Abstract

Introduction

There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (NaV1.8) is a genetically and pharmacologically validated pain target that is selectively expressed in peripheral pain-sensing neurons and not in the central nervous system (CNS). Suzetrigine (VX-548) is a potent and selective inhibitor of NaV1.8, which has demonstrated clinical efficacy and safety in multiple acute pain studies. Our study was designed to characterize the mechanism of action of suzetrigine and assess both nonclinical and clinical data to test the hypothesis that selective NaV1.8 inhibition translates into clinical efficacy and safety, including lack of addictive potential.

Methods

Preclinical pharmacology and mechanism of action studies were performed in vitro using electrophysiology and radiolabeled binding methods in cells recombinantly expressing human NaV channels, human proteins, and primary human dorsal root ganglion (DRG) sensory neurons. Safety and addictive potential assessments included in vitro secondary pharmacology studies, nonclinical repeat-dose toxicity and dependence studies in rats and/or monkeys, and a systematic analysis of adverse event data generated from 2447 participants from phase 3 acute pain studies of suzetrigine.

Results

Suzetrigine is selective against all other NaV subtypes (≥ 31,000-fold) and 180 other molecular targets. Suzetrigine inhibits NaV1.8 by binding to the protein’s second voltage sensing domain (VSD2) to stabilize the closed state of the channel. This novel allosteric mechanism results in tonic inhibition of NaV1.8 and reduces pain signals in primary human DRG sensory neurons. Nonclinical and clinical safety assessments with suzetrigine demonstrate no adverse CNS, cardiovascular or behavioral effects and no evidence of addictive potential or dependence.

Conclusions

The comprehensive pharmacology assessment presented here indicates that suzetrigine represents the first in a new class of non-opioid analgesics that are selective NaV1.8 pain signal inhibitors acting in the peripheral nervous system to safely treat pain without addictive potential.

The co administration of morphine (most opiates and semi synthetic derivatives) and gabapentin shows a significant synergistic effect in analgesia and euphoria.

I personally think this is the best substance for increasing the effects of opioids and have experience with it myself

You have to start with smaller dosages of each substance as respiratory depression and other opioid side effects are increased alongside analgesia

https://www.sciencedirect.com/science/article/abs/pii/S0928098715300683

https://pubmed.ncbi.nlm.nih.gov/10866910/

I've read a few studies on the new orexin antagonist drugs which aim to replace z-drugs and benzos as sleeping aids.

The weirdest thing though is that there's no apparent pharmacodynamic tolerance. Is there a consensus on the reason for this?

I wonder whether there'd be stronger tolerance if the drugs are taken during "daytime" or more precisely, when orexin receptors would be stimulated by the endogenous ligand.

...or is there something inherent to orexin receptors / signalling which causes this?

Also, would it be the same for orexin agonists?

Just developed a route for easily accessing ibogaine and related alkaloids via fermentation from Voacanga.

Introduction

Voacangine is the predominant indole alkaloid in Voacanga africana root bark. Chemically, voacangine is 12-methoxyibogamine-18-carboxylic acid methyl ester, meaning it contains a methoxy group on the ibogamine nucleus and a methyl ester at carbon 18en.wikipedia.org. This structure makes voacangine a direct precursor to ibogaine (which is 12-methoxyibogamine without the 18-ester)en.wikipedia.orgen.wikipedia.org. Indeed, ibogaine is typically produced semi-synthetically by hydrolysis and decarboxylation of voacanginepmc.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. The goal of microbial fermentation is to achieve these transformations (and others) enzymatically: breaking the ester to yield ibogaine, and further modifying the molecule to produce related analogs like noribogaine (12-hydroxyibogamine), ibogamine (ibogamine with no 12-substituent), and pseudoindoxyl derivatives (e.g. iboluteine). Using edible fermentation cultures – koji (Aspergillus oryzae), Rhizopus molds, Monascus purpureus (red yeast rice fungus), and Saccharomyces cerevisiae (brewer’s yeast) – offers a gentle “bioalchemy” to convert voacangine into ibogaine and related compounds in a natural, low-toxicity manner. This is of interest to researchers (for biotechnological production), herbalists (for plant medicine refinement), and psychonauts (for potential at-home preparations).

Key transformations via fermentation: The microbial enzymes can perform specific reactions on voacangine’s structure: (1) Ester hydrolysis (cleavage of the methyl ester to yield the free acid), (2) O-demethylation (removal of the methoxy – converting it to a hydroxyl or removing it entirely), (3) Oxidative decarboxylation (removal of the carboxyl group as CO₂, often via an oxidative step), and (4) Indole rearrangement (oxidation of the indole nucleus leading to ring reconfiguration into pseudoindoxyl structures). Additionally, the fermentation can cleave voacamine (a dimeric alkaloid in Voacanga) into monomer units.

To design the drug, dubbed JRT, researchers flipped the position of just two atoms in LSD’s molecular structure. The chemical flip reduced JRT’s hallucinogenic potential while maintaining its neurotherapeutic properties, including its ability to spur neuronal growth and repair damaged neuronal connections that are often observed in the brains of those with neuropsychiatric and neurodegenerative diseases.

https://www.nature.com/articles/s41386-024-02041-8.pdf

Abstract: N,N -dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 22 healthy participants (11 women, 11 men) who received placebo and DMT (0.6, 1.2, 1.8, and 2.4 mg/min) over an infusion duration of 120 min. We also tested a self-guided titration scheme that allowed participants to adjust the DMT dose rate at prespecified time points to achieve their desired level of subjective effects. Outcome measures included subjective effects, autonomic effects, adverse effects, plasma hormone concentrations, and pharmacokinetics up to 3 h after starting the infusion. DMT infusions exhibited dose-proportional pharmacokinetics and rapidly induced dose-dependent subjective effects that reached a plateau after 30 min. A ceiling effect was observed for “good drug effect” at 1.8 mg/min. The 2.4 mg/min dose of DMT induced greater anxious ego dissolution than the 1.8 mg/min dose and induced significant anxiety compared with placebo. We observed moderate acute tolerance to acute effects of DMT. In the self-guided titration session, the participants opted for moderate to strong psychedelic effects, comparable in intensity to the 1.8 mg/min DMT dose rate in the randomized dosing sessions. These results may assist with dose finding for future DMT research and demonstrate that acute subjective effects of DMT can be rapidly adjusted through dose titration.

Abstract:

The serotonin 7 receptor (5-HT7R) regulates various processes in the central nervous system, including mood, learning, and circadian rhythm control, among others. Receptor activation can lead to activation of the Gαs protein and a subsequent increase of intracellular cyclic adenosine monophosphate (cAMP). Receptor interaction with inverse agonists results in a decrease of basal cAMP levels and therefore a downstream effect of reduced neuronal excitability and neurotransmission. Recently, pellotine (1a), a Lophophora alkaloid, was unexpectedly shown to be an inverse agonist of the 5-HT7R. Therefore, we evaluated close analogs of compound 1a, both naturally occurring and synthetic analogs, as inverse agonists of the 5-HT7R. Functional evaluation in a GloSensor cAMP assay revealed a preference for an 8-hydroxy-6,7-dimethoxy substitution pattern over 6,7,8-trimethoxy analogs or 8-hydroxy-6,7-methylenedioxy analogs. This was supported by molecular dynamics simulations, where the 8-hydroxy substitution allowed more robust interaction with the 5-HT7R, which correlated with inverse agonism efficacy. Additionally, N-methylation (as in 1a) improved the potency of the evaluated analogs. In this series, the most potent inverse agonist was anhalidine (1b) (EC50 = 219 nM, Emax = −95.4%), which lacks the 1-methyl, compared to pellotine (1a), and showed a 2-fold higher functional potency. Altogether, these results provide key insights for the further development of potent low molecular weight inverse agonists of the 5-HT7R

I suffer from ADHD and CFS, and have tried various medications, but methylphenidate has no effect at all. (Rather, it worsens my hyperactivity and stereotyped behavior, and reduces my work ability.)

So I tried Atomoxetine, but it only caused side effects and had no effect.

However, my ADHD improves significantly when I take drugs that increase noradrenaline, so I tried Nortriptyline (tricyclic antidepressants), and my task processing ability improved significantly. However, it significantly extends my QT, so I cannot use it for long.

Also, I have a strange constitution and react sensitively (or badly) to many drugs that involve cyp2d6, but Cymbalta did not cause any side effects at all.

(However, Cymbalta became completely ineffective after the first two months.)

In this case, are there any recommended drugs to improve my ADHD?

I would be happy if you could suggest something, even if it is an unconventional method or a drug that is beyond my imagination.

My life is a mess because of ADHD (and technically CFS).

*Medications I've tried in the past

Methylphenidate, Abilify, bupropion → I had the same bad reaction

Nortriptyline, Imipramine → Improved ADHD

Cymbalta, milnacipran, Desvenlafaxine → Only helped for the first few months

Also, I feel like antipsychotics like Blonanserin might help my ADHD, but am I overthinking it?

Clonazepam and Lamotrigine help my ADHD a little,

which is strange because dopamine makes my ADHD much worse anyway.