So, You Want To Find a Psychedelic Guide?

find a guide

Psychedelic science and research has been getting a lot of mainstream media attention over the years and for good reason. The preliminary research suggests that psychedelics may be extremely beneficial in helping to treat mental health disorders and as tools for studying consciousness. As this research begins to hit mainstream channels, some people are left wondering, “How can I find a psychedelic guide or sitter?” If you are feeling overwhelmed by the search, feel free to set up a free 30 minute coaching session with us. We may be able to make your decision process safer and easier.

Michael Pollan, a well-respected journalist and author, released a new book called, How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence where he surveys the history of and current state of psychedelic research and therapy. In his book, Pollan describes his experiences with trained underground psychedelic guides. He also explores these experiences in this New York Times article called, My Adventures With The Trip Doctors: The Researchers and Renegades Bringing Psychedelic Drugs Into The Mental Health Mainstream. Pollan’s work has been entering the mainstream and it seems that more people are becoming interested in or curious about psychedelic therapy – so much that many people are seeking ways to find underground therapists and guides to work with.

We, at Psychedelics Today, have been receiving a lot of requests from people asking for instructions on how to obtain drugs or for us to connect them with people offering underground services. While we understand that many people are suffering and seeking psychedelic treatments, sometimes out of desperation for healing, it is not easy to provide advice. Unfortunately, because of the legal system and the current laws in The United States, we are unable to help you on either of these fronts.

With that stated, we can provide some general advice for those looking for alternatives or legal options. Please take the time to conduct your own research as well.

First Thing First

It is important to question what your intentions are and ask yourself why you may be seeking psychedelics either as therapy or as an experience.

  • Are you seeking a therapeutic experience because of a mental health issue?
  • Are you seeking a psychedelic experience for spiritual or religious reasons?
  • Are you just curious to know what the experience may feel like or what it is all about?
  • Are you looking for a recreational experience or to have fun?

Whatever your reasons or intentions are, it is important to continue to be self-reflective and question whether or not this is the right path to pursue. Also, be sure to spend time reflecting on the risk/benefit ratio.

Get Educated

Before making any quick decisions, please take your time to get educated on this topic and also reach out to others who may have previous experiences. Psychedelics Today has a lot of great podcast episodes and resources for education, so take some time exploring our site and content. If you want to get a great basic overview of psychedelics, harm reduction, safety, check out our free webinar course, 8 Common Psychedelic  Mistakes: Exploring Harm Reduction and Safety or our more in-depth course Navigating Psychedelics: Lessons on Self-Care and Integration . Here is a link to a free – 101 version of our Navigating Psychedelics class so you can get a taste.




Mental and Physical Health Considerations

While psychedelics are generally considered safe both psychologically and physiologically, there are some important considerations to take into account. These medicines and substances affect everyone differently based on the set and setting as well as a person’s own biology.

If you are seeking a psychedelic experience because you are suffering from a mental health issue or looking for psychological healing, it is important to evaluate whether or not it is the best option. The research is promising, but it also requires a lot of work, support, and follow-up treatment. Psychedelics are not always cure-alls or silver bullets.

If you are seeking this treatment out of desperation because you have read how positive or healing the experience can be, it is important to note that this change does not always happen right away. It may be important to find a psychedelic integration therapist to work with after or before. Also, ask yourself, “Have I tried other options?”

There are some powerful and effective somatic-based therapies that can be extremely cathartic and healing, such as breathwork, Somatic Experiencing, and others. A list of alternatives and somatic-based therapies can be found below in the “Experiential Therapies/Approaches” section. These therapies may be worth checking out if you have not looked into these therapies before and may also be a great first step to working with non-ordinary states of consciousness.

Exploring Legal Psychedelic Therapies and Other Alternatives

Experiential Therapies/Approaches 

One thing that comes to mind is why are you looking for a guide? Is it to heal trauma or some sort of mental health issue? Are you looking for a spiritual experience or a way to reconnect with yourself? Depending on your intention, there may be other techniques and tools. It may not be as “sexy” as partaking in psychedelic work, but it is important to ask yourself, “What is my intention?”

There are some really powerful therapies and techniques that could potentially be helpful depending on the intention. In regard to therapy or addressing mental health issues, starting with a form of experiential therapy could be beneficial. You could look into some of these somatic approaches that could be helpful for dealing with trauma and other mental health issues before trying to seek underground work or travel outside of the country to work with psychedelic medicines.

Legal Therapy Options

Ketamine-Assisted Therapy

Ketamine is an interesting substance and has recently been used to help treat depression. There are ketamine clinics throughout the United States that provide treatment for depression and other mental health issues. If you are interested in learning more about ketamine-assisted therapy, check out a few of our episodes covering the topic.

Dr. Scott Shannon – Ketamine Therapies

Alyssa Gursky – Transpersonal Art and Ketamine Therapies

Shane LeMaster – Ketamine

Cannabis-Assisted Psychotherapy 

While many people do not think of cannabis as a psychedelic, some are exploring the therapeutic potential of cannabis in a legal and therapeutic setting. There are not many clinics operating with this protocol, so it may be hard to find, but as cannabis becomes legalized in more states for medicinal use and recreational use, this may become more accessible. Here are three resources that we know of so far for cannabis-assisted psychotherapy.

Medicinal Mindfulness

Did you know that when cannabis is used intentionally and skillfully, it is psychedelic and mimics other psychedelic medicines? Our participants commonly report experiences quite similar to MDMA, Psilocybin, Ayahuasca and even DMT. Cannabis is also safe, and legal to use in Colorado in this way. As the first organization to facilitate legal psychedelic cannabis experiences in Colorado, beginning in 2014, Medicinal Mindfulness has an incredible track record of keeping our clients safe and creating profound, life changing psychedelic experiences.

Conscious Cannabis Experiences are perfect for people who are curious about psychedelics but don’t know where to start. They’re also great for experienced practitioners seeking to deepen their psychedelic practice. As trauma informed practitioners, we also work with individuals who seek deep, transformational healing. As guides, we work with creative explorers of consciousness and complex problem-solvers, pushing the edges of what is possible.

Innate Path: Ketamine and Cannabis-Assisted Psychotherapy 

Innate Path, located in Colorado, is exploring the potential of cannabis-assisted psychotherapy and ketamine-assisted psychotherapy. As mentioned on their site, “Cannabis can be a powerful catalyzer of therapeutic process.”

Innate Path combines somatic processing with ketamine or cannabis assisted work, which is a unique bottom-up approach to psychedelic-assisted therapy.

Sara Ouimette Psychotherapy

Sara Ouimette Psychotherapy, located in Oakland, CA, offers psychotherapy, psychedelic integration services, and cannabis-assisted psychotherapy. As stated on Sara’s page:

When used in a particular way, cannabis can actually amplify or exacerbate your internal experience. You can become more aware of tightness or soreness in your body. Emotions are heightened; senses are more acute. You may have access to thoughts, fears, and feelings that are normally out of reach. You may even enter a trance-like state and “journey.” In these ways, cannabis can help deepen your therapy process.

To learn more about Sara’s work and cannabis-assisted psychotherapy, check out Sara’s article called, Checking In, Not Checking Out: Cannabis-Assisted Psychotherapy

Participate in Clinical Research

One way to find a psychedelic sitter/guide is to participate in the clinical research. Check out the following for more information.

  • Clinicaltrials.gov: This is a database of clinical studies from around the country and around the world. You can use this database to search active clinical studies on psychedelics and to search for recruitment opportunities. Just perform a simple search for “psychedelic” or anything else that you may be looking for in the search box. You can filter your search option and only search studies that are currently open for “recruitment.”
  • The Multidisciplinary Association for Psychedelic Studies: If you are already not aware, MAPS is streamlining research for MDMA-assisted psychotherapy. Check out their Participate in Research page for more information about how to get involved in one of their studies.

Psychedelic Retreats and Centers

This option is not always available to everyone because of the cost of travel, accommodations and other expenses. While we understand attending a retreat or center in another country is not accessible for most, it is one of the few legal options for participating in this work. We advise doing extensive research including interviewing the retreat staff/owner and past guests before committing to international travel.

One site that we recommend for finding retreats or reviews is the Psychedelic Experience. While this site is still growing, this may be a great starting point for research. Another popular site is AyaAdvisors.

Psilocybin Retreats

Traveling to another country to participate in this work is obviously not ideal, but the option exists. Mushrooms are legal in The Netherlands, Jamaica, and Brazil. Mexico has protection for traditional medicines, and mushrooms do fall in this category.

Ayahuasca Retreats

Ayahuasca has an interesting legal status in the USA, where many groups are offering sessions in various contexts and settings from religious ceremonies (Christian or shamanic), YMCA gyms, rural retreat centers, churches, etc. Ayahuasca is legal in some countries like Peru and Ecuador. Ecuador provides licenses for shamans/facilitators which no other countries currently do.

Ibogaine Retreats

These retreats exist in Canada, Mexico and other countries around the world including where the plant is from and traditionally used – Gabon. Some facilities are very clinical and others are very traditional. Please know that Iboga and Ibogaine have some serious dangers that need to be carefully considered. There are also environmental concerns around iboga. Please don’t over-use this plant and if you go forward with it, please try to give back to the local environmental movements in Gabon.

5-MeO-DMT Retreats

We currently don’t advise people go on these retreats. The pressure on toad populations is severe and our culture’s desire for the toad venom may push this toad towards an endangered status. After interviewing toad scientists (herpetologists) we have concluded that it is not ethical to be participating in this “market”. If you feel very compelled, the more ethical path (at this point in history) is to work with synthetic molecules.

Other Alternatives

Holotropic Breathwork and Transpersonal Breathwork

Breathwork is a term used to describe breathing techniques and systems that foster self-discovery, healing, and sometimes deeply emotional and physical cathartic releases. If you have been following Psychedelics Today, you have most likely heard us talk about this technique on the show. Breathwork is actually a legal and safe way to access a non-ordinary state of consciousness. There are various schools of breathwork, but the Breathwork technique that we are most familiar with is in the lineage of Holotropic Breathwork and Transpersonal Breathwork. Holotropic Breathwork was created by Stanislav Grof, who was a pioneer in psychedelic research in the early years, and his wife Christina Grof. Breathwork can sometimes be on par with some psychedelic-like experiences.

It may not sound as sexy as psychedelic work, but do not be fooled, it can foster powerful shifts in consciousness. We have both had tremendously powerful healing experiences using Holotropic Breathwork, which plays a huge part in why we talk about it so regularly.

What is Breathwork?

Elizabeth Gibson – Dreamshadow Holotropic Breathwork

Conscious Breathwork and Conscious Cannabis | Medicinal Mindfulness

Medicinal Mindfulness is a Colorado-based organization that provides services in psychedelic integration, breathwork, and conscious cannabis work.

Medicinal Mindfulness is a consciousness community/membership organization and education program that supports individuals and groups who choose to use cannabis and psychedelics with intention and skill. Through our Community Breathwork and Conscious Cannabis Events, we facilitate legal, accessible, safe and sacred psychedelic journey experiences that integrate the four primary paradigms of intentional medicine use: Creative, Scientific, Psychological & Spiritual. Our approach is Transpersonally aligned and somatically oriented.

You can learn more about the work at Medicinal Mindfulness on this episode of Psychedelics Today with the founder, Daniel McQueen.

Daniel McQueen – Medicinal Mindfulness & Conscious Cannabis Circles


Can we help?

If we at Psychedelics Today can help you in any way, we would love to. You can contact us here or you can sign up for a free 30 minute coaching call to help you navigate through this very complex landscape. You can learn more about us here.

Conclusion and Legal Notice

Finding an underground therapist to work with is extremely difficult because unfortunately,many of these substances are still illegal. This is why we often refer people to check out techniques like Holotropic Breathwork or to find a legal way to pursue this type of work. Remember, many underground guides are putting their professional careers and lives on the line providing psychedelic work.

We advise you to learn as much as you can before breaking any law as the consequences can be severe. If there are any questions that you think are serious enough to cause harm to yourself or others, please contact a legal professional before acting.

Psychedelics Today, LLC and its affiliates can not be held liable for any action you take. We are not doctors and therefore, cannot provide any medical advice. Please be responsible and seek professional attention when necessary.

Best of luck out there, and expect us to share as much as possible when the laws change.

Navigating Your Way Through the Psychedelic Field: How to Get Involved

Psychedelics: A Re-Emerging Field

As psychedelic research re-emerges from its dark ages, the world is beginning to learn about their healing potential for various psychological disorders such as post-traumatic stress disorder, depression, and near-death anxiety due to terminal illness. The research is fascinating, exciting, and seems to be catching a lot more mainstream attention.  The preliminary research shows that psychedelics may be promising tools for mental health and could be the future of medicine. So the question is, how does one get involved in this work?

Joe and Kyle had the opportunity to talk with Ingmar Gorman, Ph.D.about how people can get involved in psychedelic research or in the field of psychedelics in general. Ingmar shared with us some really great information and we would like to recap some highlights. Some of the information provided is a mix between our own thoughts and what Ingmar mentioned.

Important Disclaimer: This is a fairly new field, so it is important to remember that the future of this work is not set-in-stone. Psychedelics are still illegal within the United States and many other countries around the world. While we remain optimistic for the future of psychedelic research, the landscape can shift at any moment. There is still a lot of work to be done!


First Thing First:

  1. Ask yourself, “Why am I interested in entering into the field of psychedelic research?”
  2. Do you want to get your foot in the door because you had an experience that changed your life or inspired you in some way? Did you have a healing experience that you want to share with others?
  3. Do you want to give back to the community in some way by furthering scientific research or inquiry? If so, what is your expertise and area of interest?
  4. What role can you play later on? Are there areas or specialties that need attention or growth?
  5. Understanding and asking yourself, “Why do I want to do this? What is my motive?”

Personal or transformational experiences may not always be the best option for pursuing an active career in researching psychedelics. Psychedelic experiences can be healing, transformative, and magical, but this does not mean you have to enter into the field of science or research. There may be other options that might suit your interests better. Obtaining a professional degree can be a well-worth investment with your time and money if that is surely a path that you wish to pursue. It is important to think outside of the box.

Also, an important thing to note here is that psychedelics are still illegal. While the research and science is happening, obtaining a research position is often difficult considering the limited amount of research. This is not to discourage any of you, but just saying it will require a lot of work! While MAPS is projecting that MDMA will be legal for psychotherapy by 2021, it is still uncertain what the laws and regulations will be. We are hopeful that the future looks bright for psychedelic careers, but it is also important to err on the side of caution as well.


General Information:

Along with asking the questions above, here is some general information or advice for individuals who not wish to pursue a traditional degree. We are all hardwired differently and earning a professional degree may not be in everyone’s best interest.

  • The Non-Traditional Approach: There are other ways to get involved that do not require the investment your time and money for a professional degree. Are you a visual artist? Do you produce music? An interviewer? Are you a product inventor? For example, Joe mentioned during the podcast that he did not feel the need to go on to pursue a mental health degree because he does not feel like being a therapist is the thing that he wants to do right now. Instead, Joe and I are creating this podcast as a resource for the community. The bottom line, is there anything that you can contribute or create for the field? Many researchers and scientists are not artists or graphic designers and the field needs art to help convey the visual experience. Look at Alex and Allison Grey or Android Jones for example.
  • Develop an Expertise: Whether you are taking a traditional or non-traditional approach, I think it is safe to say that developing an expertise is a smart approach. Develop an expertise that can translate well to psychedelic research. Ask yourself, “how can I help or what can I contribute?”
  • Apply Your Skills: Again, think about how you can develop an expertise and think about how your skills can be applied to the field. Are you an accountant or into finances? Maybe if Rick Doblin’s dream of psychedelic treatment centers become real in the future, we are going to need lots of people to manage everything.
  • Volunteer: It does not hurt to reach out and develop a relationship with the Multidisciplinary Association for Psychedelic Studies (MAPS), Erowid, Zendo Project, DanceSafe, Drug Policy Alliance, or any other psychedelic organization. These organizations might be looking for a helping hand in a project or event. Volunteering can help you become connected with an organization, develop a relationship, and maybe help you land a job somewhere! Worst case scenario, you meet some awesome people.
  • Festival Harm Reduction Services: There are various organizations that provide harm reduction services at festivals. This may be a great way to get experience in the field. Check out the Zendo Project, DanceSafe, or Kosmicare for potential future opportunities.
  • Create a Psychedelic Club or Society: Local psychedelic clubs and societies are popping up all over the place. You can create your own too! You can check out our guide Tips on Creating Your Own Psychedelic Group


Get Involved in Research

There are numerous ways to get involved in research projects. From self-report studies to actual participation, there are ways to get involved and possibly become a study participant. Here is a list of a few different options.

 


For Students:

If you are thinking about trying to get your foot in the door with psychedelic research, it is important to analyze which route you wish to take. There are many paths to choose from and you do not need always need to pursue a degree in science.

Are you currently or thinking about pursuing your Bachelor’s degree?

  • What are your interests? Are you interested in psychology or psychiatry? Neuroscience or neuropsychology? Chemistry? Biology? History or anthropology? Do you want to do therapy at some point? Figure out what interests you.
    It is recommended if you want to do therapy or conduct scientific research to earn a degree in science and psychology.
  • Find a niche or a specialty: If you’re off to an early start, figure out what you may want to focus on. If you’re a psychology student, maybe focus on trauma or addiction. Current psychedelic research is mostly focused on if these substances can be beneficial for certain psychiatric or mental disorders. The research funds are not really there for “how” these substances work, but that might not be the case down the line in a few years. The field is shifting rapidly.
  • Go to conferences: Just in case you missed this in the last section, remember to try and attend a conference or event!
  • Find A School: It is suggested that if you would like to do rigorous academic/scientific research it might be important to seek out applying to a traditional school. There are schools out there doing research and it might not hurt to look into their programs. MAPS has made a list of schools that might make psychedelic research easier.
  • Create a Club: You can always try to create a drug advocacy/policy club at your university. If you are unsure how to go about doing so, you could always check out the Students for Sensible Drug Policy and create a local chapter at your university or school.
  • Training and Education: There are plenty of training opportunities that may be helpful when thinking about adding new skills to your toolbox. Here are some examples of trainings that could be beneficial or helpful.

Harm Reduction

Techniques and Therapies

Some of these trainings/techniques may require advanced credentials and education.


Beyond The Bachelor’s Degree:

If you just had just completed your undergraduate degree, are currently a graduate student, or trying to figure out what is next, here is some advice.

  • Master’s Degree or Ph.D.: Many people get caught up on this decision/topic. Some people believe that pursuing a clinical psychology PhD or PsyD is the best option if they want to get their foot in the door with psychedelic psychotherapy. Earning a Ph.D. or PsyD or even a medical degree such as a Psychiatry is a large investment in both your time and money. This route may not be the best option for everyone and it is important to know what you are interested in or what skills you are strong in. Maybe science and math is not your strong point, so pursuing a clinical psychology degree to become a clinical psychologist may not suit you. Some people just want to be able to conduct psychotherapy and there are plenty of ways to do so, such as getting a master’s degree in clinical mental health or social work. Weigh your options and think about what fits you the best.
  • Specialty and Niche: Like the bachelor’s advice, what is your specialty or expertise? What role can you play later on? The field of psychedelic research is looking for individuals with specialties. Look into the ways how to develop an expertise in the field. If your interest is in trauma, research how to develop a focus in body psychotherapy for trauma disorders. Focus on alternative treatments for addiction.
  • Passion and Drive: Since earning a professional degree or a doctorate degree is both an investment of time and money, you are going to need to be passionate about what you are studying. There are many people who start programs and realize that it is not for them. Know that if you want to pursue a professional career in psychedelics, you’re in it for the long haul!
  • Is There Therapeutic Benefit: If you are interested in research Ingmar mentioned that the funding may not be there for questions like, “how do these substances work?” or “how do they heal?” Even though the Imperial College of London has been doing amazing “how” research (how LSD, psilocybin, and MDMA affect the brain) there is not much of that type of research going on within the United States. The MDMA-assisted psychotherapy study wanted to know not how MDMA cures or helps PTSD, but rather, does MDMA-assisted psychotherapy help with PTSD?
  • Find a Mentor or Professor: It does not hurt to research mentors or professors in the field to see where they are teaching. Katherine Maclean mentioned in our latest interview that she was interested in psychedelic research and knew that Johns Hopkins was researching psilocybin. Look for post-doctorate fellowships, internships, etc. Attend a school that is doing the research
  • Find Grants for Research: If you are enrolled in a program and can find a faculty member that supports your psychedelic mission, try to find grants or scholarship money to support your research program. The Source Research Foundation is a new organization that is helping to provide grant money to students who want to conduct psychedelic research.
  • Training and Education: As mentioned in the “For Students” section above, there are various training/education opportunities that will help you grow and develop new skills. Please view the list above for ideas.

Additional Resources

Organizations

Articles about getting involved


Best of Luck! We wish you the best of luck on your psychedelic journey and hope that you find this information useful. MAPS has a lot of great information and be sure to check out their “resource” section.

Be sure to leave a comment, subscribe to our podcast, and connect with us. We would love to hear from you – info@psychedelicstoday.com

Author: Kyle Buller

Last Updated: 5/31/2018

Why is Psilocin Orally Active?

Originally published: http://altdotmind.com/why-is-psilocin-orally-active/


This is the third article in a series on psychedelic chemistry, and the final article focusing on the tryptamine class. In the previous article we learned that though DMT and 5-MeO-DMT lack oral activity, chemistry wizards are able to change that. By making one of a variety of simple alterations to their structure they may be changed into analogs (“research chemicals”, or RCs), each possessing their own unique subset of characteristics including oral activity. That’s because the chemists changed the three-dimensional configuration of the molecules in such a way that the lone pair of electrons situated on the amine’s nitrogen (Figure 1) became shielded, thereby preventing their degradation by MAO. To recap, if one consumes monoamines (such as certain tryptamines) orally, MAO transforms them in the gut and by the time they enter the bloodstream they are no longer psychoactive – Figure 2.


Figure 1. Nitrogen has 7 electrons in total, and 5 valence electrons. It has one electron in each of the three 2p orbitals, which allows it to make three bonds (green), and two electrons in the 2s orbital which exists as a lone electron pair (blue).

 


Figure 2. After 5-MeO-DMT is consumed orally (1) it enters the gut (2) and is transformed by MAO-A (3). MAO-A uses oxygen to convert the amine into a carboxylic acid (4). This converts 5-MeO-DMT into the nonpsychoactive 5-MIAA (5-methoxyindole-3-acetic acid), the species which enters the circulatory system (5)

This article is going to unpack a study (Figure 3) that showed, by comparing the structures of the naturally-occurring molecules psilocin and bufotenin why the former is orally active while the latter is not. This is another pioneering study from the lab of Dr. David Nichols, who is, along with Albert Hoffman and Sasha Shulgin, in my estimation one of the three true giants of psychedelic chemistry. Its his work and excellent lectures from ESPD50, Psychedelic Science (2013 and 2017), and Breaking Convention that restoked my appreciation for chemistry and inspired me to not only deepened my knowledge, but also to start this series of articles. The outpourings from his majestic mind has fundamentally shaped the topics and content of these articles… Shout out Big D, whut-whut!


Figure 3.

The structure and atomic composition of a chemical are obviously critical to our understanding, and the progression of, chemistry and pharmacology. The problem with that is that molecules are small – really small. Even with today’s stupefying repertoire of advanced scientific analytical instruments, there is still no practical way for us to observe their structure directly. So instead we have devised sophisticated methods in which to do so indirectly. One of these methods is called Nuclear Magnetic Resonance (NMR) Spectroscopy, which uses information about the spin of atomic nuclei to determine what a compound’s structure looks like.

In 1980 the team at Purdue University used NMR spectroscopy to investigate how the three-dimensional structures of bufotenin and psilocybin differ from one another. Even though these two compounds are constitutional isomers (Box 1; Figure 4), there is a critical difference in their activity – psilocin is orally active, whereas bufotenin is not. This tiny change, moving the hydroxyl group from position 5 to 4 made this critical difference in the way they are absorbed by a human body. Though 2D-representations of the respective molecules are too low resolution to allude to the reason for the disparity, the researchers (correctly) suspected that by looking at their 3D-structures they would be able to understand why one molecule could resist deamination by MAO, while the other could not.


Figure 4. Bufotenin and psilocin are constitutional isomers, the only difference in their structure is the position of the hydroxyl group (-OH).

NMR spectroscopy revealed that the ethyl sidechain of bufotenin is able to rotate freely, meaning it can spin around on its own axis (Figure 5). That is however not the case for psilocin, something locks it in place, preventing it from rotating freely. The ethyl sidechains of the molecules are identical, which means that whatever is preventing the free rotation of psilocin’s ethyl sidechain is related to the hydroxyl group being situated at position 4, and not 5. To find out exactly what that was, the researchers used specialized software called LAOCN3. Before we explore what they found it would be useful to our interpretation of the results if we brushed up on a couple of elementary concepts in chemistry.


Figure 5.

There are two basic types of bonds that atoms can form with one another. The first, called an ionic bond, forms when atoms exchange electrons with one another. This happens if the encountering atoms possess large differences in their respective affinities for electrons (called electronegativity), one atom really wants to lose an electron, while the other really wants to gain it (Figure 6). So an electron (or electrons) are exchanged, and because it is negatively charged the transfer changes the charge of the each atom. The atom that gains the electron gains a negative charge and thus becomes negative, while the atom that loses the electron loses a negative charge and thus becomes positive. And as the old adage goes, opposites attract – the oppositely-charged atoms come together and form a stable bond with one another.


Figure 6. Ionic bonds.

The other type of bond that can unite atoms is a covalent bond. This happens when atoms with similar affinity for electrons encounter one another, neither really wants to lose/gain an electron so they reach a compromise – they share their electrons among each other. Both atoms pretend that the electron that it shares, as well as the electron shared by the other atom, belongs to it (Figure 7). It’s this overlap of shared electrons that connects the atoms together into a single molecule.


Figure 7. Covalent bond. 

Because there are no electrons that are transferred in the covalent bond the atoms don’t assume a charge as was the case with ionic bonds. However, that’s only partially true… In certain cases, the atoms that take part in a covalent bond do have some difference in their affinity – not enough for them to exchange electrons and form an ionic bond, but enough so that when they form a covalent bond and share electrons those shared electrons are closer to one atom than the other. This is known as a polar covalent bond. The atom to which the shared electrons are in closer proximity has a higher electronegativity and thus becomes partially negative (δ-). Conversely, the atoms with lower electronegativity are further from the shared electrons and are partially positive (δ+). Because of this asymmetrical charge, polar molecules are able to form weak bonds with other polar molecules, or with compounds that have a net charge. Now that we’ve covered some basic concepts let’s get back to the results of the study and apply what we’ve learned by taking a closer look at psilocin (Figure 8).


Figure 8. In the red area is a hydroxyl group (Figure 9), and in the blue area is a tertiary amine (Figure 10).

Figure 9. The electronegativity of hydrogen (white) is 2.1, while that of the oxygen (red) is 3.5. This difference of 1.4 in their electronegativity is not enough to form an ionic bond, but does lead to partial charges – oxygen has a higher affinity for electrons meaning the electrons are closer to it and assumes a partially negative charge (δ-), while hydrogen assumes a partially positive charge (δ+).

 


Figure 10. The tertiary amine group consists of a nitrogen (blue) with an electronegativity of 3.0, connected to three carbons (grey) each with an electronegativity of 2.5. Nitrogen has a higher affinity for electrons and pulls the electrons closer to it, leading to a partial negative charge (δ-), while the carbons have partial positive charges (δ+).

Taken together: psilocin has hydroxyl group at position 4 with a partially negative oxygen and a partially positive hydrogen, and an amine with a nitrogen that is partially negative and carbons that are partially positive. Because of these partial charges something interesting happens – the partially positive hydrogen from the hydroxyl group and the partially negative nitrogen from the amine attract one another (Figure 11).

Figure 11.

 

The hydrogen and nitrogen form a special type of bond with one another known as hydrogen bond (Box 2) which pulls the two atoms closer to one another, changing the shape of the molecule – Figures 12 and 13.

 


Figure 12. The partial positive charge on the hydrogen and partial positive charge on the nitrogen (left) are attracted to one another and form a hydrogen bond which pulls the atoms closer to each other, changing the molecule’s shape (right).

Figure 13. The hydrogen of the hydroxyl-group is bent backwards into a gauche conformation while the ethyl tail bends towards the indole ring to further shorten the distance between them.

It’s this hydrogen bond that locks the ethyl sidechain into place by forming a closed loop (Figure 14), preventing it from rotating freely. In bufotenin the ethyl sidechain can rotate freely because no such hydrogen bond exists. Because the hydroxyl-group is at position 5 and not 4, the partially charged molecules are too far away from one another to form the hydrogen bond, change the shape of the molecule, and lock the ethyl sidechain into place.


Figure 14.

But what has any of this to do with the difference in oral activity between the two molecules? Turns out, everything. It’s this hydrogen bond and closed loop formation in psilocin which shields the lone pair of electrons situated on the nitrogen. Because MAO cannot access the electrons it cannot deaminate the molecule – this is why it can pass through the gastrointestinal system unchanged.

But there’s more. The hydrogen bond and resulting closed loop formation also lead to several other important changes in the property of the molecule which further accentuates its efficacy and potency as an orally-active psychedelic tryptamine. After generating 3D-models of the respective molecules, the researchers went on to compare their pKa (Box 3) and Log P (Box 4) values..

 

When they measured the pKa and the Log P for both psilocin and bufotenin they found the following:

The pKa for Bufotenin is 9.67, meaning that at that specific pH-value equal amounts of the molecule will be present in both the ionized (water soluble) and protonated forms (lipid soluble). When the molecule is in the blood, which has a pH of about 7.4, almost all of it (99.5%) is in the ionized form. In contrast, psilocin has a pKa of 8.47, closer to the pH of blood. So for psilocin, only about 52% is in the ionized form. That means that in the blood, 48% of psilocin will be in its unionized form versus only about 0.5% when it comes to bufotenin. As it is only the unionized form of the drug that can cross cell-membranes, this has profound implications for the potency of these two drugs – psilocin is not only able to better withstand degradation by MAO, but once it is in the blood there is also much more of it available in a form that can cross cellular membranes and thus can reach the target receptors and exert an effect.

The difference in pKa is also related to the shielding of the electron lone pair by the hydrogen bond. As we have learned, amines possess a nitrogen with a lone pair of electrons. These free electrons, which carry a negative charge, are all too happy to snap up positively-charged protons (H+) from a solution they are in. This is, according to the Bronsted-Lowry acid-base theory, the very definition of a base – something that accepts protons. When it comes to psilocin the lone pair of electrons are shielded and are thus much less likely to accept protons. As a consequence, psilocin is less basic that is bufotenin.

The researchers also detected a difference in the Log P values – 1.19 for bufotenin, and 1.45 for psilocin. In the Log P scale a negative value indicates a compound which is hydrophilic, whereas a positive value indicates one that is lipophilic. Both these compounds are thus lipophilic, and psilocin, with the higher value, is more lipophilic. For drugs, in general, it is preferable for them to be lipophilic so as to be able to cross cell membranes, but not too lipophilic because then they immediately migrate to, and are stored in, the body fat. Research indicates that a Log P value of about 3.0 is the “sweet spot”, so psilocin is closer to this number, again indicating that its properties are more favourable once it enters the body.

The researchers started with a simple question: how is it that two isomeric compounds with such a small difference have such widely different properties when they are consumed orally? With NMR Spectroscopy we learned that it all has to do with the fact that because the hydroxyl group of psilocin is a little bit closer to the amine it was able to form a hydrogen bond between the two groups. This hydrogen bond shields the electron lone pair from deamination by MAO, which means that, unlike bufotenin, psilocin is orally active. The hydrogen bond also decreases the molecule’s proton-accepting capacity thereby decreasing its pKa value which means that at blood pH there is more of psilocin in the non-ionized (lipid soluble) form which is able to cross cell membranes and thus enter the central nervous system (CNS). Finally, we saw that it also affected the Log P value, and that psilocin is a more lipophilic compound, closer to an ideal value for drugs to effectively enter and bind to the appropriate receptors in the CNS.

I hope you enjoyed this journey, in the next article we will start our exploration of the phenethylamine class.


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About the Author

Faan Rossouw was born and raised in Cape Town (South Africa) and currently resides in Montreal (Canada). He holds a MSc in Plant Science, and is the co-founder and Chief Strategy Officer of Indeeva Biomedical, a medical cannabis company that focuses on producing condition-specific cannabinoid therapeutics. Faan possesses theoretical expertise and practical experience in biological production systems, natural and pharmaceutical product development, phytochemistry, and psychopharmacology. Though his background is rooted in science he is most passionate about, and thrives in, the intersection of science, the humanities, and commerce. He is interested in how we can leverage the properties of the new global economy to develop superior and sustainable therapeutic solutions. In his free time he loves to practice Brazilian Jiu Jitsu, spend time in nature with his partner Robyn, or kick back in his lazy boy with a book, a cup of pu-erh tea and his cat Luna.

Be sure to check out Faan’s site – alt.MIND