPTSD so we are not really sure. See our answer above about psychedelics for PTSD though. There is promising suggestive data for psychedelics treating regular PTSD but there is still a lot of work to do. In our 2020 paper, we also included several people who likely would have met criteria for borderline personality disorder. They tolerated the treatment well and benefited just like everyone else. Also, in our larger sample, we saw evidence of attachment anxiety going down after the psilocybin treatment. Obviously, borderline personality disorder and PTSD are distinct entities from cPTSD.

Why is the psychedelic mushroom strain “Penis Envy” called Penis Envy?

This variety of Psilocybe cubensis is particularily phallic, and not in a small way.

We grow this in the lab, very potent, slow grower, exceptional.

Also, very risky googling that strain on image search!

Hi! Can you explain the neuroscience behind the mechanisms of action of psilocybin and LSD? It seems the research is all over the place

Jake: You are correct; we are still just beginning to understand the neural mechanisms behind the effects of psychedelics. To begin, we know that the classic psychedelics (e.g. LSD, psilocybin) achieve their effects primarily through activating serotonin 5-HT2A receptors. These receptors are widely distributed across the cerebral cortex, explaining the wide-ranging effects psychedelics can have on cognition. Activation of these receptors by psychedelics consistently leads to decreased within network connectivity and increased between network connectivity. In other words, brain regions that are typically synchronized and communicating with each other are less synchronized and start to have increased connection with new regions of the brain. This may in-part underlie why people are able to think in new ways and achieve new insights under psychedelics. It can also explain the synesthesia that is commonly reported as audio and visual areas of the brain become more integrated. Others have emphasized that decreases in default mode network (DMN) activity during psychedelic states could underlie things like ego dissolution or a loss of sense of self. However, this notion has begun to be challenged in recent years as many substances can induce decreased DMN activity without having the same effects of psychedelics. In other words, changes in DMN activity may be a general marker of altered states of consciousness rather than being something “special” with psychedelics.

I'd love to learn more about how psilocybin and LSD are so effective at treating cluster headaches. What changes or happens in our brains to stop the clusters? How does this change result in remission for sometimes several years just from one treatment?

Josh and Jake: We would love to know as well! No one knows at this point. Some hypotheses direct effects on constriction of the blood vessels, neuroplasticity effects in the brain, and others.

Can you share more about your back pain trial? Why are psychedelics potentially helpful for managing pain? Do we know how they compare or are complementary to medicines like gabapentin? Have they been found to relieve acute and chronic pain?

I imagine back pain carries a huge economic and social toll. Can side effects of using pain management psychedelics ever be curbed for settings like work and home? Thanks.

Josh: Great question! We think of it two ways: First, there has been some evidence that psychedelics can be analgesics (they can directly decrease pain intensity). This hasn’t been well studied though. If it is true, however, we hope to see this “direct” effect on pain in our trial. Second, there is a fair amount of evidence that psychedelics can help people become “unstuck” and be able to change longstanding patterns of thought and behavior (e.g., depressogenic thought patterns, addictions like smoking etc…). The end of life studies, for example, suggest that psilocybin therapy can help people change their relationship to their impending death (i.e., the cancer wasn’t cured but people had more fulfilling lives in the time they had left). So, even if psilocybin does not decrease pain intensity in the long term, we hypothesize that psilocybin therapy could help people change their relationship to their pain and live more fulfilling and satisfying lives even if the pain intensity does not substantially change.

No idea about how they compare to traditional treatments as we don’t know much about how well they work. Hopefully our study will provide this kind of information!

Do you guys encounter patients experiencing "bad trips" and if so, how do you deal with it? I personally just put on "estimated prophet" and smoke a cigarette - that works every time.

Josh: Yes, participants in our studies sometimes have what we call “challenging experiences” during psychedelic dosing which can include intense anxiety, feeling like you are going to die or go insane etc… However, these experiences have always been manageable by the therapists with grounding, tolerance, and reassurance. No medications have needed to be used in our studies or almost all of the modern studies. Furthermore, the presence of challenging experiences is not related to clinical improvement or people recommending the treatment to other people, i.e. people still get better and still say the treatment was helpful and that they would recommend participating to a friend.

Hi folks, big fan of the work all researchers are doing in this space as I feel it addresses a big need in our current offerings for mental health.

My question is, how are you controlling the dosage in the clinical trials with naturally derived psilocybin? Does this mean you are grinding up mushrooms? Do you think it is likely we will see multiple variations of synthetic variations of psilocybin in the future being developed by industry?

Ryan:

Great question! this drives at the heart of botanical drugs.

At Filament Health, we are growing the mushrooms, grinding, and then extracting them. We are very careful that our process keeps all related psychoactive components in their original ratios. We then purify and standardize the dosage to the specific clinical dose. This is done in a capsule or tablet.

Because these are going into FDA clinical trials, the consistency, safety, and controls required to manufacture specific doses is very controlled.

I think we will start to see quite a lot of analogues of psilocybin and other compounds coming into the mainstream, however, many of these compounds are New Chemical Entities and will go the same pathway as any new drug candidate. It's important to remember that Psilocybin itself (as mushrooms) has been consumed for thousands of years!

I have been to several mental health professionals and tried medication over the last 15 years, but I've run out of the more main stream options to treat my depression. Are there professionals who are currently treating the public with psychedelics or is it's use limited to studies?

When I brought it up to my previous therapist, they were sceptical and didn't know anyone employing this method.

Josh: Depends on the country. In the US, I do not know of any above ground people treating patients with psychedelics. There are treatment centers that provide ketamine assisted psychotherapy (KAP). Whether ketamine is a psychedelic is up for debate and whether KAP is any more effective than regular ketamine treatment is also not known. Otherwise, yes, the only way to get psychedelic therapy legally at this point in the US is to participate in a clinical trial.

How seriously do these substances treat mental illnesses as compared to SSRIs, etc? Can somebody with depression actually transform into a different person and change their life permanently with the influence of psychedelics?

Josh: If you are asking if psychedelic treatments can effectively treat mental illnesses, then yes. The studies that have been conducted do suggest they can be an effective rapid-acting treatment for multiple disorders including depression and substance use disorders. I would say that the literature is not definitive but is highly suggestive. Also, there are anecdotes of people transforming their life after psychedelic treatment and multiple studies have shown that personality traits like openness to new experience can dramatically change after a psychedelic experience. Whether these changes are permanent, like forever, is not really known although the studies have followed people out to a year in some cases with sustained improvements.

Thanks for doing this, guys. With the inherent dangers, and indeed misleading information out there, can you provide some proven resources on cultivating and more importantly identification of the psilocybin mushrooms one can consume safely?

Ryan: The best place for the amateur cultivator (in my opinion) is r/shroomers. I think it is still very important to note that when consuming the fresh/dried/ground mushrooms from a harvest, it is impossible to give yourself a known dose of psilocybin. Some of these individual mushrooms (from the same harvest) can vary upwards of 4X! The only solution to this as a natural product chemist is to standardize the dose through extraction and stabilization.

What dosing forms are we likely to see with natural products like psilocybin?

Ryan: Psilocybin is orally bioavailable and because of this, the most studied dosage form is oral. However, there are some companies looking at sublingual for by-passing first-pass metabolism, transdermal for sustained release, and in some cases even I.V. administration where instant effects are required.

Could there be a genetic dependence on fungi especially psych reactive fungi?

Consider historical consumption for early European populations, and having a little fungus with dinner.

Quite a few interesting theories out there for this. I think the current answer is: nobody knows!

Do you guys mainly use cubensis? I ask because I’m kind of curious if theres ever been any lab quality research into using a comparable dosage of something like panaelous cyanescens. I’m wondering specially about micro dosing, and whether the increased potency would have similar or greater antidepressant effects, as it seems as if less is more when it comes to shrooms, in my experience at least.

We do mainly use cubensis! However, we are currently growing around 70 different strains crossing multiple differens species and genera of psilocybin containing mushrooms. I am happy to say that Panaelous cyanescens is one of them! We are especially interested in exactly as you describe, therapeutic effect and efficacy of different strains and molecules! Stay Tuned!

Do you think Mind Medicine (MNMD) is a good investment long term?

Sorry, we are not financial advisors!

I have acquired an allergy to fungus. Is there a non-fungal psilocybin? Or do I need to look elsewhere for psychedelic relief?

Many of the clinical trials currently underway are using synthetic psilocybin!

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Josh: It is hard to tell from your post but some of the things you mention are concerning so I think you should speak to a mental health professional. Here is a link to a national helpline if you are in the US: https://www.samhsa.gov/find-help/national-helpline