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

 

An Introduction to Psychedelic Tryptamine Chemistry

An Intro to Tryptamine Chemistry

Originally published: http://altdotmind.com/an-introduction-to-psychedelic-tryptamine-chemistry/


The ensuing series of articles are intended for the general reader that, like myself, have an appreciation for the beauty of chemistry, and/or desire to learn more about it. That being the case I am going to be pedantic throughout the articles, deconstructing technical terms and “dirty pictures”* with the assumption that you do not know what they mean. That way we can learn them as we go along. If you are already fluent in Chemistrian, it goes without saying that you are free to skip over these and peruse selectively. This first article is an introductory exploration of the tryptamine class, and will be followed by further forays into other interesting aspects related specifically to this class before I move on to the others. Enjoy.

The Three Main Classes of Psychedelics

There are three classes to which most psychedelic compounds belong – the tryptamines, phenethylamines, and ergolines (Figure 1). The tryptamines include most of the well-known naturally-occurring psychedelics, including compounds derived from entheogenic fungi (psilocybin and psilocin), DMT, 5-MeO-DMT, bufotenin, and ibogaine. Mescaline is the only common naturally-occurring phenylethylamine, yet the class includes numerous well-known synthetic compounds such as MDMA and the 2-C’s. Ergolines most notable representatives include the naturally-occurring LSA and the semi-synthetic compound that turned on a generation, LSD.


Figure 1. Notable psychedelic tryptamines include (from top right): 5-MeO-DMT and bufotenin (Bufo alvarius), psilocybin and psilocin (Psilocybe mushrooms), ibogaine (Tabernanthe iboga), DMT (Chacruna viridis), and various analogs including: 4-HO-MET (pictured), 5-MeO-DiPT, DPT, MET, and 4-AcO-DMT. Notable phenethylamines include (from top left): Mescaline (Peyote), the 2C’s (Inventor Sasha Shulgin pictured), MDMA (MAPS logo), and a wide range of analogs including: Bromo-DragonFLY (pictured), DOM, DOI, and NBOMe. Notable ergolines include (from top): LSD, LSA (Ipomoea sp), and various analogs including: AL-LAD (pictured), ALD-52, and 1-P-LSD.

Tryptamines

Psychedelics of this class are all derived from tryptamine (Figure 2), a ubiquitous endogenous ligand and agonist of the human trace amine-associated receptor 1 (TAAR1). The name tryptamine is derived from its structural similarity to l-tryptophan (Figure 3), an essential amino acid and the precursor to both serotonin and melatonin.


Figure 2. Tryptamine consists of an indole ring connected to an amine through an ethyl attached to position 3.


Figure 3. L-tryptophan

Substituted Tryptamines

Although the “template” for psychedelics tryptamines is the molecule with all the various positions presented in Figure 2, in actuality there are limitations to how this manifests in psychedelic compounds. This is either because certain modifications are either difficult to impossible, or they lead to inactive compounds. An example of this is if something is attached to position 2 (Figure 2) the compound becomes a serotonin-2A receptor antagonist therefor losing its psychoactivity. Based on these restrictions we can simplify the template presented in Figure 2 to Figure 4, which is called the ‘substituted tryptamine’. The three main changes that synthetic chemists can make to derive psychedelic analogs is derived from this figure.


Figure 4.

First, one can add side chains to either position 4 or 5, and those side chains have to contain an oxygen molecule. We can confirm this by looking at all the well known psychedelic compounds that have side chains attached to the ring – bufotenine has a hydroxyl (OH) group at position 5, 5-MeO-DMT has a methoxy (O-CH3) at position 5, psilocin has a hydroxyl (OH) group at position 4, and psilocybin has a phosphoryloxy (OPO3H2) at position 4. All at position 4 or 5, all with an oxygen included.

The second major change that can be made is a substitution at the α-position. Chemists can methylate (add a methyl group) the alpha-position to change a non-orally active species into one with orally active. We will explore this in full detail in the next article.

The final feasible change is adding sidechains to positions N1 or N2. All five of the major naturally-occurring species we have discussed thus far possess methyls at both positions (hence “dimethyl” from which the DM in DMT is derived – more below). These methyls may be substituted with more complex alkyls, another way in which chemists can turn non-orally active tryptamines into orally active species.


Psychedelics Tryptamines

Now that we have an idea of the chemical “archetype” of tryptamine psychedelics and the possible changes chemists can make, let’s have a look at the five most well-known naturally-occurring examples: DMT, 5-MeO-DMT, bufotenin, psilocybin, and psilocin.

DMT

The substitutive name for DMT is N,N-dimethyltryptamine. One of the most magical parts of learning chemical language is that from it one can deduce what they actual molecule looks like, and vice-versa. Let’s explore that using DMT as an example. Starting from the back we have tryptamine (blue), so we know that is the foundation of our molecule – the indole ring with an ethyl in position 3 attaching to an amine. Then we have “dimethyl” (red), meaning two methyls. Okay so now we know it’s the tryptamine molecule that has two methyls added to it. And where are these two methyls? They’re both positioned on the nitrogen of the amine, hence ‘N,N’.


Figure 5.

What’s interesting about N,N-dimethyltryptamine is that it forms the foundation for all four other compounds we are going to discuss. In other words, all four of them are N,N-DMT with a little something extra. We can see that because the term is contained within the substitutive name of all four other molecules. Let’s have a look.


5-MeO-DMT

The substitutive name for 5-MeO-DMT is 5-methoxy-N,N-dimethyltryptamine (Figure 6). We can see that it has the whole name of DMT in it, so when we draw it we know we can start with that molecule – a tryptamine with two methyls on the amine (red and blue). What’s left is ‘5-methoxy’, which means that at position 5 we have a methoxy (green). A methoxy is a combination of a methyl and an oxygen – hence the name.


Figure 6

Bufotenin

The substitutive name for bufotenin is 5-hydroxy-N,N-dimethyltryptamine (Figure 7). As was the case with 5-MeO-DMT, the molecule has DMT as a starting point (red and blue). But this time, instead of a methoxy at position five, we have a hydroxy, -OH (green).


Figure 7

Psilocin

The substitutive name for psilocin is 4-hydroxy-N,N-dimethyltryptamine (Figure 8). Same story, it starts with the structure of DMT (red and blue). If we compare them, we can see the psilocin is extremely similar to bufotenin, the only difference being where bufotenin had the hydroxy at position 5, here it’s at position 4 (green). In a future article we will learn why this small change is crucial to ensure that psilocin, unlike bufotenin, is an orally active species.


Figure 8

Psilocybin

The substitutive name for psilocybin is 4-phosphoryloxy-N,N-dimethyltryptamine (Figure 9). By now I’m sure you’ve grokked it – it’s a DMT molecule (red and blue) with a little something extra. As with it’s cousin psilocin, that something extra is at position 4, but here instead of a hydroxy, it’s a phosphoryloxy with the composition OPO3H2 (green).


Figure 9

All five molecules and their substitutions are reviewed in Figure 10 below.


Figure 10.

In the next article we will continue to explore psychedelic tryptamine chemistry by looking at the two changes synthetic chemists can make to DMT and 5-MeO-DMT to make them orally active.

Cover Image by Greg A. Dunn (www.gregadunn.com)

* = Sasha Shulgin used to affectionately refer to organic molecule structures as “dirty pictures”.



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


Ibogaine Treatment: A Psychedelic Answer to Opiate and Heroin Addiction

The use of heroin and abuse of opiate pain-relievers has reached an all-time high in the USA. The addictive nature of these drugs has left us scrambling for treatment options that can offer us freedom from this epidemic.

The fact is, traditional treatments don’t work for everyone, and many are starting to look for more effective alternatives. Treatment that results in long-lasting sobriety is different for each individual.

When a traditional method isn’t working, it may be time to consider something new. Ibogaine is one such treatment, and the rise in opiate addiction has led to an increased interest in this alternative treatment for opiate and heroin addiction.

Iboga and Ibogaine

Ibogaine is just one of the many alkaloids found in the Tabernanthe Iboga shrub. Raw Iboga is one of the most powerful psychedelic plants in the world and has been used for its profound spiritual effect on those who experience it.

Iboga plant and Ibogaine molecule. Photo: Samwise – via Chacruna.net

This is why, for centuries, the Bwiti religion of Africa have been using Iboga as a way to induce introspection and a higher self-awareness.

In the early 1900s Ibogaine was extracted from the Iboga root and used by athletes, in very small doses, as a stimulant. At the time, Ibogaine was used because of the way that it excites certain pathways within the brain.

But in the 1960s, all of that changed.

Ibogaine as an Addiction Treatment

Howard Lotsof was suffering from an addiction to heroin when he tried Ibogaine for the first time in 1962. He was 19 years old and experimenting with any substance he could find.

Hours after trying the Ibogaine, Lotsof had an epiphany—he had not taken opiates for almost a day, yet, he had no withdrawal symptoms.

He waited, but the withdrawals never came.


Howard Lotsof. Source: https://psychedelictimes.com/iboga/the-legacy-of-ibogaine-therapy-pioneer-howard-lotsof/

Ibogaine had allowed Lotsof to break his heroin addiction with just one dose. He knew immediately that these implications could have a massive impact on others who were struggling with heroin and opiate addiction.

But, given the importance of this conclusion, Lotsof realized he needed to perform further testing. So, he rounded up a few of his opiate and heroin-addicted friends, gave them the Ibogaine, and the results were stunning—none of his friends went into withdrawal.

This was the beginning of Ibogaine treatment for addiction. As Lotsof introduced more and more studies on the effects of Ibogaine on withdrawal, it became a real point of interest for scientists who were looking for more effective ways to help addicts beat their dependence.

Unfortunately, this also came at a time when the US government began making psychoactive substances illegal. Ibogaine was classified as a Schedule 1 drug, putting it in the same class as the drugs that it was meant to treat. It also made it very difficult for scientists to study its positive effects on addiction.

Lotsof was forced to study Ibogaine and treat addicts in Europe, where he founded the Global Ibogaine Therapy Alliance. He worked hard to try and change the laws in the USA and other countries, but, unfortunately, lacked the resources he considered necessary to do so.

 


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How Does Ibogaine Treat Physical Withdrawal?

Ibogaine has a unique effect on the chemical levels in the brain.

When the addict begins using opiates, these drugs release massive quantities of chemicals that plug into the brain’s neurotransmitters.

The brain becomes addicted to these high levels of pleasure-inducing chemicals, changing the way that the brain would normally function.

Because of these addictive adaptations, when the supply of drugs is cut off, the brain goes into a frenzy. Depression, seizures, and other symptoms are often the result. This is what we call withdrawal.

Ibogaine has the ability to work on the chemical receptors in the brain. It repairs neurons in the brain that have been damaged due to opioid addiction. It also restores balance to the brain so that naturally produced chemicals can work properly to control feelings of pleasure and happiness.

This gives addicts a fresh start, and the ability to start focusing on changing their lifestyle, instead of just fighting withdrawals.

But Ibogaine doesn’t just treat the withdrawal symptoms, it also affects the brain on a psychological level.

Psychological Effects of Ibogaine

In many addicts, though not all, Ibogaine induces a dreamlike state.

Those who have experienced this state often say that Ibogaine made them face their fears, past traumas, and helped them conquer many of the underlying reasons that caused their addiction in the first place.

This kind of psychological clarity and introspection is unique to the effects of Ibogaine and psychedelic medicines.

This is also why Ibogaine has been recommended, by some, as a treatment for trauma and other mental conditions—such as depression, anxiety, and PTSD.

The psychedelic effects of Ibogaine have the ability to treat these mental issues in ways that therapy never could. Some describe it as taking a look at themselves from the outside in, finally being able to address the core of their problems and address the root cause.

Is Ibogaine Right for You?

Just like any other treatment method, Ibogaine requires close supervision from medical professionals. Because of the way Ibogaine reacts in the body, it can be dangerous. This is why it is recommended that Ibogaine treatment should be done in a medical setting.

No treatment is risk-free, and it’s important to be educated before undergoing treatment with Ibogaine.

Addiction is a deeply personal disease and one that requires a different type of treatment for every individual. Ibogaine is not for everyone. It’s important to look into all of your options and talk to your physician.

Sobriety is possible. Every individual deserves a happy and successful life. Take the time to study all of the treatment options available and make the right decision for you or your loved one.


About the Author

Aeden Smith-Ahearn

Aeden Smith-Ahearn was a massive heroin addict for 7 years. After trying every traditional treatment method available, he put his last hope into Ibogaine treatment. Now, he has been clean and sober for 5 years while also helping thousands of addict find freedom through Ibogaine. He is currently the treatment coordinator for Experience Ibogaine (https://ExperienceIbogaine.com) treatment centers and works hard every day to help people find success and happiness in life.