DMMDA

Shulgin listed the dosage of DMMDA in PiHKAL as 30 to 75{{nbsp}}mg and the duration as 6 to 8{{nbsp}}hours. He reported DMMDA as producing LSD-like subjective effects: images, mydriasis, ataxia, and time dilation. DMMDA is not mentioned much in literature outside PiHKAL.

== Pharmacology ==

The mechanism behind the subjective effects of DMMDA has not been specifically established. In PiHKAL, Shulgin asserts that the subjective effects of 75{{nbsp}}mg of DMMDA are equivalent to those of 75 to 100{{nbsp}}μg of LSD. LSD is a well-known partial agonist of the serotonin 5-HT_2A receptor. This may suggest that DMMDA is also an agonist or partial agonist of the 5-HT_2A receptor.{{Citation needed|date=April 2025}}

DMMDA is equivalent to 12 "mescaline units" in terms of potency. DMMDA's isomer DMMDA-2 is equivalent to 5 "mescaline units" in terms of potency.{{Cite journal | author = Clare, Brian W. | year = 1990 | title = Structure-Activity Correlations for Psychotomimetics. 1. Phenylalkylamines: Electronic, Volume, and Hydrophobicity Parameters | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 7 | pages = 687–702 | doi = 10.1021/jm00164a036 | pmid = 2299636 | url = https://www.erowid.org/archive/rhodium/pdf/sar.psychotomimetics-1.pdf | access-date = 2025-01-07}}

Repeated administration of mescaline (3,4,5-trimethoxyphenethylamine), a somewhat similar compound to DMMDA, has shown to slowly create tolerance. This may suggest that the same applies to DMMDA.{{cite journal | vauthors = Kovacic P, Somanathan R | title = Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships | journal = Oxidative Medicine and Cellular Longevity | volume = 2 | issue = 4 | pages = 181–190 | date = September 2009 | pmid = 20716904 | pmc = 2763256 | doi = 10.4161/oxim.2.4.9380 | publisher = Wiley }} {{Creative Commons text attribution notice|cc= by4 |url=|authors=|vrt=|from this source=}}

Computational prediction with ProTox-3.0 predicts that DMMDA has the following toxicological properties from most probable to least probable: respiratorically toxic (P=0.76), nephrotoxic (P=0.58), ecotoxic (P=0.54), and carcinogenic (P=0.51). DMMDA is also predicted to cross the blood–brain barrier (BBB) (P=0.80).{{cite journal | vauthors = Banerjee P, Kemmler E, Dunkel M, Preissner R | title = ProTox 3.0: a webserver for the prediction of toxicity of chemicals | journal = Nucleic Acids Research | volume = 52 | issue = W1 | pages = W513–W520 | date = July 2024 | pmid = 38647086 | pmc = 11223834 | doi = 10.1093/nar/gkae303 }}

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DMMDA is predicted to be metabolized via cytochrome CYP3A4 (P=0.60). DMMDA is somewhat similar to 3,4-methylenedioxy-1-N,α-dimethylphenylethylamine which is primarily metabolized into 3,4-dihydroxy-1-N,α-dimethylphenylethylamine. This may suggest that DMMDA can be metabolized into 3,4-dihydroxy-2,5-dimethoxy-1-α-methylphenylethylamine. It is also worth noting that the metabolism of 3,4,5-trimethoxyphenylethylamine results in the demethylation of its methoxy groups, which may suggest that metabolism of DMMDA may also result in the demethylation of its methoxy groups.{{cite journal | doi=10.1124/jpet.111.180612 | title=Metabolism and Disposition of 3,4-Methylenedioxymethamphetamine ("Ecstasy") in Baboons after Oral Administration: Comparison with Humans Reveals Marked Differences | date=2011 | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=338 | issue=1 | pages=310–317 | pmid=21493752 | pmc=3126644 | vauthors = Mueller M, Goodwin AK, Ator NA, McCann UD, Ricaurte GA }}

File:Pseudodillapiolesynthesis.png

Shulgin explains in his book that DMMDA has 6 isomers similar to TMA. DMMDA-2 is the only other isomer that has been synthesized as of yet. DMMDA-3 could be made from exalatacin (1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene). Exalatacin can be found in the essential oil of both Crowea exalata and Crowea angustifolia var. angustifolia.{{cite journal | vauthors = Brophy JJ, Goldsack RJ, Punruckvong A, Forster PI, Fookes CJ | title = Essential oils of the genus Crowea (Rutaceae). | journal = Journal of Essential Oil Research | date = July 1997 | volume = 9 | issue = 4 | pages = 401–409 | doi = 10.1080/10412905.1997.9700740 }} In other words, exalatacin is an isomer of both apiole and dillapiole, which can be used to make DMMDA and DMMDA-2 respectively. Additionally, yet another isomer of DMMDA could be made from pseudodillapiole or 4,5-dimethoxy-2,3-methylenedioxyallylbenzene.{{cite patent| country = US| number = 4,876,277| status = patent| title = Antimicrobial/antifungal compositions| gdate = 1989-10-24| inventor = Burke BA, Nair MG | assign1 = Plant Cell Research Institute, Inc., Dublin, Calif. | url = https://patents.google.com/patent/US4876277A/en?oq=US4876277A}} The last two isomers of DMMDA are 5,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine and 4,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine.

Like all other α-methylphenylethylamine derivative compounds, DMMDA and its regioisomer have two enantiomers due to the methyl group being in the alpha position of the ethyl group in position number 1 on the benzene ring.{{cite journal | vauthors = Campbell JL, Kafle A, Bowman Z, Blanc JC, Liu C, Hopkins WS | title = Separating chiral isomers of amphetamine and methamphetamine using chemical derivatization and differential mobility spectrometry | journal = Analytical Science Advances | volume = 1 | issue = 4 | pages = 233–244 | date = December 2020 | pmid = 38716384 | doi = 10.1002/ansa.202000066 |doi-access=free | pmc = 10989161 }} There is no information regarding the differences in the pharmacological effects of (S)-DMMDA and (R)-DMMDA.

Shulgin describes the synthesis of DMMDA from apiole in his PiHKAL. Apiole is subjected to an isomerization reaction to yield isoapiole by adding to solution of ethanolic potassium hydroxide and holding the solution at a steam bath. Isoapiole is then nitrated via a Knoevenagel condensation to 2-nitro-isoapiole or 1-(2,3-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by adding it to a stirred solution of acetone and pyridine at ice-bath temperatures and treating the solution with tetranitromethane. The pyridine acts as a catalyst in this reaction. 2,5-dimethoxy-3,4-methylenedioxybenzaldehyde can also be used as precursors in this step of the synthesis. The 2-nitro-isoapiole is finally reduced to freebase DMMDA by adding it to a well-stirred and refluxing suspension of diethylether and lithium aluminium hydride under an inert atmosphere. The reduction can also be achieved with pressurized hydrogen. Finally, the freebase DMMDA converted into its hydrochloride salt.

: File:2-nitro-isoapiole.png

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Shulgin's synthesis of DMMDA can reasonably be considered unsafe, at least by modern standards, since it uses tetranitromethane for its nitration reaction, which is toxic, carcinogenic and prone to detonating.{{ Cite web | url = https://ntp.niehs.nih.gov/ntp/roc/content/profiles/tetranitromethane.pdf | work = Report On Carcinogens | edition = 12th | year = 2011 | title = Tetranitromethane | access-date = 2012-08-14 | author = National Toxicology Program | publisher = National Toxicology Program | url-status = live | archive-url = https://web.archive.org/web/20130131171438/http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Tetranitromethane.pdf | archive-date = 2013-01-31 | author-link = National Toxicology Program }} DMMDA can be made from apiole via other safer methods. Among other methods, DMMDA can be synthesized from apiole via the intermediate chemical 2,5-dimethoxy-3,4-methylenedioxyphenylpropan-2-one or DMMDP2P in the same manner as MDA is made from safrole.

DMMDP2P can be made from apiole via a Wacker oxidation with benzoquinone. DMMDP2P can be alternatively made by subjecting apiole to an isomerisation reaction to yield the thermodynamically stabler internal alkene, isoapiole, followed by a peroxyacid oxidation, with for example peracetic acid, and finally a hydrolytic dehydration.{{cite journal | vauthors = Cox M, Klass G, Morey S, Pigou P | title = Chemical markers from the peracid oxidation of isosafrole | journal = Forensic Science International | volume = 179 | issue = 1 | pages = 44–53 | date = July 2008 | pmid = 18508215 | doi = 10.1016/j.forsciint.2008.04.009 }} Peroxyacids can be made by combining hydrogen peroxide with an acid like formic acid or acetic acid to create performic acid or peracetic acid. It has been suggested that peroxynitric acid could also be used in this synthesis.{{cite web | vauthors = Morris H |title=This Chemist Made 200KG of MDA a WEEK |url=https://www.youtube.com/watch?v=exampleurl |website=YouTube |date=2022-12-25 |access-date=2024-12-13}} The oxidation first creates an epoxide in the alkene of isoapiole and then isopaiole glycol's monoformate ester if peracetic acid is used.{{cite journal | vauthors = Waumans D, Hermans B, Bruneel N, Tytgat J | title = A neolignan-type impurity arising from the peracid oxidation reaction of anethole in the surreptitious synthesis of 4-methoxyamphetamine (PMA) | journal = Forensic Science International | volume = 143 | issue = 2–3 | pages = 133–9 | date = July 2004 | pmid = 15240033 | doi = 10.1016/j.forsciint.2004.02.033 }} The hydrolysis is usually acid-catalyzed with a strong acid, such as sulphuric acid or hydrochloric acid, because the strong acid will also result in the intermediary isoapiole monoformyl glycol being dehydrated to DMMDP2P via a pinacol rearrangement. It is worth noting that a small amount of the epoxide can form a carboxycation, which can rearrange itself to DMMDP2P, or react with water to form isoapiole glycol. Thus only one reagent, sulphuric acid, is needed for both the hydrolysis and dehydration and both reactions can be done in the same reaction vessel. Then the DMMDP2P can then be subjected to a reductive amination with a source of nitrogen, such as ammonium chloride or ammonium nitrate, and a reducing agent, such as sodium cyanoborohydride, an amalgam of mercury and aluminium or pressurized hydrogen, to yield freebase DMMDA.{{cite journal | vauthors = Braun U, Shulgin AT, Braun G | title = Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine) | journal = Journal of Pharmaceutical Sciences | volume = 69 | issue = 2 | pages = 192–195 | date = February 1980 | pmid = 6102141 | doi = 10.1002/jps.2600690220 }}{{cite book | vauthors = Clayden J, Greeves N, Warren S |title=Organic Chemistry |year=2012 |pages=234–235 |publisher=Oxford University Press |isbn=978-0-19-927029-3 |language=en}}{{cite book | vauthors = Carey FA, Sundberg RJ |title=Organic Chemistry B: Reactions and Synthesis |year=2007 |pages=403–404 |publisher=Springer |isbn=978-0-387-68350-8 |language=en}}{{cite book | vauthors = Smith MB, March J |title=March's Advanced Organic Chemistry |year=2007 |pages=1288–1290 |publisher=John Wiley & Sons |isbn=978-0-471-72091-1 |language=en}}{{cite book | vauthors = Turcotte MG, Hayes KS |title=Amines, Lower Aliphatic Amines, Kirk-Othmer Encyclopedia of Chemical Technology |year=2001 |publisher=John Wiley & Sons |location=New York}}

:File:Modernfixed synthesis.png{{clear-left}}

Sodium borohydride usually is not used as a reducing agent due to it being much stronger than sodium cyanoborohydride; this usually results in side products in addition to DMMDA. Reductive aminations are exothermic reactions. Thus it is necessary to employ different methods of cooling the reaction mixture to prevent overheating; this can be accomplished by using a large amount of solvent or an ice bath, for example. The use of a mercury amalgam is unsafe due to mercury's well-known toxic effects on the central nervous system. It is also worth noting that in addition to peracetic acid, other peroxy acids can be used for the peroxy acid oxidation of isoapiole and other analogues of isoallylbenzene in general. For example, combining nitric acid with hydrogen peroxide would result in the same reaction.

DMMDA was first described in the scientific literature by Alexander Shulgin and colleagues by 1967.{{cite journal | vauthors = Shulgin AT, Sargent T | title = Psychotrophic phenylisopropylamines derived from apiole and dillapiole | journal = Nature | volume = 215 | issue = 5109 | pages = 1494–1495 | date = September 1967 | pmid = 4861200 | doi = 10.1038/2151494b0 | url = https://chemistry.mdma.ch/hiveboard/rhodium/dmmda.shulgin.html| url-access = subscription }}{{cite journal | vauthors = Shulgin AT, Sargent T, Naranjo C | title = The chemistry and psychopharmacology of nutmeg and of several related phenylisopropylamines | journal = Psychopharmacol Bull | volume = 4 | issue = 3 | pages = 13 | date = December 1967 | pmid = 5615546 | doi = | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=a15476299fba3b3a535958d0b198e813816ce768}}

• Substituted methylenedioxyphenethylamine
• Substituted methoxyphenethylamine
• Dimethoxymethylenedioxyamphetamine
• Methoxymethylenedioxyamphetamine
• 2,3,4,5-Tetramethoxyamphetamine (TeMA)

{{Reflist}}

• [https://isomerdesign.com/pihkal/explore/58 DMMDA - Isomer Design]
• [https://www.erowid.org/library/books_online/pihkal/pihkal058.shtml DMMDA - PiHKAL - Erowid]
• [https://isomerdesign.com/pihkal/read/pk/58 DMMDA - PiHKAL - Isomer Design]

{{Psychedelics}}

{{Serotonin receptor modulators}}

{{Phenethylamines}}

Category:2,5-Dimethoxyphenethylamines

Category:Hydroxyquinol ethers

Category:Methylenedioxyphenethylamines

Category:Psychedelic phenethylamines