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Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation
- Thread starter deeMte
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Ruffles
Established member
And I quote:
2.2.1. Active pharmaceutical ingredients
DMT used in this study was obtained by basic aqueous extraction from pulverized root bark of Mimosa tenuiflora (The Mimosa Shop, Brazil), with n-heptane as organic solvent. DMT was purified by crystallization and then recrystallized to DMT hemifumarate via salt precipitation.
--- It sounds fancy, but it`s easier to say STB to FASA and Re-X in isopropanol.
The DMT hemifumarate was vacuum-dried, returned to freebase form, back extracted into n-heptane. Finally, DMT was recrystallized as DMT succinate, dried under vacuum, and formulated as tablets for the study medication.
--- Now, this is the tricky part. Why DMT succinate? Better taste, better absorption or reduced salivation? Authors say nothing about this choice. And did they SASA (or something like so) from heptane? Gotta email the authors for their reasoning on this.
Harmine hydrochloride (Harmine HCl, ≥98 % HPLC-tested) was procured from Santa Cruz Biotechnology Inc. (Dallas, Texas 75220, USA) and further purified via basic precipitation, recrystallization and HCl precipitation, and then subjected to the same quantitative and qualitative analysis as DMT, yielding a final purity of 99.9 %.
--- Got it from Texas` Santa Cruz goat and rabbit killers? Why not get it from Sigma which manufactures it next door from the researchers? Strange procurement. Then did they Manske`d the thing (never tried this one so only theoretically familiar)? Interesting that they picked harmine only, to keep it hoasca-like analog?
2.2.2. Pharmaceutical formulation
The oromucosal formulation was manufactured by separate wet granulation of DMT succinate and harmine HCl with calcium phosphate (template inverted particle (TIP) particles; Galvita AG, Basel, Switzerland; [20]) to yield TIP particles loaded with 25 % DMT or 25 % harmine. The DMT- and harmine-loaded TIP particles blends were then mixed in a turbula mixer to yield the seven different ratios used in this study (DMT:Harmine [mg]:[mg]; 0:120, 60:120, 90:120, 120:120, 120:0, 120:60, 120:90).
--- So here is the angle for the paper, in my humble opinion. The delivery system, the true product. TIP particles. Ayahuasca is just a hype or buzz-word to help promote TIP and whatever proprietary formulation that will be made in the future of Galvita AG. Not complaining, just releasing paranoia. The tech looks undeniably awesome, a calcium phosphate sponge-like shell for microencapsulation. TIP paper. ``a unique particle geometry, which is characterized by a particle size of 20 μm and a hollow cavity enclosed by a specially engineered porous shell.`` ``The cavity of the TIP particles retains the drug in its crystalline or amorphous state, while the porous shell can be modified to have mucoadhesive properties to extend the residence time of the particles on the oral mucosa. These particles can still be compacted into the ODTs or used in orally dissolving films for a wide range of patients’ ages``. Now, it is not specified which variation of TIP was used for the D-H combos, but I bet they used just the basic one and not the fancy surface modification that makes it more mucoadhesive and whatnot. From the tek paper, there is no indication that TIP by itself would increase sublingual absorption, in fact, there are plenty of teks out there that are specific for this purpose. In my interpretation, TIP or no TIP, what people felt and scored was basically what those 99% pure salts should do, with individual variations from swallowing too fast to tolerance.
Then, the blends were mixed with the superdisintegrant croscarmellose sodium (3 %), with the addition of sucralose (0.5 %), menthol (0.5 %), and peppermint flavor (0.5 %) for taste masking. The final blend was then compacted into fast-disintegrating orodispersible tablets. The final doses per tablet were one third of the target doses, enabling successive administration in three incremental steps (e.g., for the 120 mg DMT plus 120 mg harmine condition one tablet contained 40 mg of DMT and 40 mg of harmine). All dosage information for DMT and harmine refers to the freebase weight of DMT and harmine.
--- So eventually they make a small tablet and finalize the formulation, sounding a lot like melatonin supplement products, except with the menthol and mint flavor. Now those supposedly do increase sublingual absorption, but they claim `for taste masking`. And why 3 incremental swallows of 40 mg of each? `Cause for some the taste of those salts may be a bit too much.
There is plenty of stuff to discuss from the bioassay parts of the work... after some thorough digestion of the contents.
2.2.1. Active pharmaceutical ingredients
DMT used in this study was obtained by basic aqueous extraction from pulverized root bark of Mimosa tenuiflora (The Mimosa Shop, Brazil), with n-heptane as organic solvent. DMT was purified by crystallization and then recrystallized to DMT hemifumarate via salt precipitation.
--- It sounds fancy, but it`s easier to say STB to FASA and Re-X in isopropanol.
The DMT hemifumarate was vacuum-dried, returned to freebase form, back extracted into n-heptane. Finally, DMT was recrystallized as DMT succinate, dried under vacuum, and formulated as tablets for the study medication.
--- Now, this is the tricky part. Why DMT succinate? Better taste, better absorption or reduced salivation? Authors say nothing about this choice. And did they SASA (or something like so) from heptane? Gotta email the authors for their reasoning on this.
Harmine hydrochloride (Harmine HCl, ≥98 % HPLC-tested) was procured from Santa Cruz Biotechnology Inc. (Dallas, Texas 75220, USA) and further purified via basic precipitation, recrystallization and HCl precipitation, and then subjected to the same quantitative and qualitative analysis as DMT, yielding a final purity of 99.9 %.
--- Got it from Texas` Santa Cruz goat and rabbit killers? Why not get it from Sigma which manufactures it next door from the researchers? Strange procurement. Then did they Manske`d the thing (never tried this one so only theoretically familiar)? Interesting that they picked harmine only, to keep it hoasca-like analog?
2.2.2. Pharmaceutical formulation
The oromucosal formulation was manufactured by separate wet granulation of DMT succinate and harmine HCl with calcium phosphate (template inverted particle (TIP) particles; Galvita AG, Basel, Switzerland; [20]) to yield TIP particles loaded with 25 % DMT or 25 % harmine. The DMT- and harmine-loaded TIP particles blends were then mixed in a turbula mixer to yield the seven different ratios used in this study (DMT:Harmine [mg]:[mg]; 0:120, 60:120, 90:120, 120:120, 120:0, 120:60, 120:90).
--- So here is the angle for the paper, in my humble opinion. The delivery system, the true product. TIP particles. Ayahuasca is just a hype or buzz-word to help promote TIP and whatever proprietary formulation that will be made in the future of Galvita AG. Not complaining, just releasing paranoia. The tech looks undeniably awesome, a calcium phosphate sponge-like shell for microencapsulation. TIP paper. ``a unique particle geometry, which is characterized by a particle size of 20 μm and a hollow cavity enclosed by a specially engineered porous shell.`` ``The cavity of the TIP particles retains the drug in its crystalline or amorphous state, while the porous shell can be modified to have mucoadhesive properties to extend the residence time of the particles on the oral mucosa. These particles can still be compacted into the ODTs or used in orally dissolving films for a wide range of patients’ ages``. Now, it is not specified which variation of TIP was used for the D-H combos, but I bet they used just the basic one and not the fancy surface modification that makes it more mucoadhesive and whatnot. From the tek paper, there is no indication that TIP by itself would increase sublingual absorption, in fact, there are plenty of teks out there that are specific for this purpose. In my interpretation, TIP or no TIP, what people felt and scored was basically what those 99% pure salts should do, with individual variations from swallowing too fast to tolerance.
Then, the blends were mixed with the superdisintegrant croscarmellose sodium (3 %), with the addition of sucralose (0.5 %), menthol (0.5 %), and peppermint flavor (0.5 %) for taste masking. The final blend was then compacted into fast-disintegrating orodispersible tablets. The final doses per tablet were one third of the target doses, enabling successive administration in three incremental steps (e.g., for the 120 mg DMT plus 120 mg harmine condition one tablet contained 40 mg of DMT and 40 mg of harmine). All dosage information for DMT and harmine refers to the freebase weight of DMT and harmine.
--- So eventually they make a small tablet and finalize the formulation, sounding a lot like melatonin supplement products, except with the menthol and mint flavor. Now those supposedly do increase sublingual absorption, but they claim `for taste masking`. And why 3 incremental swallows of 40 mg of each? `Cause for some the taste of those salts may be a bit too much.
There is plenty of stuff to discuss from the bioassay parts of the work... after some thorough digestion of the contents.
aizoaceous
Titanium Teammate
The authors of that 5-MeO-DMT succinate paper expressed concern that the fumarate would bond covalently to the amino nitrogen in a Michael addition if their product were autoclaved to sterilize, though they didn't actually test that. So maybe it's the same here? Very interesting paper, thanks.
Ruffles
Established member
Given that terminal sterilization by an autoclave may be required in the future preparation of sterile solutions of the 5-MeO-DMT drug product, the potential for this known reactivity with fumaric acid eliminated it as an acceptable salt form. Succinic acid is a structurally similar dicarboxylic acid but lacks the conjugated double bond present in fumaric acid and would not exhibit similar chemical reactivity.
Nice catch aizoaceous.
Nice catch aizoaceous.
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