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

The Art of Appetizing Aromatics: Part 2 of Psychedelic Chemistry


This is the second article in a series on psychedelic chemistry. In the previous article, I introduced the tryptamine class of psychedelics, and we discussed five well-known examples: DMT, 5-MeO-DMT, bufotenine, psilocybin, and psilocin. While the latter two, primary psychedelic constituents of Psilocybe mushrooms (Figure 1), are orally active, neither DMT, 5-MeO-DMT, nor bufotenine are. In this article we will explore two types of alterations that synthetic chemists can make to those molecules to bestow oral activity upon them. These alterations lead to the psychedelic tryptamine analogs (“research chemicals”): AMT (Indopan), MiPT, DiPT, 5-MeO-aMT (Alpha-O), 5-MeO-MiPT (Moxy), and 5-MeO-DiPT (Foxy Methoxy).


Figure 1.

Monoamine Oxidase

L-monoamine oxidase (MAO) is a family of enzymes that catalyze the oxidation of monoamines. Monoamines contain a single amine connected to an aromatic ring via a 2-carbon chain, and include neurotransmitters such as serotonin and norepinephrine, as well tryptamines (Figure 2) such as DMT, 5-MeO-DMT, and bufotenin. The reason therefore that these compounds are not active after being consuming orally is because once they enter one’s gut they are inactivated by MAO.


Figure 2.

If you want to experience the psychedelic effects of these compounds there are two basic strategies. The first is to use a route of administration that bypasses the gut. Smoking and vaporizing are by far the most common ways to achieve this, but are also the most intense (rapid onset) and shortest-lasting methods. Accordingly, some people favour other non-oral routes such as sublingual (under the tongue), insufflation (in the nasal passage), and rectal administration. Each of these administration routes has its own set of unique pharmacokinetic properties that may be favoured by certain people depending on the context and/or intention. Different strokes for different folks.

But that applies equally to oral delivery, which is unsurpassed in terms of its simplicity (swallow and then you’re done), ease (no thumbing around the butthole or snorting fiery salts up your schnoz), and duration. Except for transdermal delivery, which is technologically complex and has severe restrictions on what can be administered, oral delivery is the longest lasting. Hence its popularity for journeyers that wish to go in deep. So even with a number of non-oral administration routes available, there is still good reason to utilize the oral route.

How to do so if we all walk around with an enzyme in our belly that will deactivate the psychedelic? Simple – consume another compound, called a monoamine oxidase inhibitor (MAOI), that will deactivate that enzyme. Ayahuasca is a prime example of this, though there are a number idiosyncratic formulas of the brew, in essence, it is based on two core ingredients (Figure 3). One contains DMT, the most common being chacruna (Psychotria viridis), and the other contains the MAOI, which is always the ayahuasca vine (Banisteriopsis caapi).


Figure 3. A pot filled with chacruna leaves containing DMT, as well woody material from the ayahuasca vine containing harmine, tetrahydroharmine, and harmaline (MAOI’s). The former provides the visionary punch, the latter ensures that DMT is not broken down in the gut and is able to enter the blood plasma unchanged.

Synthetic chemists love to ask “what if” questions. Like “what if” I make this simple change to the molecular nature of the compound, how does that then affect its properties? These type of questions are explored not only in the name of scientific curiosity, but also because studying how simple changes affect the properties of compounds informs us about its structure-activity relationship, as well provide intimations of what the target receptor looks and behaves like. To the specific question of whether or not a simple alteration to DMT/5-MeO-DMT can actuate oral activity chemists have thus far provided two answers –  α-methylation (Figure 4) and N-alkylation (Figure 6).


α-Methylation


Figure 4.

As we covered previously, DMT is a tryptamine molecule with two methyls at the N-position. So what would happen if, instead of adding two methyls to the N-position of the tryptamine, we added a single methyl to the alpha-position? This yields AMT (alpha-methyltryptamine; Figure 5), a molecule originally developed in the ‘60s by a Michigan-based pharmaceutical company called Upjohn and which was prescribed in the USSR as an antidepressant. It is at once psychedelic, entactogenic (like MDA/MDMA), and a stimulant with an oral dose typically lasting upwards of 12 hours.


Figure 5.

The same goes for 5-MeO-tryptamine (mexamine) – if instead of adding two methyls to the N-position to form 5-MeO-DMT we add a single methyl to the alpha-position, we get 5-MeO-AMT – 5-methoxy-alpha-methyltryptamine (Figure 5). This orally-active and potent psychedelic, commonly known as ‘Alpha-O’, is sometimes peddled as faux-LSD. This is problematic as, unlike LSD with no known lethal toxicity, 5-MeO-AMT has lead to deaths at fairly low doses. It’s not a War on Drugs, it’s a War on People.

With both AMT and 5-MeO-AMT there is a chiral centre at the alpha-position. Attaching a single methyl to the alpha position potentially yields either an S- or R-configuration. Both are psychoactive, both orally active, but work by Dr. David Nichols lab has found that the S-enantiomer is more potent.


N-Alkylation


Figure 6.

With N-alkylation we manipulate DMT and 5-MeO-DMT as the departure point to realize oral activity. Both these molecules possess two methyls on the amine nitrogen. Work again by Dr. Nichols’ lab has found that if you replace one, or both, these methyls with isopropyl, the molecule becomes orally active (Figure 7).

 


Figure 7.

In the case of DMT, if a single methyl is replaced by an isopropyl it results in MiPT (N-methyl-N-isopropyltryptamine), an obscure psychedelic with indistinct effects first introduced to the world in TiHKAL. In the case of 5-MeO-DMT, the same single substitution results in 5-MeO-MiPT (5-methoxy-N-methyl-N-isopropyltryptamine). Commonly known as “Moxy”, it is an extremely potent (4 to 6 mg p.o.) psychedelic with stimulating properties.

As my articles on chemistry are intended for the general reader, I just want to take a brief moment here to remind you that the reason I always write out the substitutive name of each compound is because it describes the actual molecule. If we know the substitutive name, we can draw the molecule, and vice-versa. Let’s briefly review this by using Moxy as an example (Figure 8), but please feel free to skip over to the next paragraph if this is old news for you by now. Starting from back we have tryptamine, so our “foundational” structure is an indole ring with an ethylchain at 3 which connects to an amine group (blue). Then we start from the front – at position 5 we have a methoxygroup (green), at N1 we have a methyl (fuschia), and then at N2 we have an isopropyl (red).


Figure 8.

If both methyls are substituted by isopropyl, in the case of DMT the result is DiPT (N,N-diisopropyltryptamine), another bizarre creation of Sasha that primarily produces audial distortions. With 5-MeO-DMT the double substitution leads to 5-MeO-DiPT (5-methoxy-N,N-diisopropyltryptamine) which likely has the most endearing street name of any psychedelic – “foxy methoxy”. Note that in both cases, though making the additional isopropyl substitution retains oral activity, it decreases potency.


What’s Going On Here?

So why is it that in both the case of DMT and 5-MeO-DMT replacing a methyl with a slightly larger and more complex compound makes it impervious to deamination by MAO thereby giving it oral activity? To give us a clue we need to look at the nitrogen in the amine group – Figure 9. In order for MAO to deaminate a molecule, it needs to access the lone electron pair of electrons (blue) on the nitrogen. A change in the molecule, such as substituting functional groups, changes its 3D-conformation. In the case of substituting a methyl with an isopropyl group on the amine, it changes the molecule’s 3D shape in such a way that shields the lone pair of electrons from MAO, thus giving it oral activity.


Figure 9. Nitrogen has 7 electrons in total, and 5 valence electrons. It has one electron in each of the three 2p orbitals, which allow it to make three bonds (green), and two electrons in the 2s orbital which exists as a lone electron pair (blue).

How do we know this is the case that it’s the molecule’s 3D shape that protects the lone pair from attack by the MAO and thus allows it to retain oral activity? Earlier in this article, I said that MAO breaks down tryptamines. We then spoke about DMT and 5-MeO-DMT, but what about psilocybin and psilocin? They are naturally-occurring tryptamines, yet they are also orally active – how so? Pioneering work by Dr. David Nichols in the ‘80s using NMR spectroscopy showed that the fact that psilocin has a substitution at position 4 and not 5 (as with DMT/5-MeO-DMT) causes a critical change in the molecule’s 3D structure which ensures the compound is orally active. This study and all the profound implications for psychedelic chemistry gleamed from it will be the topic of our next article.


Afterword:

If it is your intention to consume DMT, and especially 5-MeO-DMT, orally by combining it with an MAOI  please do your homework. And once you’ve done your calculations, double-check them. Terence McKenna used to quip that the only real danger with DMT is “death by astonishment”. Though that is the case for smoking it, overdoing orally-administered DMT/5-MeO-DMT can lead to serotonin shock, convulsions, and in some cases, death. The Psychedelic Ship is leaving the harbour, please don’t drop any cannonballs on the deck.  

 

Cover image by Unknown Artist. If this is your work, I apologize for not crediting you, I searched high and low for your name but could not find it. Please message me and I will correct this.



About  Faan Rossouw

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