tag:nikobidin.com,2014:/feedNikita Obidin2024-03-28T15:27:07-07:00Nikita Obidinhttp://nikobidin.comobidinnikita@gmail.comSvbtle.comtag:nikobidin.com,2014:Post/a-briefer-on-mdma-toxicity2024-03-28T15:27:07-07:002024-03-28T15:27:07-07:00A Briefer on MDMA Toxicity<p><strong>1. Introduction</strong></p>
<p>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 (<a href="https://pubmed.ncbi.nlm.nih.gov/12351788/">https://pubmed.ncbi.nlm.nih.gov/12351788/</a>) 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. </p>
<p><strong>2. Neurological Adverse Effects of MDMA</strong></p>
<p>2.1 MDMA Neurotoxicity in Animal Models</p>
<p>Incidence of MDMA neurotoxicity has been demonstrated most clearly in preclinical animal studies, as is standard practice for small-molecule pharmaceutical research. Nonhuman primates have been commonly used as a model organism for MDMA neurotoxicity research given rough approximations in CNS structure to humans. In an excellent review, (Capela et al.) found that in a general sense, MDMA neurotoxicity is broadly observable in three distinct phenomena: serotonergic terminal loss, neuronal degeneration in several brain regions, and acute neuroinflammation (<a href="https://pubmed.ncbi.nlm.nih.gov/19373443/">https://pubmed.ncbi.nlm.nih.gov/19373443/</a>). (Hatzidimitriou et. al) found abnormal brain 5-HT innervation patterns were still evident in MDMA-treated monkeys seven years after a single dose of administration (<a href="https://pubmed.ncbi.nlm.nih.gov/10366642/">https://pubmed.ncbi.nlm.nih.gov/10366642/</a>). (Ricaurte et. al) administered s.c doses of MDMA to squirrel monkeys at doses approximating human therapeutic strength MDMA and found only partial recovery in the number of serotonergic presynaptic markers (<a href="https://pubmed.ncbi.nlm.nih.gov/1374470/">https://pubmed.ncbi.nlm.nih.gov/1374470/</a>). (Ricaurte et al.) in an earlier paper also demonstrated that MDMA selectively damages serotonergic neurons in nonhuman primates (<a href="https://pubmed.ncbi.nlm.nih.gov/2454332/">https://pubmed.ncbi.nlm.nih.gov/2454332/</a>). These results suggested that MDMA produces lasting effects on serotonergic neurons in nonhuman primates, with most brain regions showing evidence of persistent denervation and some showing signs of reinnervation (thalamus) or possibly even hyperinnervation (hypothalamus). (Mueller et al.) administered single oral doses of MDMA to squirrel monkeys and found that even the lowest single doses (equivalent to 1.6 mg/kg in humans or ~120 mg) produced significant serotonergic neurochemical deficits (<a href="https://academic.oup.com/ijnp/article/16/4/791/790204">https://academic.oup.com/ijnp/article/16/4/791/790204</a>). </p>
<p>Significant evidence of MDMA neurotoxicity has also been demonstrated in rodent species. (Touriño et al) demonstrated notable hyperthermia, DA terminal loss, and glial activation in MDMA-treated mice at 20 mg/kg (<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009143">https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009143</a>), though the authors found that these effects could be attenuated with the co-administration of THC. (Mueller et al.) found significant signs of monoamine terminal loss at room temperature in both rat and mouse (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558829/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558829/</a>).<br>
(Herndon et. al) found a robust microglial response within 12 hours of MDMA administration, however found that direct injection of MDMA did not significantly activate microglia, suggesting a significant contribution of MDMA metabolites to MDMA neurotoxicity (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930364/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930364/</a>). (Cadoni et. al) took a different approach and examined the effects of a low dose repeat regimen of MDMA on adolescent rodents. Groups treated at 5 and 10 mg/kg showed reduced density of tyrosine hydroxylase positive neurons and a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to an MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory (<a href="https://pubmed.ncbi.nlm.nih.gov/28603026/">https://pubmed.ncbi.nlm.nih.gov/28603026/</a>). (Frau et al.) examined the neurotoxicity of racemic MDMA, as well as its two optical isomers, R-MDMA and S-MDMA. Racemic MDMA consistently increased levels of CD11b and GFAP, both markers of neuroinflammation and microglial activation, however this effect was found to be mediated solely by the S-enantiomer. S-MDMA was also associated with hyperlocomotion and hyperthermia, whereas R-MDMA did not contribute to these effects (<a href="https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.12060">https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.12060</a>).</p>
<p>Cognitive and behavioral batteries have also been evaluated on MDMA-treated animals to evaluate potential effects on learning and memory. (Sprague et. al) compared untreated rodents to those treated with s.c MDMA on spatial learning and memory using the Morris water maze test. No statistical differences were found in MWM platform acquisition latency or pathlength between controls and MDMA-treated animals. Probe trials revealed significantly higher proximity score averages and significantly reduced preference for the target quadrant in the MDMA-treated animals. The study demonstrates that hippocampal serotonergic lesions induced by MDMA may be ostensibly linked to a reference memory deficit in rats tested with the MWM (<a href="https://pubmed.ncbi.nlm.nih.gov/12834800/">https://pubmed.ncbi.nlm.nih.gov/12834800/</a>).</p>
<p>(Moyano et al.) found that acute MDMA administration to rats resulted in reduced NR1 and N2RB protein levels and impaired passive avoidance training (<a href="https://pubmed.ncbi.nlm.nih.gov/14985918/">https://pubmed.ncbi.nlm.nih.gov/14985918/</a>). (Gouzoulis-Mayfrank et. al) evaluated the long-term neuropsychological effects of adolescent MDMA exposure on rodents, through the performing of repeated learning and memory tasks during the rodents lifespan. The performance of drug treated rats was notably worse on tasks requiring cognitive flexibility, such as the water maze task. While some persistent cognitive deficits were found, no significant group differences in serotonin or dopamine levels were found in any of the measured regions of the brain changes, cortical or subcortical (<a href="https://www.scirp.org/reference/referencespapers?referenceid=2113205">https://www.scirp.org/reference/referencespapers?referenceid=2113205</a>). Lastly, (Fernandez-Castillo et al.) conducted a wide ranging study on MDMA’s impact on gene expression patterns, finding that genes related to inflammation, cytotoxicity-associated neuroadaptation, and immune responses (<a href="https://www.researchgate.net/publication/304817206_MDMA_Ecstasy_and_Gene_Expression_in_the_Brain">https://www.researchgate.net/publication/304817206_MDMA_Ecstasy_and_Gene_Expression_in_the_Brain</a>). </p>
<p>2.2 MDMA-Metabolite Neurotoxicity Studies</p>
<p>In addition to results demonstrating the neurotoxicity of MDMA in animals, research has been conducted to better elucidate mechanisms of this toxicity. Much of this has centered on the metabolic profile of MDMA and on the exacerbating properties of hyperthermia, which will be discussed in a later section. (Jones at al) found that glutathione (GSH) and N-acetylcysteine conjugates of alpha-methyldopamine, which are second-order metabolites of MDMA and selective neurotoxins, were present in rat striatum after subcutaneous injection of MDMA (<a href="https://jpet.aspetjournals.org/content/313/1/422?ck=nck">https://jpet.aspetjournals.org/content/313/1/422?ck=nck</a>). (Bai et. al) had previously shown that both of these conjugates were selective neurotoxins in the mouse brain (<a href="https://pubs.acs.org/doi/abs/10.1021/tx990084t">https://pubs.acs.org/doi/abs/10.1021/tx990084t</a>). Using mouse brain synaptosomes, (Barbosa et al.) evaluated the prooxidant effects of the A-MeDA, N-Me-a-MeDA, 5-GSH-a-MeDA, and other thiolated metabolites of MDMA. They found that the metabolites time- and dose-dependently increased H2O2 and quinoprotein production, though notably having no effect on mitochondrial polarization (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346242/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346242/</a>). (Capela et al) further demonstrated that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols and induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones (<a href="https://pubmed.ncbi.nlm.nih.gov/17467183/">https://pubmed.ncbi.nlm.nih.gov/17467183/</a>). </p>
<p>2.3 Cognitive effects of MDMA use in humans</p>
<p>Though accurate measurements of the extent of neurotoxicity in humans are difficult to collect, pilot studies have been conducted in test subjects to better elucidate the effects of MDMA use on cognitive tasks, learning, and memory. (Halpern et al.) assessed cognitive function in 52 MDMA users with no prior drug experience and only found moderate detrimental cognitive effects across all subjects (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf</a>). (Schilt et al.) examined the relationship between MDMA use and cognitive performance in 188 subjects, split into MDMA and non-MDMA using groups. Though immediate follow-ups did not show a statistically significant discrepancy in the battery of neurocognitive tests, change scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident MDMA users compared with persistent MDMA-naive subjects (<a href="https://pubmed.ncbi.nlm.nih.gov/17548754/">https://pubmed.ncbi.nlm.nih.gov/17548754/</a>). (Wagner et. al) found that in a data set of 96 naïve non-polydrug MDMA users, cognitive performance declined with repeat use as well as with later onset of MDMA use (<a href="https://www.sciencedirect.com/science/article/abs/pii/S0278584614002413#:%7E:text=Cognition%20and%20psychopathology%20were%20associated,attention%20and%20information%20processing%20speed">https://www.sciencedirect.com/science/article/abs/pii/S0278584614002413#:~:text=Cognition%20and%20psychopathology%20were%20associated,attention%20and%20information%20processing%20speed</a>). (Reay et. al) showed that MDMA polydrug users showed impairments in set shifting, memory updating, and social judgement processes (<a href="https://journals.sagepub.com/doi/abs/10.1177/0269881106063269">https://journals.sagepub.com/doi/abs/10.1177/0269881106063269</a>). Finally, (Hanson et. al) also found notable signs of cognitive impairment in MDMA users (in memory, attention, and motor function), however this was primarily limited to users with clinically dysfunctional MDMA use (<a href="https://psycnet.apa.org/record/2004-12175-005">https://psycnet.apa.org/record/2004-12175-005</a>). Lastly, in the most comprehensive neuroimaging study to-date [Kish et. al 2010] concluded that the serotonergic deficits of MDMA users remained present after “controlling for every potential confound we could address.”</p>
<p><strong>3. MDMA effects on the cardiovascular system and body temperature</strong></p>
<p>MDMA has also been extensively studied with respect to its effects on the cardiovascular system and body temperature. (Liechti et al) found that MDMA produced an acute and dose-dependent increase in core body temperature in humans, consistent with hyperthermia. At higher doses, Liechti found that MDMA induced hyperpyrexia, which can lead to intravascular coagulation, rhabdomyolysis, and renal or other organ failure (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008716/#:%7E:text=The%20data%20show%20that%20MDMA,in%20a%20controlled%20laboratory%20setting">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008716/#:~:text=The%20data%20show%20that%20MDMA,in%20a%20controlled%20laboratory%20setting</a>). (Fantegrossi et. al) compared MDMA to its optical isomers, R- and S-MDMA, in their capacity to drive hyperthermia and locomotor activity. Notably, racemic MDMA and S-MDMA produced locomotion and hyperthermic effects in mice, while R-MDMA did not. Cage crowding was found to adversely affect lethality, with greater crowding resulting in a higher percentage of deaths. (<a href="https://pubmed.ncbi.nlm.nih.gov/12563544/">https://pubmed.ncbi.nlm.nih.gov/12563544/</a>).</p>
<p>(Koczor et. al) set out to explore the acute cardiotoxicity associated with MDMA, including tachycardia and arrhythmia, which are associated with cardiomyopathy. Extensive MDMA use caused DNA hypermethylation and hypomethylation that was independent of gene expression as well as differential gene expression in 558 genes, including changes to MAPK and circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) (<a href="https://pubmed.ncbi.nlm.nih.gov/26251327/">https://pubmed.ncbi.nlm.nih.gov/26251327/</a>). These cardiovascular effects were further studied by (Bexis et. al) who found that MDMA produced a prolonged increase in systolic and diastolic blood pressure in rodents, as well as isomeric contractions. The authors found that these effects were mediated by MDMA’s agonism at the alpha-adrenoreceptors (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189797/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189797/</a>). (Badon et. al) studied the effects of binge doses of MDMA on cardiovascular parameters in rodents. Subsequent MDMA doses were accompanied by hypotension and bradycardia. The hearts of treated rats contained foci of inflammatory infiltrates (lymphocytes and macrophages), some of which contained necrotic cells and/or disrupted cytoarchitecture. MDMA produced cardiac arrhythmias in some rats (<a href="https://pubmed.ncbi.nlm.nih.gov/12183645/">https://pubmed.ncbi.nlm.nih.gov/12183645/</a>). Lastly, although understudied compared to other serotonergic agents, MDMA’s agonism at the 5-HT2B receptor subtype has been evaluated in the context of valvular heart disease risk. (Setola et. al) found that MDMA produced fenfluramine-like proliferative actions on valvular interstitial cells in-vitro. The group also demonstrated that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. These results suggest that long-term MDMA use could lead to the development of fenfluramine-like VHD (<a href="https://pubmed.ncbi.nlm.nih.gov/12761331/)">https://pubmed.ncbi.nlm.nih.gov/12761331/)</a>). (Baumann et al.) similarly found that MDMA had potential for inducing VHD, especially with repeat dosing (<a href="https://pubmed.ncbi.nlm.nih.gov/19897081/">https://pubmed.ncbi.nlm.nih.gov/19897081/</a>) </p>
<p><strong>4. Additional Toxicity Information</strong></p>
<p>Beyond the first-order neurological and cardiovascular risks of MDMA, research has also been conducted on the toxicity of MDMA in other organ systems as well as developmental effects. Though individual cases of hepatic injury have been reported (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671195/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671195/</a>), a comprehensive review of MDMA’s effects on liver function was lacking until (Cajanding), who demonstrated wide ranging toxic effects in liver (<a href="https://pubmed.ncbi.nlm.nih.gov/31462520/">https://pubmed.ncbi.nlm.nih.gov/31462520/</a>) across three clinical studies. Furthermore, (Shahraki et. al) demonstrated changes in the lipoprotein of rats after MDMA administration, potentially showing a hepatoxic profile for MDMA (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331654/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331654/</a>). <br>
Developmental Toxicity was demonstrated by (Barenys et. al), who conducted a review of teratogenic and developmental effects of MDMA. The primary results showed that MDMA exposure during pregnancy impairs neuromotor function in infants. In rats, postnatal exposure to MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus (<a href="https://iris.uniroma1.it/retrieve/e383532c-48ce-15e8-e053-a505fe0a3de9/Barenys_Developmental_2020.pdf">https://iris.uniroma1.it/retrieve/e383532c-48ce-15e8-e053-a505fe0a3de9/Barenys_Developmental_2020.pdf</a>).<br>
Lastly, though a relatively underexplored space, the role of mitochondrial dysfunction in MDMA’s neurotoxic effects should be noted. (Quinton and Yamamoto) found evidence implicating impaired metabolic fluxes in MDMA-induced neurotoxicity (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497800/#R124">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497800/#R124</a>). (Alves et. al) found that ALCAR provided some protection against these effects (<a href="https://pubmed.ncbi.nlm.nih.gov/19015003/">https://pubmed.ncbi.nlm.nih.gov/19015003/</a>). </p>
<p><strong>5. Mitigation of risks/ REMS</strong></p>
<p>Despite these risks, they should be weighed in the context of the demonstrated clinical benefit of MDMA, which is substantial. This is especially relevant given the serious consequences of non-treatment/ineffective treatment of PTSD. In the case of the MAPS protocol, the limited number of sessions (3) as well as the capped total dose (125 mg {t=0} + 62 mg {t=2hr}) can reduce the total liability of the drug from a cardiovascular and neurological standpoint. Given that existing evidence shows that accumulation of selective neurotoxic metabolites and hyperthermia are both contributors to MDMA’s direct CNS toxicity, limiting the number of sessions and lowering the temperature in the therapy setting may dampen the extent of neuroinflammation that is commonly seen in accompanying animal studies. </p>
<p>However, these steps may come at a cost for treatment resistant cases of PTSD or cPTSD, where the index trauma and onset of symptoms may be highly complex or may have happened in childhood. Cases like these may require more than 3 sessions before symptoms fully subside, and the patient can recover. Furthermore, a strict restriction in the number of sessions will likely limit the clinical use of MDMA outside of trauma therapy, such as for indications like mood and substance disorders where a more regular dosing protocol may be required. Therapists could consider co-administered of agents such as Vitamin-C, ALCAR, and ALA, which are often used alongside MDMA in a clandestine setting to supposedly reduce the neurotoxicity of MDMA, though there are few well-controlled studies on their efficacy. </p>
<p>Additionally, as previously alluded to in Section 2, non-racemic or chiral forms of MDMA with an increased fraction of the R-isomer seem to reduce or eliminate the neurotoxicity and hyperthermia of racemic or S-MDMA while preserving MDMA’s prosocial effects in rodents. Further pharmaceutical development may extend the potential reach of MDMA into other indications within mental health therapeutics. Lastly, de novo empathogens or those developed as non-neurotoxic analogues of MDMA may provide an alternative route for using entactogenic substances to treat mental illness. </p>
<p><strong>6. Nuance and context for evaluating existing data</strong></p>
<p>It is important to recognize the limitations of the summary and analysis of the data above. Firstly, there are inherent limitations to drawing conclusions from canine, rodent, and non-human primate studies due to ADME and other differences between animal models and humans. Furthermore, certain ‘markers’ of neurotoxicity such as reduced levels of monoamines may not establish a causal link with direct neuronal damage or may be transient, with subsequent rebounds to pre-administration levels. Furthermore, existing neurotoxicity literature on MDMA may have been biased by the political and social taboo of entactogens and hallucinogens during the 1990s, when much of this work was performed. In human studies, polydrug effects and inability to control API quality and purity may have also exaggerated the cognitive effects of MDMA neurotoxicity. Still, these markers of toxicity are still stubbornly present in newer studies, which have focused on single drug users and more robust animal neurotoxicity studies on racemic MDMA. The need for safer and more effective empathogens continues to exist.</p>
tag:nikobidin.com,2014:Post/further-explorations-into-naturally-occurring-isoquinolines2020-07-16T07:24:19-07:002020-07-16T07:24:19-07:00Further explorations into naturally-occurring isoquinolines: the aporphines<p><a href="https://svbtleusercontent.com/6tKWE2asCHPuTduoDj1AM60xspap.png"><img src="https://svbtleusercontent.com/6tKWE2asCHPuTduoDj1AM60xspap_small.png" alt="Screen Shot 2020-07-15 at 5.45.07 PM.png"></a><br>
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 <a href="http://nikobidin.com/isoquinolines-structural-analogues-of-the-hidden-third-family">in a previous post</a>, 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<sub>2A</sub> selective agonist with a number of other properties, including bronchodilating and anti-inflammatory effects. Okay everything makes sense so far. Selective 5-HT<sub>2A</sub> agonism is the bread-and-butter of psychedelic science. </p>
<p>If one chops off the benzene-conjugated methoxy groups, you get the base structure of aporphine, with comes in R and S enantiomeric flavors. Many plants of the <em>Nymphaea</em> family, better known as water lillies, produce aporphine derivates, such as nymphaeine and nymphaline. Some, like <em>Nymphaea caerulea</em> contain better-studied derivatives like nuciferine. Where things get interesting is with the plant <em>Nymphaea caerulea</em> in particular, which has been known to a number of ancient civilizations in the Fertile Crescent and the Indian Subcontinent who used and wrote about it in ceremonial and religious contexts. No doubt that <em>Nymphaea caerulea</em> has within it alkaloids which have psychoactive and possibly hallucinogenic properties. At this point, it’s a game of find the needle in the haystack though the base aporphine and nuciferine are certainly promising candidates. <a href="https://pubs.acs.org/doi/10.1021/jm960189i">A 1996 paper</a> in Journal of Medicinal Chemistry did a partial pharmacological profile of about 30 different aporphine derivatives and found some interesting results. </p>
<p><a href="https://svbtleusercontent.com/dvBBws9nctkkcLgf3nEZMv0xspap.png"><img src="https://svbtleusercontent.com/dvBBws9nctkkcLgf3nEZMv0xspap_small.png" alt="Screen Shot 2020-07-15 at 5.50.29 PM.png"></a></p>
<p><a href="https://svbtleusercontent.com/q7HnCqRULLUuitaAhNhZvC0xspap.png"><img src="https://svbtleusercontent.com/q7HnCqRULLUuitaAhNhZvC0xspap_small.png" alt="Screen Shot 2020-07-15 at 5.51.38 PM.png"></a></p>
<p>Although the screen only included the one variant of receptor 5-HT (the 1A subtype), several variants on the list showed quite strong affinity, namely 4,6,14, and 23. There were also a number of compounds which showed good affinity for D<sub>1</sub> and D<sub>2</sub>. It is not entirely clear whether these compounds have antagonistic effects at 5-HT<sub>1A</sub>, though the paper claims that this may be the case. Certainly aporphine has been found to be a D<sub>1</sub> and D<sub>2</sub> antagonist. Nantinine is well known to block the effects of MDMA due to its antagonism at 5-HT<sub>2A</sub>. The question remains where the psychoactive and downright psychedelic effect is coming from. Is this simply the downstream manifestations of a dopamine receptor blockade or something different? Perhaps a more thorough study of these compounds would provide a hint. </p>
<p><strong>References</strong></p>
<p>Hedberg, Martin H., et al. “11-substituted R-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.” Journal of medicinal chemistry 39.18 (1996): 3503-3513.</p>
tag:nikobidin.com,2014:Post/phenethylamines-i-have-feared-and-loathed2020-07-03T00:28:10-07:002020-07-03T00:28:10-07:00Phenethylamines I have feared and loathed<p><a href="https://svbtleusercontent.com/cvBLxFXLeMaajDn7MFQPBo0xspap.png"><img src="https://svbtleusercontent.com/cvBLxFXLeMaajDn7MFQPBo0xspap_small.png" alt="Screen Shot 2020-07-07 at 4.55.10 PM.png"></a><br>
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 shaman using a completely chemically-uninterpretable drug cocktail: totally a-okay. But if it’s run with a synthetic pure compound of known quantity: immediate banishment. It’s silly of course in the sense that in either case there are centrally active compounds with particular affinities and whether yours comes from a three step synthesis or from a plant is really irrelevant to your brain’s serotonin receptors. </p>
<p>That said, I thought it might be fun to talk about the compounds that didn’t quite make it into PIHKAL, or which made it in with a substantial disclaimer. As in, phenethylamines that are both centrally active and unlikely to make it into a clinical trial anytime soon. There are a few genuine reasons for discussing negative valence compounds and they have nothing to do with filling up space. Firstly, getting a better grasp on what doesn’t work and why may give us some clues on how to design better compounds. Given how concentrated the activity seems to be at a few critical ring positions and what a wide variance of effects is hence generated, this may give us some design clues from a therapeutics perspective. </p>
<p>Secondly, phenethylamines in particular are a source of endless fascination because of the interplay of the amphetamine-like TAAR1/D1-agonist effects and the tryptamine-like 5-HT<sub>2A</sub>-agonist effects. This can be both beneficial, reducing the potential for negative valence during a clinical infusion and also a recipe for disaster if the pharmacodynamics and dosage of the compound are less-than-ideal. </p>
<p>It is also the case that due to these non-specific effects, phenethylamines seem to have a generally less ideal safety profile compared to lysergamides or tryptamines. One notorious nasty side effect is vasoconstriction. Another is serotonin syndrome when the compound has both serotonin transporter activity and is a MAOI. Occasional deaths have been attributed to compounds of this class, though the culprits mostly seem to be general mishandling, inaccurate dosing, mislabeling, or haphazard co-administration. Nevertheless, these and other reasons make me suspect that even ‘safer’ phenethylamines like 2C-B won’t be getting FDA approval anytime soon. </p>
<p><strong>2C-P</strong></p>
<p><a href="https://svbtleusercontent.com/qMZWBj1kouNPkaWxTdJbSP0xspap.jpeg"><img src="https://svbtleusercontent.com/qMZWBj1kouNPkaWxTdJbSP0xspap_small.jpeg" alt="plan.001.jpeg"></a></p>
<p>2C-P combines the traditional di-methoxylated phenethylamine with a propyl-substitution at the 4 position. The 4 position is the critical R-group for 2C compounds, sort of akin to the 4 and 5 on the indole benzene ring for tryptamines. Substitutions at the 4 tend to change the subjective effects and duration of the drug considerably. With the case of 2C-P it produces a compound with very high potency (6-10 mg dosage range) and quite long periods of activity, up to 20 hours. Yes, 20 hours! Not to mention that peak effects don’t take place for 3-5 hours after oral consumption. The subjective effects themselves tend to vary in terms of valence with some reports of notable physical discomfort. As a potential treatment though, the long activity time and onset time is unlikely to work in its favor. </p>
<p><strong>2C-G</strong></p>
<p><a href="https://svbtleusercontent.com/biNxwqD523nMfqWkYXccUp0xspap.jpeg"><img src="https://svbtleusercontent.com/biNxwqD523nMfqWkYXccUp0xspap_small.jpeg" alt="plan.001 copy.jpeg"></a></p>
<p>2C-G is another phenethylamine with a somewhat lower potency than 2C-P balanced by an even longer effect time (18-30 hrs!). I was considering not including this on the list primarily because the subjective effects are largely subdued, having no strong visual or tactile components. 2C-G is classified as more of a ‘insight enhancer’ by Shulgin and is probably best suited for a role in psychotherapy. The extremely long effect time seems to cast doubt over that possibility. As with the other phenethylamines, the toxicity and pharmacology of 2C-G is poorly worked out or non-existent altogether. </p>
<p><strong>Bromo-DragonFLY</strong></p>
<p><a href="https://svbtleusercontent.com/qTJ3drtpaHkG1DVT4N2dvP0xspap.jpeg"><img src="https://svbtleusercontent.com/qTJ3drtpaHkG1DVT4N2dvP0xspap_small.jpeg" alt="dragonfly.jpeg"></a></p>
<p>Somewhere near the top of the list of unfortunate creations to come out of David Nichols’s lab is this monstrosity with two furans fused onto a 2C-B structural variant. Firstly the pharmacology of Bromo-DragonFLY tells us that it is a non-subtype specific 5-HT<sub>2</sub> agonist. It’s also a MAO-A inhibitor, which strongly inhibits oxidative deamination of 5-HT, thereby increasing its overall nastiness. Due to being confused for the related, but far less potent 2C-B-FLY, there has been an unfortunate string of overdoses. At higher, non-therapeutic doses, reports indicate vasoconstriction so extreme that it causes tissue necrosis, seizures, and near fatal asphyxia. More-over subjective effects have been described as “like being dragged to hell and back again. Many times. It is the most evil [thing] I’ve ever tried. It lasted an eternity.” Oh and it lasts up to 3 days. No gracias. </p>
<p><strong>25B-NBOMe</strong></p>
<p><a href="https://svbtleusercontent.com/cHwC9gZ3yB9javuCNavpxv0xspap.jpeg"><img src="https://svbtleusercontent.com/cHwC9gZ3yB9javuCNavpxv0xspap_small.jpeg" alt="mbe.jpeg"></a></p>
<p>25-NBOMe is a relatively unknown derivative of 2C-B created at the Free University of Berlin in 2004. Anecdotal reports suggest that an active dose is something in the range of 250-500 µg with a 12 to 16 hour duration time. The compound is also structurally analogous to 25I-NBOMe and probably shares much of its risk profile. The high potency makes it a high risk for overdosing if taken nasally. High doses have also been linked to thrombosis and vasoconstriction similarly to Br-DragonFLY. On the side of subjective effects, things are not helped by the wide range of experiences ranging from changes in tactile perception to paranoia and ego death. Certainly the narrow range between a safe and lethal dose is quite debilitating for any medical use. </p>
<p><strong>3C-BZ</strong> </p>
<p><a href="https://svbtleusercontent.com/wLN8s575rZbx7tfcbzdt4p0xspap.jpeg"><img src="https://svbtleusercontent.com/wLN8s575rZbx7tfcbzdt4p0xspap_small.jpeg" alt="plan.006.jpeg"></a></p>
<p>This is another Shulgin substituted amphetamine with some bizarrely differing effects. The activity time is quite long, up to 24 hours, and the dosage of activity seems quite wide. Based on the few reports available, the lower dosages below 50 mg seem to induce a wakeful, emotionally vulnerable, and not-always-positive place, along with the amphetamine-like kick. At higher doses, the reports seem to suggest an almost LSD-like experience. Most of the subjects described being physically exhausted after the experience, which seems to subjectively drag on forever. What is notable and can be learned from is the drug’s tendency to produce differing amphetamine-like effects at low dosages and tryptamine-like OEVs at higher levels. Certainly elucidating the pharmacodynamics would cast some light on this observation. </p>
<p><strong>2C-G5</strong></p>
<p><a href="https://svbtleusercontent.com/pw5nmXcFMYq1je4PZRFEME0xspap.jpeg"><img src="https://svbtleusercontent.com/pw5nmXcFMYq1je4PZRFEME0xspap_small.jpeg" alt="weord.jpeg"></a></p>
<p>2C-G5 is technically a derivative of 2C-G and is often classed as such, though it has a distinctive benzonorbornane ring system at the critical 4 position on the phenethylamine. Such chemical stapling is bound to produce some unique effects. In this case, it produces a compound with an active period of 48 hours. Though the effects are somewhat subdued compared to other compounds of this class, it’s probably the longest acting phenethylamine to be included in PIHKAL. Furthermore, as Shulgin notes himself, it’s a racemate due to the benzonorbornane chiral center. Separation of the optical isomers might provide some insight into the binding of these compounds at their receptors, though the process of separation is a time consuming one. </p>
<p><strong>Conclusion</strong> </p>
<p>A number of other synthetic phenethylamines synthesized by both Shulgin and others present similar challenges. Notably, 2C-T-4, 2C-T-8, and 2C-T-9 have some unfortunate properties including long periods of duration and nausea, as well as a bunch of negative valence subjective effects. The hope in cataloguing drugs with unfavorable properties is to begin a process of understanding the experiences better and hopefully to build better ones in the future. As stated before, phenethylamines despite all of their downsides are an endless source of fascination due to the wide range of effects and effect times in humans. </p>
<p><strong>References</strong> </p>
<p>1.) Shulgin, Alexander, and Ann Shulgin. TIHKAL: the continuation. Transform press, 1997.</p>
<p>2.) Parker MA, Marona-Lewicka D, Lucaites VL, Nelson DL, Nichols DE “A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor”. Journal of Medicinal Chemistry. (1998) 41 (26): 5148–9.</p>
<p>3.) Heim, Ralf. Synthese und Pharmakologie potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur: Entwicklung eines neuen Struktur-Wirkungskonzepts. Diss. 2004.</p>
<p>4.) Shulgin, Alexander, and Ann Shulgin. PIHKAL: a chemical love story. Transform Press, 1995.</p>
tag:nikobidin.com,2014:Post/isoquinolines-structural-analogues-of-the-hidden-third-family2020-07-01T14:49:04-07:002020-07-01T14:49:04-07:00Isoquinolines: structural analogues of the mysterious third family<p>Isoquinolines are a rather large naturally-occurring family of benzopyridines which find medical applications in everything from antihypertensives to anti-retrovirals to anesthetics. But they have an interesting hidden side which is to date pretty unexplored. </p>
<p>Those familiar with Alex Shulgin’s work will no doubt remember making their way through PIHKAL, first through the autobiographical chapters and then the synthesis portion where phenethylamines (a family which includes 2C-B, 2C-C, MDMA, and mescaline) are described in impressive detail. Some have also picked up TIHKAL, the continuation of the journey through the space of hallucinogenic compounds, this time covering tryptamines (psilocin, bufotenine, DMT, and LSD) with the same basic book structure. </p>
<p>Not including the various compiled studies and reports that Shulgin wrote over the course of his career, there is a third major book with the unassuming title <em>The Simple Plant Isoquinolines.</em> More ominously, in the introduction, Shulgin calls this <em>The Third Book.</em> The first obvious question involves the nature of the substances involved, namely isoquinolines. Most well-known hallucinogenic compounds, whether psilocin, mescaline, DMT, or LSD, belong to one of two classes of compounds: the phenethylamines and the tryptamines. Tryptamines are partially structurally analogous to the neurotransmitter serotonin while phenethylamines resemble dopamine and norepenephrine. A visual example of this is shown below. Notice the similarities in the chemical structures of the vertical columns:</p>
<p><a href="https://svbtleusercontent.com/97U1mmx1oZCSxeL8faav910xspap.jpeg"><img src="https://svbtleusercontent.com/97U1mmx1oZCSxeL8faav910xspap_small.jpeg" alt="Untitled.001.jpeg"></a></p>
<p>But wait! LSD, PRO-LAD, and AL-LAD which are in a technically separate family called the lysergamides look quite different by comparison at first glance due to the several bulky aromatic groups. </p>
<p><a href="https://svbtleusercontent.com/hZZGjjzmLcwwQJ52GUravb0xspap.png"><img src="https://svbtleusercontent.com/hZZGjjzmLcwwQJ52GUravb0xspap_small.png" alt="Screen Shot 2020-06-29 at 10.40.45 PM.png"></a></p>
<p>Looking closer however, we see the familiar tryptamine structure popping out at us and even a phenethylamine hiding in plain sight, just invisible due to its incorporation into the aromatic groups. </p>
<p><a href="https://svbtleusercontent.com/jGve3tPS4L8F5j9f1NYzAL0xspap.png"><img src="https://svbtleusercontent.com/jGve3tPS4L8F5j9f1NYzAL0xspap_small.png" alt="Screen Shot 2020-06-29 at 10.44.39 PM.png"></a></p>
<p>Coming back around to isoquinolines and their structure, we need to imagine folding the amino terminated alkyl chain on one of the tryptamine indoles or the phenethylamine benzenes, thereby forming a new ring.</p>
<p><a href="https://svbtleusercontent.com/eYmtdMt2Pz9moXTKTrzXWm0xspap.png"><img src="https://svbtleusercontent.com/eYmtdMt2Pz9moXTKTrzXWm0xspap_small.png" alt="Screen Shot 2020-06-29 at 10.48.47 PM.png"></a><br>
<a href="https://svbtleusercontent.com/e8DCbimAZsS75KQDAx2Pro0xspap.png"><img src="https://svbtleusercontent.com/e8DCbimAZsS75KQDAx2Pro0xspap_small.png" alt="Screen Shot 2020-06-29 at 10.48.59 PM.png"></a></p>
<p>The tryptamine variant is known as tetrahydrobetacarboline whereas the phenethylamine variant is a tetrahydroisoquinoline. Those familiar with TIHKAL will notice that the carboline-like molecule looks somewhat familiar and they would be entirely right. Harmaline and Harmine, both monoamine oxidase inhibitors which Shulgin describes, are derivatives of this basic structure. Ibogaine has some similar visual characteristics but has a cycloheptane ring straddling the indole versus a cyclohexane. </p>
<p><a href="https://svbtleusercontent.com/e5GprvDpqYGy2Ebr6Q86MJ0xspap.png"><img src="https://svbtleusercontent.com/e5GprvDpqYGy2Ebr6Q86MJ0xspap_small.png" alt="Screen Shot 2020-06-30 at 12.09.11 PM.png"></a></p>
<p>All three of the compounds are known to have hallucinogenic effects according to TIHKAL, though differing somewhat from the ‘traditional’ psychedelics. Harmaline is known to produce closed and open eye visual distortions in the 200+ milligram dosage range with a rather high body load and effects resembling paranoia.<sup>1</sup> The seeds of the <em>Peganum harmala</em> plant tend to produce a psychoactive effect as well at the gram scale, though these contain a number of other alkaloid species including harmine. More importantly, due to the monoamine oxidase inhibitory effects of Harmine-like betacarbolines, they have been consumed to make tryptamines such as DMT orally active.<sup>2</sup> While we may not think of MAOIs as having central activity, subjective reports seem to suggest otherwise. They unfortunately also tend to have a less-than-favorable profile which includes nausea, hypotension, blurred vision, paresthesia, and general discomfort. </p>
<p><a href="https://svbtleusercontent.com/o1s6ibfowDZcnkhzQ7y69u0xspap.jpeg"><img src="https://svbtleusercontent.com/o1s6ibfowDZcnkhzQ7y69u0xspap_small.jpeg" alt="Untitled.004.jpeg"></a></p>
<p>Another known hallucinogenic substance of the isoquinoline class is glaucine, found in a number of different plant species in the family <em>Papaveraceae.</em> Glaucine is an anti-inflammatory bronchodilator, which acts as a calcium channel blocker.<sup>3</sup> The naturally occurring (S)-isomer also has activity at the important 5-HT<sub>2A</sub> receptor.<sup>4</sup> While it is a relatively unknown hallucinogenic compound, some clinical reports have indicated that it has broadly dissociative effects as well as open and closed eye visuals.<sup>5</sup></p>
<p>The other two molecules shown above are both isoquinoline alkaloids of the <em>Lophophora Williamsii</em> cactus, also known as peyote.<sup>6</sup> While the phenethylamine mescaline is generally considered to be the primary active hallucinogen, the complex set of auditory, visual, and tactile features that make up the subjective effects of peyote may be attributed to activity of these compounds, whether alone or in combination.<sup>7</sup> </p>
<p>Coming back to <em>The Simple Plant Isoquinolines,</em> it’s notable that the vast majority of Shulgin’s third book is devoted to characterizing various isoquinolines and their origin plant species. Notably unlike PIHKAL or TIHKAL, there are no reports of effects in humans and many of the indexed compounds have never been synthesized. While it is likely that many of these plant alkaloids have no significant activity at 5-HT<sub>2A</sub>, nor hallucinogenic effects, nor anti-depressive properties, they remain a fascinating direction of research for a few reasons.</p>
<p>Firstly, as described above, there are a number of isoquinoline compounds which have demonstrably shown CNS activity and have noted hallucinogenic properties. Secondly, the index of isoquinolines with possible CNS effects is vast and largely unexplored, making it a ripe direction for investigation. </p>
<p>Perhaps with the growing interest in psychedelics research currently ongoing and a number of clinical trials in the works, the mysterious field of isoquinolines will finally be elucidated. </p>
<p><strong>References</strong> </p>
<p>1.) Shulgin, Alexander, and Ann Shulgin. TIHKAL: the continuation. Transform press, 1997.</p>
<p>2.) Morales-García, Jose A., et al. “The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.” Scientific reports 7.1 (2017): 1-13.</p>
<p>3.) Cortijo, J., et al. “Bronchodilator and anti‐inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes.” British journal of pharmacology 127.7 (1999): 1641-1651.</p>
<p>4.) Heng, Hui Li, et al. “In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors.” Chemical biology & drug design 93.2 (2019): 132-138.</p>
<p>5.) Rovinskiĭ, V. I. “Acute glaucine syndrome in the physician’s practice: the clinical picture and potential danger.” Klinicheskaia meditsina 84.11 (2006): 68.</p>
<p>6.) Schultes, Richard Evans. “The appeal of peyote (Lophophora williamsii) as a medicine.” American Anthropologist 40.4 (1938): 698-715.</p>
<p>7.) Schultes, Richard Evans. “The botanical and chemical distribution of hallucinogens.” Annual Review of Plant Physiology 21.1 (1970): 571-598.</p>
tag:nikobidin.com,2014:Post/a-short-review-of-the-neurobiological-activity-of-tryptamines2020-06-29T15:37:25-07:002020-06-29T15:37:25-07:00The neurobiological activity of hallucinogenic tryptamines<p>the full preprint containing a tryptamine index is available at <a href="https://www.dropbox.com/s/orchzuivtsoos1y/Tryptamines%20of%20Interest.pdf?dl=0">https://www.dropbox.com/s/orchzuivtsoos1y/Tryptamines%20of%20Interest.pdf?dl=0</a></p>
<p><strong>TLDR</strong></p>
<ul>
<li><p>Hallucinogenic tryptamines appear highly effective against a variety of neuropsychiatric conditions</p></li>
<li><p>Central activity, including hallucinogenic properties, depends on functional selectivity at the 5-HT<sub>2A</sub> receptor</p></li>
<li><p>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</p></li>
<li><p>Central activity in humans is highly dependent on specific chemical functional group substitutions at the 4 and 5 positions on the benzene indole ring</p></li>
</ul>
<p><strong>Longer Abstract Summary</strong></p>
<p>Tryptamine-derived compounds, many of them hallucinogenic, have been found to be potent pharmaceutical agents<sup>1</sup>. In particular, psilocin (4-HO-DMT) and 5-methoxy-dimethyltryptamine (5-MeO-DMT) have performed exceptionally well in controlled studies across a variety of conditions, including depression, anxiety disorders, post-traumatic stress disorder, and substance addiction, even after a single treatment.<sup>2,3</sup> Mostly naturally occurring species have been investigated although many synthetic alternatives have the potential to offer preferable qualities including higher potency and improved valence, making them safer and more effective in the clinical setting.<sup>4,5</sup> In this review, I describe our current knowledge of molecular and receptor circuitry involved in the hallucinogenic action of tryptamines as well as some challenges and prospects in ensuring physical and psychological safety of hallucinogenic tryptamines in the clinical setting. </p>
<p><strong>Introduction</strong></p>
<p>Despite a large volume of research into the psychiatric applications of tryptamine and phenethylamine-derived compounds, an unfavorable political climate and broad fear over misuse in the late 1960s shut down a significant portion of further studies and academic work, despite highly promising results.<sup>6</sup> Simultaneously, the discovery rate for new neuropharmacological small molecule agents has been exceptionally slow with few notable successes.<sup>7</sup> As an example to illustrate this point, current rates of efficacy for the most effective antidepressant selective serotonin reuptake inhibitors (SSRIs) average below 50 percent with a significant number of drawbacks including dependency and serious side effects.<sup>8,9</sup> </p>
<p>Nevertheless, the last two decades have witnessed the revisiting of previously neglected compounds which have shown to be effective in treating a wide range of neuropsychiatric disorders. In particular, tetrahydrocannabinol (THC) has been used for the treatment of epilepsy, Dravet syndrome, and for the prevention of nausea caused by certain cancer medications, amongst other conditions.<sup>10</sup> Esketamine, a glutamate receptor antagonist and enantiomer of ketamine, was found to treat depressive symptoms in patients and subsequently approved for use by the United States FDA.<sup>11</sup> </p>
<p>Presently, serotonologic compounds such as psilocin, DMT, and 5-methoxy-DMT have been resurrected as potential treatments for depression, anxiety, post-traumatic stress disorder, substance abuse, and personality disorders. While many of the initial results have been highly promising, challenges remain including physiological and psychological safety. While many of the compounds tested have a number of highly beneficial properties including generally low substance abuse profiles, they can also induce negative symptoms such as paranoia and cause fearful episodes.<sup>12</sup> </p>
<p>As the new wave of serotonological therapeutics begins to mature, it is possible structural derivatives of existing hallucinogenic compounds will play a role in improving safety, generalizability, and efficacy.<sup>13</sup> Based on the work done by a number of medicinal chemists, chiefly among them Dr. Alexander Shulgin, a number of such derivative compounds have already been synthesized with some preliminary reports on their effects and pharmacological properties available.<sup>14,15</sup> The lesser known compounds have relatively few controlled subjective reports and require further study while having some potentially intriguing properties. </p>
<p>All such compounds are variations of the indole-related tryptamine class, a parent structure shown in Figure A with substitution groups marked with R values. Serotonin (5-HT), one of the most ubiquitous neurotransmitters, is a tryptamine derivative, while certain dimethylated variants (such as DMT) are endogenous to humans and can be found in blood and cerebrospinal fluid.<sup>16</sup> </p>
<p>Variation in the hallucinogenic effects of each compound is a function of many variables including dosage, body weight, method of consumption, lipophilicity of the drug, structural polarity, and differential agonism against neural receptors, most notably the 5-HT class. Certain patterns of structure-based drug activity can be understood from research and reports conducted over the past several decades.<sup>17</sup> </p>
<p><a href="https://svbtleusercontent.com/5g6CMr4ddsnWT7FUWvMkiK0xspap.png"><img src="https://svbtleusercontent.com/5g6CMr4ddsnWT7FUWvMkiK0xspap_small.png" alt="Screen Shot 2020-06-16 at 12.28.22 PM.png"></a><br>
<em>Figure A: The molecular structure of tryptamine</em></p>
<p>Activity in the primary tryptamine is highly dependent on substitutions at the R4 and R5 indole benzene positions and the RN1, RN2 and R-alpha positions on the amino-terminated chain. By contrast, preliminary work by Shulgin and others has found that substitutions at other positions on the indole structure produce primarily inhibitory effects with decreased potency and activity. Additionally, increasingly long alkylation at the RN1 and RN2 positions produces noticeably diminishing activity.</p>
<p>Understanding the functional differences in binding and activity between various substituted tryptamines will be an essential area of research to better understand their mechanism of action in the brain and improve safety. </p>
<p>Beyond simply the discovery of safer psychedelic compounds, future therapies will need to be adjusted to the needs of each patient. A single negative experience with a psychedelic drug, even in the clinical setting, could lead to aversion to future treatment. To avoid such an outcome, treatments must protect against the psychological dangers inherent in hallucinogenic drugs. Development of such treatments will require careful considerations of drug structure, activity, dosage, setting-of-treatment, time course, and other related factors. </p>
<p><strong>Neural correlates of tryptamine activity</strong></p>
<p>One of the many challenges in elucidating the mechanism of action of psychedelic tryptamines in the brain is the complex interrelationship between the compound, its dosage, characteristics, personality of the subject, and exterior factors such as the setting in which it is consumed.<sup>18</sup> A decade or so after the discovery of LSD, the presence of serotonin was detected in the mammalian brain. In the late 1960s, it was hypothesized that hallucinogenic compounds may have direct agonism at the 5-HT receptors, specifically discriminating from other non-hallucinogenic compounds at the 5-HT2A receptor.<sup>19</sup> This evidence was further strengthened by a study showing controlled inhibition of the hallucinogenic effects of psilocin by pairing it with a 5-HT2A antagonist and demonstrating functional selectivity at the 5-HT2A receptor.<sup>20</sup></p>
<p>Additionally, further studies have revealed that hallucinogenic tryptamines enhance glutamatergic transmission in the cerebral cortex at both a functional neuronal level and in the context of behavioral tasks.<sup>21</sup> It was first reported twenty years ago that 5-HT induced a rapid increase of spontaneous glutamatergic excitatory postsynaptic potentials (EPSPs)/excitatory postsynaptic currents (EPSCs) in cortical pyramidal cells of visual cortex layer V, with the most pronounced effect in areas having above normal 5-HT2A expression.<sup>22</sup> While several theories have been proposed to explain the increase in cortical glutamate, none has thus far been definitively conclusive. Though most work on frontal cortex neurotransmitters has focused on glutamate, 5-HT2A activation was also found to increase extracellular GABA, thereby producing both excitation and a feed-forward inhibition of cortical pyramidal cells.<sup>23</sup></p>
<p>Much of the initial work on such neuronal effects was performed using single cell recordings from brain slices which are often not representative of an intact and functional cortex. More recently, ultra-high field multimodal brain imaging has revealed that psilocybin induced region dependent alterations in glutamate in the prefrontal cortex and the hippocampus. Moreover, regional alteration in glutamate was predictive of both positive and negative valence in the hallucinogenic effect based on subject feedback.<sup>24</sup></p>
<p>Further research on rhythmic patterns of activity originating in cortical and subcortical areas has revealed certain interesting clues. Combining opto- and pharmacogenetic manipulations with electrophysiological recordings, it was discovered that 5-HT inhibits slow oscillations within the entorhinal cortex via the activation of Som interneurons via the 5-HT2A receptor. Intravenously administered DMT reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Furthermore, peak effects induced the emergence of theta and delta oscillations. One possible proposed explanation involves the switching from exterior information processing to interior endogenous perception, linked to phenomena such as REM sleep.<sup>25</sup> </p>
<p>While a definitive mechanism of action of hallucinogens is still not apparent, existing work has elucidated some of the functional pathways on a cellular, systemic, and behavioral level. Further research into fundamental neuroscience will be required to fully uncover the picture. Figure B shows a table of known receptor Ki values (in µM) for a set of hallucinogenic tryptamines. </p>
<p><a href="https://svbtleusercontent.com/jgpJNATvnzRaYG72i2K2KP0xspap.png"><img src="https://svbtleusercontent.com/jgpJNATvnzRaYG72i2K2KP0xspap_small.png" alt="Screen Shot 2020-06-29 at 12.50.01 PM.png"></a></p>
<p><em>Figure B: A table of receptor Ki values (all values are in µM) for tryptamine variants with hallucinogenic properties</em></p>
<p><strong>Considerations for safety in the clinical use of tryptamines</strong></p>
<p>The future prospects of tryptamines, both of synthetic or naturally-occuring origin will be dependent in large part on physical and psychological safety in the course of treatment. In early psychedelic research, two treatment approaches were explored: one focused on administering low doses of a hallucinogenic or empathogenic compound in the course of multiple sessions of psychoanalytic therapy; the other uses higher doses of psychedelic agents in the course of one or a few sessions to achieve a “peak” experience. While many contemporary studies showing high efficacy have utilized the latter paradigm, many experts have expressed the need for caution to mitigate the risk of negative experiences or “bad trips.” Hallucinogens known to induce “peak” experiences such as DMT, 5-MeO-DMT, and psilocin also have a documented history of negative psychological and physical side effects. Several paths for the reduction of risk could include: </p>
<p>–> Ensuring a comfortable and safe setting for patient infusions is kept to minimize possible stress throughout the treatment. </p>
<p>–> Pairing multiple compounds to reduce anxiety throughout the infusion and mitigate side effects such as nausea. </p>
<p>–> The development of novel tryptamine compounds which result in fewer negative valence responses. </p>
<p>In particular, pairing empathogens normally associated with increased valence with hallucinogenic compounds could have possible beneficial effects in the form of reduced anxiety and fear responses during treatment. Further research will be necessary to determine the efficacy and possible dangers of such approaches, notably cardiac and cross-interactivity risks. </p>
<p><strong>Conclusion</strong></p>
<p>The present review is an attempt to accomplish a few things. Firstly, it is to give a very succinct background on our existing knowledge of tryptamine activity in the brain. Secondly, it is to talk about some hurdles in the clinical use of psychedelic substances, namely physical and psychological safety and to suggest a few possible paths forward including drug discovery and combinatorial approaches. Not discussed within the review but of great importance is also the difficulty of evaluating novel tryptamines with complex visual and auditory components not usually suitable for animal models. The revolutionary potential of empathogenic and hallucinogenic substances depends not only in their effectiveness as agents but also on ensuring the safety of a broad clinical pool. </p>
<p><strong>References</strong></p>
<ol>
<li><p>Nichols, David E., Matthew W. Johnson, and Charles D. Nichols. “Psychedelics as medicines: an emerging new paradigm.” Clinical Pharmacology & Therapeutics 101.2 (2017): 209-219.</p></li>
<li><p>Johnson, Matthew W., and Roland R. Griffiths. “Potential therapeutic effects of psilocybin.” Neurotherapeutics 14.3 (2017): 734-740.</p></li>
<li><p>Davis, Alan K., et al. “5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety.” The American journal of drug and alcohol abuse 45.2 (2019): 161-169.</p></li>
<li><p>Andersson, Martin, Mari Persson, and Anette Kjellgren. “Psychoactive substances as a last resort—a qualitative study of self-treatment of migraine and cluster headaches.” Harm reduction journal 14.1 (2017): 60.</p></li>
<li><p>Dargan, P.; Wood, D. “Novel Psychoactive Substances: Classification, Pharmacology and Toxicology.” First Edition. Academic Press. (2013).</p></li>
<li><p>Doblin, Richard E., et al. “The Past and Future of Psychedelic Science: An Introduction to This Issue.” (2019): 93-97.</p></li>
<li><p>Gribkoff, Valentin K., and Leonard K. Kaczmarek. “The need for new approaches in CNS drug discovery: why drugs have failed, and what can be done to improve outcomes.” Neuropharmacology 120 (2017): 11-19.</p></li>
<li><p>Jakobsen, Janus Christian, et al. “Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis.” BMC psychiatry 17.1 (2017): 58.</p></li>
<li><p>Ioannidis, John PA. “Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?.” Philosophy, Ethics, and Humanities in Medicine 3.1 (2008): 14</p></li>
<li><p>Lim, Keane, Yuen Mei See, and Jimmy Lee. “A systematic review of the effectiveness of medical cannabis for psychiatric, movement and neurodegenerative disorders.” Clinical Psychopharmacology and Neuroscience 15.4 (2017): 301.</p></li>
<li><p>Daly, Ella J., et al. “Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial.” JAMA psychiatry 76.9 (2019): 893-903.</p></li>
<li><p>Ona, Genís. “Inside bad trips: Exploring extra-pharmacological factors.” Journal of Psychedelic Studies 2.1 (2018): 53-60.</p></li>
<li><p>Riedlinger, Thomas J., and June E. Riedlinger. “Psychedelic and entactogenic drugs in the treatment of depression.” Journal of Psychoactive Drugs 26.1 (1994): 41-55.</p></li>
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tag:nikobidin.com,2014:Post/mdma-and-neurotoxicity2020-06-26T18:32:03-07:002020-06-26T18:32:03-07:00Enantiomeric MDMA and Neurotoxicity<p>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.<sup>1,2</sup></p>
<p>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.<sup>3</sup> 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 expression, which are dopamine and serotonin transporters respectively.<sup>4</sup> Furthermore, some studies have shown MDMA associated apoptosis (cell death) in cortical neurons.<sup>5</sup></p>
<p>While this is certainly troubling, there are a few caveats to consider. Firstly, most of the work done has been in lab rodents and primary neuron culture which to put it mildly, does not always translate to humans. Secondly, the claims about MDMA neurotoxicity seem to be the most reliable at very high concentrations and incidences-of-use. A 2015 systemic review<sup>6</sup> found “no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures.” Thirdly, there are questions about the differential neurotoxicity of MDMA versus its metabolites. Research has shown that the MDA metabolite, produced by hepatic N-dealkylation, may be the cause of some of the neurotoxic effects seen with MDMA systemic administration.<sup>7</sup> Nevertheless, concerns over the safety profile remain. </p>
<p>This brings us back to the Emory University research from a few years ago. The work, led by Daniel Curry and Matthew Young, compared administration of standard S(+)R(-)- racemic MDMA to the R(-)-MDMA enantiomer in rodents. While the R-MDMA seemed to act similarly to the racemic variant in promoting social behavior and reducing fear responses, it didn’t produce signs of neurotoxicity, increase locomotor activity, or cause hyperthermia. More impressively, this result held with repeat high doses. The claims about neurotoxicity came in a few different flavors. Firstly, there were no signs of reactive astrogliosis, which is a marker of CNS damage. This was confirmed with a GFAP immunoassay. </p>
<p><a href="https://svbtleusercontent.com/WhuVUuJUZY1xszB87kGND0xspap.png"><img src="https://svbtleusercontent.com/WhuVUuJUZY1xszB87kGND0xspap_small.png" alt="Screen Shot 2020-06-26 at 2.48.15 PM.png"></a></p>
<p>Secondly, there were fewer changes to serotonin, dopamine, and DAT levels across brain regions with the enantiomeric form of MDMA versus the racemic.</p>
<p><a href="https://svbtleusercontent.com/7oahB3AN82N6SKwP4VWoup0xspap.jpg"><img src="https://svbtleusercontent.com/7oahB3AN82N6SKwP4VWoup0xspap_small.jpg" alt="nihms913648f4.jpg"></a></p>
<p>Of course, there are still questions relating to drug tolerance and other adverse effects outside of the brain. But the Emory group’s research is a major step forward in reducing the risk profile of MDMA, as it moves into clinical use. It remains to be seen whether neurotoxicity becomes a concern with the relatively infrequent infusions budgeted for PTSD, currently the main target for MDMA as a clinical tool. Nevertheless, a safe version of MDMA would have significant benefits in place of a chronically administered worse alternative and is highly exciting for that reason. </p>
<p>The biggest next step for this research is getting human clinical data for R(-)-MDMA to hopefully show that it has comparable prosocial properties to the racemic variant. Surprisingly, nothing has emerged so far on this front although increasing interest in MDMA due to MAPS may change this. </p>
<p>Sources: </p>
<ol>
<li><p>Pitts, Elizabeth G., et al. “(±)-MDMA and its enantiomers: potential therapeutic advantages of R (−)-MDMA.” Psychopharmacology 235.2 (2018): 377-392.</p></li>
<li><p>Curry, Daniel W., et al. “Separating the agony from ecstasy: R (–)-3, 4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.” Neuropharmacology 128 (2018): 196-206.</p></li>
<li><p>Battaglia, G. E. O. R. G. E., et al. “3, 4-Methylenedioxymethamphetamine and 3, 4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H] paroxetine-labeled serotonin uptake sites.” Journal of Pharmacology and Experimental Therapeutics 242.3 (1987): 911-916.</p></li>
<li><p>Commins, D. L., et al. “Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.” Journal of Pharmacology and Experimental Therapeutics 241.1 (1987): 338-345.</p></li>
<li><p>Capela, Joao Paulo, et al. “Ecstasy induces apoptosis via 5-HT2A-receptor stimulation in cortical neurons.” Neurotoxicology 28.4 (2007): 868-875.</p></li>
<li><p>Mueller, F., et al. “Neuroimaging in moderate MDMA use: a systematic review.” Neuroscience & Biobehavioral Reviews 62 (2016): 21-34.</p></li>
<li><p>O'hearn, E., et al. “Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity.” Journal of Neuroscience 8.8 (1988): 2788-2803.</p></li>
</ol>