This week’s post will be a shorter one than usual but I wanted to do another medium-intensity dive into the mysterious ‘third’ or ‘fourth’ family of hallucinogenic substances, depending on your taxonomic preference. Like I mentioned in a previous post, isoquinolines are a relatively unexplored group of naturally-occurring molecules which are somewhat ubiquitous in many plant species. They’re understudied partially due to their relative abundance and partially due to a lack of interest in elucidating activity in humans. I specifically wanted to focus on a subfamily of isoquinolines, known as aporphine derivatives. I’ve already talked about one of them, namely glaucine! Glaucine is a 5-HT_2A selective agonist with a number of other properties, including bronchodilating and anti-inflammatory effects. Okay everything makes sense so far. Selective 5-HT_2A agonism is the bread-and-butter of...

A. Introduction. MDMA is an exciting and promising clinical compound which has shown promise in the treatment of serious mental health conditions such as PTSD. It has also been explored for a variety of indications ranging from obsessive compulsive disorder (OCD) to intimate couples therapy. There are, however, certain limitations on the use of MDMA in a clinical context. MDMA’s neurotoxic and cardiotoxic effects have been widely discussed in scientific literature and are explored in ‘Briefer on MDMA toxicity.’ However, MDMA tolerance is also a critical and largely underexplored issue. Anecdotally, this is often described as a permanent or long term ‘loss-of-magic.’ (https://www.vice.com/en/article/y3pejk/losing-the-magic-mdma). Tolerance to MDMA has also been demonstrated in relevant preclinical literature and in some human studies. In this briefer, we hope to better understand the...

1. Introduction

Despite the promise of MDMA’s role in the future of clinical psychiatry and its demonstrated efficacy in treating PTSD, concerns about the safety of MDMA have continued to make the rounds. Despite well-known cases (https://pubmed.ncbi.nlm.nih.gov/12351788/) where MDMA neurotoxicity was falsely reported, subsequent nonclinical studies with racemic MDMA have shown consistent markers of toxicity, in some cases at human therapeutic and recreational doses. This briefer will describe some of these findings and will discuss possible strategies for overcoming these challenges so that MDMA’s scope of possible clinical use can be widened.

2. Neurological Adverse Effects of MDMA

2.1 MDMA Neurotoxicity in Animal Models

Incidence of MDMA neurotoxicity has been demonstrated most clearly in preclinical animal studies, as is standard practice for small-molecule pharmaceutical...

In the course of a burgeoning interest in psychedelic medicine, one comes across two broad categories of similarly interested characters. You will find that some are neurotically obsessed with rigor and refuse to even discuss what these things do on a subjective level while others will insist you sit down and listen to their story of aligning a colleague’s moon chakra using an herbal intoxicant. While the two sides seem to disagree on pretty much everything, there does seem to be a common distaste for anything that’s not a ‘typical’ psychedelic like psilocybin or ayahuasca. Wait, no, you can’t move that hydroxy group from the 4 to the 5 position! Once the conversation drifts in that direction, they seem to conjure up images of underground drug labs in Ohio run by people named ‘toad pRofit$’ being raided by the DEA. On a cultural level, we’ve decided that if a therapy is run with a...

the full preprint containing a tryptamine index is available at https://www.dropbox.com/s/orchzuivtsoos1y/Tryptamines%20of%20Interest.pdf?dl=0

TLDR

• Hallucinogenic tryptamines appear highly effective against a variety of neuropsychiatric conditions

• Central activity, including hallucinogenic properties, depends on functional selectivity at the 5-HT_2A receptor

• Neural correlates of psychedelic activity includes glutamatergic transmission in the cerebral cortex, inhibition of slow oscillations, increases in extracellular GABA, and an increase in spontaneous signal diversity

• Central activity in humans is highly dependent on specific chemical functional group substitutions at the 4 and 5 positions on the benzene indole ring

Longer Abstract Summary

Tryptamine-derived compounds, many of them hallucinogenic, have been found to be potent pharmaceutical agents¹. In particular, psilocin...

Some exciting research came out of Emory University a few years ago, though it was not widely reported at the time. Leonard Howell (who has since retired) and his group discovered that while racemic MDMA (a mixture of the R(-) and S(+) enantiomers) produced neurotoxic effects in mice, administering just the R(-)-enantiomer did no such thing.^1,2

To give some background, the neurotoxicity of MDMA has been suspected for quite some time, going back a few decades. While the mechanism has not been fully uncovered, MDMA appears to produce damage to the serotonergic axon terminals in the striatum, hippocampus, and prefrontal cortex.³ As a result, we seem to find lower expression levels of tryptophan hydroxylase (the rate limiting enzyme involved in serotonin synthesis) and 5HT (serotonin itself) in rodents after a series of heavy doses of MDMA, as well as lower levels of DAT and SERT...