Phenethylamines 0 danger with mescaline and the heart?

[donotdothis]

"All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk."

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease - PubMed

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation...

pubmed.ncbi.nlm.nih.gov

 

[mr peabody]

Safety pharmacology of acute mescaline administration in healthy participants​

British Journal of Clinical Pharmacology - 2024 Nov 25​

Abstract​

Aims: Psychedelics, including mescaline, may serve as novel treatments for depression and anxiety. However, data is scarce on the safety of mescaline.

Methods: The present pooled analysis included two double-blind, randomized, placebo-controlled studies with a total of 48 participants and 96 mescaline administrations. Single oral-dose administrations (n = 16/dose) of mescaline at doses of 100-800 mg were used. Acute subjective and autonomic effects and acute and subacute adverse effects were recorded. Liver and kidney function, blood cell counts, and "flashbacks" were documented at the end of the studies.​

Results: Positive subjective effects dose-dependently increased and were higher than negative subjective effects for all mescaline doses. Autonomic effects increased moderately. Systolic blood pressure remained < 180 mmHg in all participants. Of all mescaline administrations, diastolic blood pressure > 100 mmHg was measured in 6%, heart rate > 100 beats/min was measured in 3% and body temperature > 38 °C was measured in 5%. The total number of acute adverse effects was 51, 12, 179, 143, 165 and 180 at 100, 200, 300, 400, 500 and 800 mg doses of mescaline, respectively. Nausea was dose-limiting. Kidney and liver function and blood cell counts remained normal. "Flashbacks" were reported after 2% of all mescaline administrations. Systolic blood pressure and heart rate were similarly increased by the high dose of mescaline (500 mg), LSD, and psilocybin. Notably, the increase in heart rate in response to the low dose of 300 mg mescaline exceeded the increase in heart rate in response to the high dose of 500 mg mescaline.​

Conclusions: These findings suggest that the administration of single mescaline doses up to 800 mg are safe in a controlled clinical setting with regard to acute psychological and physical harm in healthy participants.​

https://pubmed.ncbi.nlm.nih.gov/39587436/

 

[mr peabody]

Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects​

British Journal of Clinical Pharmacology - 2024 Nov 25

Abstract​

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently.​

Introduction​

Mescaline (3,4,5-trimethoxyphenethylamine) is a serotonergic psychedelic with a long history of ethnomedical use [1, 2]. Other classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT), which have regained interest in psychiatric research. LSD and psilocybin are particularly being investigated as treatments for depression and anxiety-related disorders [3–7]. Mescaline is found as an alkaloid in different species of cacti (e.g., peyote or San Pedro) in North and South America. The radiocarbon dating and alkaloid analysis of archeological specimens of peyote buttons revealed that mescaline was used for more than 5000 years by native North Americans [8]. Subjective effects of mescaline were scientifically investigated and described starting at the end of the 19th century and throughout the 20th century [9–13]. In contrast to other classic psychedelics, there has been little contemporary clinical research on mescaline. A recent first study determined the dose-equivalence of mescaline, LSD, and psilocybin and found no differences in the overall quality of subjective effects between these three classic psychedelics [14].​

Results​

Mescaline increased systolic and diastolic blood pressure and body temperature relatively similarly at the 200-800 mg doses compared with placebo (Fig. 3). In contrast, mescaline increased heart rate more dose-dependently compared with placebo (Fig. 3). Co-administration of ketanserin reversed the mescaline-induced elevations of blood pressure and heart rate. The peak blood pressure responses to mescaline were not significantly reduced by ketanserin because the onset of the effect of ketanserin occurred after the mescaline-induced increase in blood pressure. The peak effect of mescaline (800 mg) on heart rate and body temperature was significantly reduced by ketanserin. Mescaline dose-dependently increased pupil size and reduced the light reflex compared with placebo. Ketanserin transiently reduced these mescaline-induced changes in pupillary function. Mescaline dose-dependently induced acute (0–14 h) and subacute (14–30 h) adverse effects on the List of Complaints compared with placebo. Frequent acute adverse effects included fatigue, headache, lack of concentration, and nausea.​

Conclusion​

The present study characterized acute subjective and autonomic effects of different doses of mescaline. Starting at the 200 mg dose of mescaline, it produced dose-dependent psychedelic effects up to 800 mg, with no ceiling effect. The 800 mg dose of mescaline produced significant subjective bad drug effects and emesis. The present mescaline dose-response data may be useful for defining doses in future psychedelic research in healthy subjects and patients. The co-administration of ketanserin together with 800 mg mescaline attenuated the acute response, confirming that serotonin 5-HT2A receptors are primarily involved in psychedelic effects of mescaline in humans.

Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects - PMC

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action ...

pmc.ncbi.nlm.nih.gov

 

[mr peabody]

Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants​

Abstract​

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin.​

Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants - PubMed

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological...

pubmed.ncbi.nlm.nih.gov

 

[mr peabody]

Effects of hallucinogenic drugs on the human heart​

Pharmacol., 01 February 2024

Abstract​

Hallucinogenic drugs are used because they have effects on the central nervous system. Their hallucinogenic effects probably occur via stimulation of serotonin receptors, namely, 5-HT2A-serotonin receptors in the brain. However, a close study reveals that they also act on the heart, possibly increasing the force of contraction and beating rate and may lead to arrhythmias. Here, we will review the inotropic and chronotropic actions of bufotenin, psilocin, psilocybin, lysergic acid diethylamide (LSD), ergotamine, ergometrine, N,N-dimethyltryptamine, and 5-methoxy-N,N-dimethyltryptamine in the human heart.

In this review, “drugs of interest” include the following organic molecules: bufotenin, psilocin, psilocybin, lysergic acid diethylamide (LSD), ergotamine, ergometrine, N,N-dimethyl-tryptamine and 5-methoxy-N,N-dimethyltryptamine. These drugs of interest are referred to as tryptamine derivatives. These drugs of interest are thus structurally similar to 5-hydroxyl-tryptamine (serotonin, 5-HT), the physiological agonist at serotonin receptors. Unlike indirect sympathomimetic drugs (e.g., metamphetamine, amphetamine), these compounds probably do not act solely or mainly as releasers of noradrenaline from storage sites in the human heart. In contrast, they are directly activate serotonin receptors in the heart. However, at least in vitro these tryptamines or related tiophene analogs may also act as monoamine transport releasers.

The hallucinogenic effects of these compounds are explained by the stimulation of 5-HT2A-serotonin receptors in the brain. In the heart, these drugs of interest can activate serotonin receptors. However, serotonin increases the force of contraction and beating rate in the human heart via 5-HT4-serotonin receptors and not via 5-HT2A-serotonin receptor. In contrast to other species 5-HT2A- (rat) or 5-HT3-(guinea pig) serotonin receptors do not increase force in the human heart. In order to provide a small animal model for human 5-HT4 serotonin receptors in the heart, we have generated transgenic mice that overexpress the human 5-HT4-serotonin receptor in the heart (5-HT4-TG). In cardiac preparations from 5-HT4 TG, serotonin increased the force of contraction (). Serotonin does not increase the force of contraction in isolated mouse cardiac preparations from wild-type mice.

Interestingly, some of these drugs of interest (e.g., LSD) also activate histamine receptors, namely, H2-histamine receptors in the human heart. In the human heart, unlike in some animal hearts, H2-histamine receptors primarily mediate the positive inotropic or positive chronotropic effects of exogenous or endogenous histamine. To study human H2-histamine receptors in a small animal model, we generated transgenic mice that overexpress the H2-histamine receptors in the heart (H2-TG), wherein histamine increased the force of contraction.

Except for LSD, all the drugs of interest occur naturally. They are found mainly in plants or moulds. Some hallucinogenic compounds are present in high concentrations in animals, such as frogs or even in humans. The present review of the effects of the drugs of interest is limited to the mammalian heart, more specifically the human heart.

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1334218/full