I’m George Greer, medical director of the Heffter Institute that researches psilocybin. AMA!

I'm interested to know on which ways it will improve symptoms of depression and anxiety - after all these conditions are multifaceted, and whilst they may help some symptoms do they worsen others at all?

It is too early to know the ways it will improve these symptoms. We know it helps those symptoms in cancer patients, but they are in a different situation from people without cancer. Some people do feel more anxious during psilocybin treatment, but with professional support they are able to get through this anxiety.

What symptoms though? Does it help reduce intrusive thoughts/concrete thinking? Or does it improve sleep and diet? Does it improve energy and motivation? Depression is so multifaceted - I'm so fascinated in these new treatments but I really want to know HOW they help depression in patients with cancer.

In the Johns Hopkins study, the two primary therapeutic outcome measures were the widely used clinician-rated measures of depression and anxiety.

In the Johns Hopkins study, there were 15 secondary measures focused on psychiatric symptoms, moods, and attitudes, including self-rated measures of overall quality of life and meaningful existence during life-threatening illness, anxiety about death, positive attitudes about death, life meaningfulness, and understanding of self, others, and life in general. These scales and measures were developed by many other psychiatrists and clinicians and applied in this new research.

NYU's study also focused on anxiety and depression symptoms related to cancer and death, including cancer-related demoralization (e.g. loss of meaning/hope/purpose, desire for hastened death). These studies did not specifically measure impact on sleep, diet, or energy.

If you could choose how the laws that governed psilocybin where changed, what would you do and how would you incorporate it into the medical world and society?

Heffter was not created to advocate for changes to federal drug policy but rather to explore unanswered scientific questions and to help determine how medicines like psilocybin can alleviate suffering among patients who are not benefitting from available treatments.

Heffter scientists believe psilocybin research has the potential to improve the lives of millions of people, and that potential is best achieved when psilocybin is administered by a doctor with special training and used in a therapeutic setting.

What do you call a therapeutic setting? Is it inspired by the traditional set-up? Is there music? Songs? Do the doctor speak with the psilocybin user?

In all of the recent psilocybin studies, the laboratory is set up to feel like a living room. After preparatory sessions to build a rapport between the patient and the therapist and to establish expectations for the session, the patient takes a psilocybin pill and reclines on a couch with eyeshades on and headphones on with relaxing music.

Trained clinicians are on hand to answer questions and provide support during the session, but depression symptoms and death are not discussed in depth during the psilocybin session. Afterwards, follow-up talk therapy is conducted to integrate what is often a mystical, meaningful experience for the patient.

That's why we think the therapeutic setting and preparatory and integration sessions are so critical, and why we envision psilocybin always being administered by doctors in a safe place and never prescribed for take-home use.

I deal with anxiety issues and the mere thought of taking a hallucinogen is pretty terrifying. Is it a smaller dosage that just aids in the anxiety?

The recent studies at NYU and Johns Hopkins suggest that a smaller dose is probably insufficient to address anxiety. That's because researchers have found psychospiritual effects shift patients' general life perspectives as a result of a peak/mystical experience with the higher doses.

The biological effect (activation of the serotonin 2A receptor) of a small, psychologically inactive dose alone probably would not achieve the results researchers have seen so far, but it's not possible to know for sure yet because there's no way to experiment with psilocybin in a way that isolates the biological effects from the psychospiritual effects.

The psilocybin experience can indeed be very intense and can create short-term anxiety even in study participants. That's why we emphasize the importance of the preparatory and integration sessions, and why we believe it's critical that psilocybin be administered in a clinical setting under the supervision of a trained therapist.

A friend used psilocybin, from mushrooms (one time dose) to aid him to quit smoking cigarettes. He said that as he started feeling the effects of the mushrooms, he smokes a few cigs. and got pretty sick. After the sickness passed he just relaxed and enjoyed the rest of the night. He hasn't smoked in nearly 2 years now.

What is your opinion regarding the science behind this?

Smokers in a research study had similar results, but they had psychiatric screening beforehand plus special therapy to help them quit smoking, too. There is no systematic scientific research on people taking psilocybin mushrooms on their own to quit smoking, and that is definitely something that is not recommended because of safety concerns.

Thanks for doing this. What are the proposed mechanisms of action for the positive effects?

There are probably both biological effects, through activation of the serotonin 2A receptor, as well as psychospiritual effects through the shift in the person's general life perspective as a result of the peak/mystical experience.

Do you believe the lasting effects are based on the type of experience "on" the drug?

Yes, at least partly. The peak/mystical experience that patients experience after taking psilocybin was found to correlate with and mediate the positive therapeutic outcomes. We can't say with 100% certainty how much of the outcomes were due to the psychospiritual effects and how much due to the biological effects of psilocybin, but there's reason to believe that the shift in patients' life perspectives is behind the lasting effects of this therapy treatment.

Are you looking for research assistants? I'd love to work on some of the projects that Heffter's doing. Heck, I'd even do it for free. I'm about to graduate with a BS in neuroscience. Do you have any advice for people interested in pursuing this type of research?

I'd like to know the answer to this as well. I'm about to get my B.S. in Chemistry, and I've been dreaming of studying psychedelics for the better part of a decade now (particularly the phenethylamines as outside of Sasha Shulgin's work and research on MDMA, PEAs have been thoroughly understudied). More specifically, I'm interested in investigating mechanisms of psychedelic-neuroreceptor interactions and looking for qualitative (or quantitative, if the studies became rigorous enough from a physical organic chem. perspective)-structure-activity relationships (QSARs) between receptors and their psychedelic ligands. Maybe those sorts of studies are many years away yet, but is there anyone at the Heffter Institute that is pursuing that sort of research? If not, then would anyone at the Institute happen to know of a group that is doing those types of studies or is interested in pursuing them?

And now a much broader question: what's the Heffter Institute's ideal long term research plan? Is the research focus going to remain with the classical indole psychedelics for the foreseeable future? Or are there plans to diversify the research portfolio to more exotic and less well known compounds over the next 5-10 years? Obviously the federal legal obstacles make genuine long term planning incredibly challenging, and there may be so much more for us to learn about psilocybin that the Institute won't have the time or resources to devote to any/many other psychedelics, but I'd love to know where current psychedelic researchers want to see the field go over the next decade or two (especially to see how those visions line up with my own!).

Thanks very much for this question — I took it to Heffter President David Nichols, who is a preeminent expert in chemistry and pharmacology. (Conversely, I'm a psychiatrist by trade.) This is what Dr. Nichols told me:

Even Shulgin’s work on PEAs is not definitive. He tested his compounds in only a few people, and those studies were not controlled or randomized with a placebo, so no conclusions can be derived from his publications other than the active dose ranges for the compounds he studied. No one at Heffter is studying the structure-activity relationships of these compounds. Tom Ray published a preliminary study of affinities of several potential psychedelics at a number of brain receptors. His numbers, however, would need to be re-evaluated. Furthermore, affinities are not really the important data, but rather how well the particular receptors are activated by the ligands. In addition, each receptor can activate a number of signaling pathways. So one would need to focus on a few most interesting compounds and then assess their affinities and efficacies at a variety of receptors where they have affinity.

Advancing such studies further into humans would be nearly impossible; you would need to carry out preclinical toxicology studies in animals for each compound you wished to study. It would be a Herculean effort, and would cost many hundreds of thousands of dollars. In animals, there has been no evidence in behavioral studies that any receptor other than the 5-HT2A receptor is very important, although for some compounds the 5-HT2C and 5-HT1A receptors play a role. But animal studies don’t give you the kind of data you need to conclude whether other receptors might have a subtle effect on behavior. At present we do not know of any group pursuing this type of research; there simply is no funding source for work like that.

Heffter scientists realize that other psychedelic substances may have useful therapeutic properties, e.g. LSD or mescaline, but the great cost to actually carry out clinical studies means that we must have a compelling reason to pursue those research directions. That is, what can LSD or mescaline do that psilocybin can’t? Our pilot studies with psilocybin are estimated to have cost $20,000-25,000 per subject. If even a small pilot study requires at least 10 subjects, then you are looking at a minimum cost of about $250,000, even for LSD or mescaline.

With respect to “more exotic” substances, again, you would need to carry out preclinical toxicology studies, usually in two animal species. That cost is around $200,000 these days. So you’d first need to find a chemist to make high purity substance for the study, which would involve a cost, followed by the toxicology studies. Then, if the toxicology studies found nothing damaging to the animals, you could think about putting that compound into humans in a Phase 1 clinical study. The advantage of using psilocybin, LSD, or mescaline is that they have a long history of human use and do not require the preclinical toxicology testing that a new compound would need. In practical terms, it seems doubtful at this time that some of the more exotic compounds will be studied in humans. Of course, if some billionaire approached Heffter and said that they wanted to fund such studies...

Thanks so much for your interest and support. One of Heffter's key roles in this landscape is to incubate the next generation of psilocybin researchers and guides, so that young scientists like yourself can pick up the torch from older scientists like me!

My advice to people interested in pursuing this work is to join forces with investigators at major institutions where Heffter is already funding this research — places like NYU, Johns Hopkins, University of Alabama, UCLA, and others. If you'd like us to keep you in mind when we fund more research, please fill out the form at http://heffter.org/contact/ and we'll keep your résumé on file.

In the meantime, I suggest you pick the best graduate program that interests you, regardless of the lack of any focus on drugs like psilocybin. After you graduate, there will probably be more universities conducting research in this area.

Thanks for this AMA! These new studies look exciting. How many studies are currently in progress now, and where are they being done? How many more studies need to be done before the results are conclusive?

Thanks for your questions! There's a lot of research happening now and more coming soon. Heffter-funded research is currently exploring the use of psilocybin to treat depression in Switzerland and addictions to cocaine (at the University of Alabama Birmingham), alcohol (at NYU), and tobacco (Johns Hopkins).

We’re currently reviewing proposals to study treatments for obsessive-compulsive disorder and demoralization in long-term HIV survivors. Heffter scientists are also conducting basic science research into the neurophysiology of brain activity, consciousness, and behavior associated with psilocybin.

To prove that the results are "conclusive" and to seek FDA approval to make psilocybin available with a doctor's prescription, we'll need to conduct a larger, multi-site Phase 3 trial, likely on the indication for cancer patients with anxiety and depression. Conversations with the FDA have already started, and we hope they'll give approval to start that work in 2017.

Thanks! How many people participate in a Phase 3 trial? Once such a trial is done re: cancer patients and anxiety/depression, will other Phase 3 trials need to happen before psilocybin can be indicated as treatment for addictions, OCD, and other ailments?

We don’t know how many subjects the FDA will require for Phase 3 for this single-treament approach, as it is very novel in psychiatry. So we would not want to speculate on that. Whether other Phase 3 studies will be required is unknown, as this is a very unique drug to go through the FDA approval process.

How do you choose who can participate in the studies?

Our process to this point has been to carefully screen potential study participants so as to exclude those with certain medical or psychiatric conditions, including family history of schizophrenia, bipolar disorder, or suicide. Each of the studies has inclusion and exclusion criteria to ensure that participants have the best chance at achieving positive outcomes. Our ultimate goal is to alleviate suffering.

Does Heffter conduct the screenings? Outside of funding the studies, what role does Heffter play?

Heffter plays a few different roles in this research. Drawing on the scientific expertise of the leading investigators around the world, Heffter incubates the next generation of researchers and guides. Heffter vets new scientific approaches, specifically by reviewing research protocols and having outside scientists ensure the science is rigorous and careful.

Heffter supports proof-of-concept studies by providing funding to procure the psilocybin, conduct the research, and publish the findings, though the institutions where the research is conducted (NYU and Johns Hopkins in the most recent case) screen their participants themselves. All of this work allows Heffter to gather the evidence base for therapeutic treatments.

Besides the 3 you list explicitly, could you elaborate on what the other inclusion/exclusion criteria are?

Thanks for doing this AMA and look forward to your response!

There is a lot of detail on this, and you can read the full studies (for free!) from the link at the top of this page, but here's a short summary:

Beyond family history of schizophrenia, bipoloar disorder or suicide, the recent Johns Hopkins study excluded patients with cancer or other diseases that involved the central nervous system; hepatic dysfunction; paraneoplastic syndrome or "ectopic" hormone production by the primary tumor; cardiovascular conditions; high blood pressure; epilepsy; renal insufficiency; insulin-dependent diabetes; pregnancy, nursing or lack of effective birth control; daily use of psychoactive prescription medications; alcohol or drug dependence; or dissociative disorder, anorexia or bulimia.

The Johns Hopkins study was open to patients ranging from 21 to 80 years old who had a high school or equivalent level of education and a potentially life-threatening cancer diagnosis. All study participants agreed not to use nicotine for at least 2 hours before psilocybin administration, and not again until questionnaires were completed approximately 7 hours after administration and agreed to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 hours of each psilocybin administration.

Hope this is helpful!

Does taking a dose of laboratory psilocybin cause the same side effects as eating the mushroom directly, such as nausea?

Side effects are very individual with all drugs. Regarding mushrooms, they are different, too, so there is nothing definite to say about a comparison. Nausea and/or vomiting occurred in 15% of the Hopkins patients and nausea in 14% of the NYU patients.

Thanks for doing this AMA!

A lot of people that are being treated for depression with current methods take antidepressants from the SSRI family of drugs, interestingly enough these are said to lessen or even prevent the effects of psilocybin mushrooms. Has this been addressed, or do you plan to address it in your research?

If I understand correctly, in order for a patient to be able to benefit from the effects of psilocybin they would have to reduce or discontinue their ssri antidepressant, which in itself could open the doors for suicidal ideation or even suicide attempts.

Patients generally stop SSRI treatment before receiving psilocybin because we believe it can attenuate the effects of psilocybin. In the research so far, this has not resulted in suicidal ideation or attempts. In the two recent studies, psilocybin was found to produce 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. About 80% of participants saw improvements in attitudes about life, mood, relationships, and spirituality.

Fascinating! How soon after discontinuing an ssri were patients administered psilocybin?

Usually about two weeks. Here's the actual language from the Hopkins study with cancer patients: For individuals who have intermittent or PRN use of investigational agents, psychoactive prescription medications, medications having a primary pharmacological effect on serotonin neurons, or medications that are MAO inhibitors, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose.

Have you taken a dose of your own medicine?

I can't answer personal questions, but I can say that we are inspired to do this work because we believe there is unexplored potential in these substances and there is a chance to improve the lives of millions of people who are suffering from conditions that are not currently being treated adequately.

What is your opinion on people using psilocybin for spiritual reasons, regardless of cancer? Many attest to its power to improve psychological health when used responsibly: do you have an opinion on how laws should treat the drug?

Psilocybin is a powerful medicine and it is Heffter’s position that the positive effects found in research to date are achieved only when administered by a doctor with special training and used in a therapeutic setting. Safety has not been demonstrated for psilocybin when used outside of a structured clinical or laboratory setting, and we strongly caution against recreational use of psilocybin because of potential adverse psychological reactions like acute anxiety, disorientation, traumatic episodes, risky or violent behavior, the need for medical help, and even suicide attempts.

I wonder if Heffter makes similar claims about a far more dangerous drug, alcohol, or if they're fine with it being in the grocery store. I smell a double standard: forgive my frankness.

You're absolutely right that alcohol ruins lives. That's why Heffter is excited to investigate other conditions that might be successfully treated with psilocybin therapy, including Heffter-funded research currently being conducted at NYU to explore the use of psilocybin to treat alcoholism. The pilot study at the University of New Mexico found extraordinary results in this area, and it's part of the reason we think there is tremendous unexplored potential in psilocybin and why we're continuing to fund research.

http://heffter.org/addiction/

Way to dodge the question. I asked why your group treats a more dangerous drug (alcohol) less seriously than a less dangerous drug (psilocybin).

We consider psilocybin a drug to treat alcohol addiction, so we are treating alcohol very seriously as a substance of abuse, and one of the worst ones. That’s why we’re doing so much work to help people with that problem. Our group is a scientific research institute, and we are not studying any benefits of alcohol use.

You just advocated psilocybin prohibition via prescription only access for use in a medical setting. Do you similarly advocate alcohol prohibition?

We understand where you're coming from, but just to be clear Heffter is a scientific research organization and does not advocate for policy changes to regulate psilocybin, alcohol, or any other substances. In fact, as a non-profit scientific research institute, Heffter cannot advocate for changes in laws.

We have not conducted research on the use/abuse of alcohol, so there have been no statements from our researchers about that in any of their publications. But we believe alcohol addiction is a very serious public health problem.

We do not make a policy recommendation on psilocybin, but do caution people about its lack of demonstrated safety outside the medical setting. We have found that the therapeutic setting we use in our research maximizes the safety of the participants and is most conducive to achieving the positive findings discovered in recent studies.

We respect that others look at these issues more broadly and defer to conversations that are happening elsewhere, but for the rest of this AMA I'll stay focused on the science related to psilocybin.

how long would you approximate it would take to have enough information from studies to move on a legal pathway?

I would give a rough guess of 5-10 years before prescription approval for psilocybin.

Can you define "a dose"? How much is one dose?

In the two studies with cancer patients, the dose was around 22 mg of synthesized psilocybin for a 150 pound person.

Do you have any thoughts/knowledge about mushrooms/psilocybin helping people with arthritis? I have psoriatic arthritis and I find that they help with my pain and inflammation tremendously even when I take them at low enough doses that I don't feel any psychoactive effects.

There has been some research in animals that shows very low doses of a drug with some activity similar to psiloycbin can reduce inflammatory processes in asthma and atherosclerosis. But no research has been done with arthritis that I know of, and there have been no studies of this effect in humans. So there is just not more to say about this, except that every person is very unique and that it is hard to tell what treatment causes what results outside of a scientific study with statistics on many subjects.

Thank you for the response. I really hope that research is done on this one day. I believe it has the potential to help a lot of people like me.

Thank you for the question! Heffter also feels psilocybin has the potential to help people.

Does the dose that you provide to people give them an experience of ego death? Every time I experience it, it throws me down into a place that I don't want to be again. How do you coach people through something that is inherently terrifying like becoming disconnected from their person?

The psilocybin experience was very intense for many of the patients in the studies, with many saying afterwards that it was among the most important spiritual events of their lives. It can certainly be anxiety-inducing and emotionally challenging for some.

That's why research participants are carefully screened to prevent people who might have a traumatic experience with psilocybin from being in a study. Also, the therapy program includes work before the psilocybin session to prepare participants who have never taken a psychedelic before — to ensure a productive and safe mindset — and then integration sessions afterwards to make sense of the experience.

We believe those sessions contribute to the sustained relief from anxiety and depression found the studies. The safe and supportive setting of the psilocybin session itself also helps ensure the risk of negativity is minimized, though not eliminated, and the experience is therapeutically productive.

I love this kind of research! As you probably know in the 1960s research was done with LSD on children (aged around 10) that had early onset schitzofrenia (which i believe is now called autism?) and it seemed to have a positive effect over the course of multiple sessions (around 10 sessions). Children in the study who were at first "living in their own world" later got the need of human attention and were able to attend school.

You mentioned psilocybin having a bad effect on people with schitzofrenia or the risk of getting it. Do you think psilocybin could have the same effects as these studies from the 60s? or do you think LSD doesnt have the same effect with regard to (early onset) schitzofrenia.

And what do you think of these studies from the 60s anyways?

We believe negative psychological episodes are possible for patients at risk for schizophrenia, which is why those patients are excluded from participating in research. However, these children probably had autism, which has no relationship with schizophrenia in terms of psychosis risk, though it is not that easy to tell the difference between the two disorders. LSD apparently helped these children, and new research using modern research design would be needed to understand if and how well such a treatment would work

The studies you mention and others conducted in the 1950s and 1960s often did not adhere to the kinds of safety protocols and modern research standards to which we hold ourselves today. So we look at that early science as being potentially useful for inspiring new areas of inquiry, but generally do not depend on those studies as standalone proof for therapeutic effects.

Instead, we intend to work with the FDA to design and conduct new studies that demonstrate safety and efficacy so that psilocybin can be approved for prescription use.

Hi George, thanks for doing what you and your team are doing. Why is it that you desire to help people?

We believe that psilocybin has great unexplored potential to alleviate suffering in patients whose needs aren't being adequately met by existing treatment models.

As a psychiatrist, I've spent my professional life trying to help people overcome problems, and see this research as reopening another way to improve people's lives and make their remaining days happier ones. That's what inspires our work and why we're so excited by these new findings.

What's your take on the "perceptual valving" hypothesis of psychedelic action?

(Since I'm not sure if it's widely discussed: the hypothesis says that psychedelics act by broadening the tuning of perceptual interpretations of sensory information. So sensory information that the brain would normally be 99.9999999% likely to categorize as "cat" becomes "90% chance is cat, 10% chance is dragon." Sort of analogous to increasing the temperature parameter in an energy system.)

There are many hypotheses that describe the mechanism by which psychedelics like psilocybin act on the brain. Heffter scientists conduct basic science research into the neurophysiology of brain activity, consciousness, and behavior associated with psilocybin, so we hope to delve into this more in coming years.

One of the most interesting studies I've seen recently looked at patients' brains in an fMRI scanner after they had taken LSD and found that it fostered connections between areas of the brain that don't usually talk to each other. You can read more about that work here: http://www.nature.com/news/brain-scans-reveal-how-lsd-affects-consciousness-1.19727

Is psilocybin like LSD in that it has the potential to trigger schizophrenic breaks in people predisposed to schizophrenia?

Yes, we believe that is a real possibility in people who are at risk for schizophrenia, based on their personal and family histories. That’s why patients with those warning signs are excluded from being research participants.

Sigh... no magical anti-depressant remedy for me. Uncle has schizophrenia.

Even though Heffter believes psilocybin holds the potential to help people, it is not the only remedy available. It definitely would not be good for someone with schizophrenia.