EMDT, DiPT, 2-Me-DET and 2-Me-DMT: The Auditory Effect

[nuke]

EMDT is a standard agonistic ligand for the 5-HT6 receptor; it is known that this receptor serves to function somehow in the auditory system.

2-Me-DMT, 2-Me-DET, and DiPT are all effective disturbers of the auditory system in humans, with DiPT being the most potent.

EMD-386,088 is an extremely potent agonist at the 5-HT6 receptor.

My thoughts are that strong agonists for this receptor (and thus auditory system distortion) have hydrophic regions:
1.) Between the non-cyclic amine in tryptamine and the pyrroline ring.
2.) At the 2-position of the tryptamine, extending outward.

With the free rotation of the alkylamine "tail" in DiPT, it could meet both of these proposed specifications well (whereas DPT could be hindered by interactions/conformations with the receptor).

I would be hopeful that human assays of either EMDT or EMD-386,088 might produce an effect of auditory distortion.

 

[Doctor Abalaba]

Awesome data. I'm currently engaged in some DiPT work for my thesis. Do you have sources/refs for this info (other than Shulgin's).
Why only the 5-HT6 receptor? There are other points of overlap between 5-HT and the auditory system. For example, in the brainstem (1,2), and in various places in auditory nuclei (3). Also relevant is the role of serotonin 1a, considering the trypt class's affinity for that receptor, and the serotonin reuptake protein, in AEPs (auditory evoked potentials) (4,5).
Dr Thomas Ray is currently finishing up his analysis of the binding data of 32 psychedelics. It will be the first article to address DiPT's neurological effect. I'm not sure the relationship with 5HT6 is accurate, but I can't argue about that until it is published.
What I find interesting is that there are other, non-DiPT analogues which possess that auditory effect.
By the way, do you know if the MDO-Dipt analogues possess prominent auditory properties? Shulgin barely touches on these guys.

Im sure on day, DiPT will shed light on higher auditory processes. But for some reason, very few people have tried to study it.



1- Thompson, Ann M.; Serotonin immunoreactivity in auditory brainstem neurons of the postnatal monoamine oxidase-A knockout mouse. Brain Research, Vol 1228, Sep 2008. pp. 58-67.
2- Thompson, Ann M.; Lauder, J. M.; Postnatal Expression of the Serotonin Transporter in Auditory Brainstem Neurons.Preview Developmental Neuroscience, Vol 27(1), Jan-Feb 2005. pp. 1-12.
3- Zeng, ShaoJu; Li, Jia; Zhang, XinWen; Zuo, MingXue; Distinction of neurochemistry between the cores and their shells of auditory nuclei in tetrapod species. Brain, Behavior and Evolution, Vol 70(1), Jun 2007. pp. 1-20.
4- Chen, Tai-Jui; Yu, Younger W. -Y.; Hong, Chen-Jee; Chen, Ming-Chao; Tsai, Shih-Jen;Association analysis for the C-1019G promoter variant of the 5-HT1A receptor gene with auditory evoked potentials in major depression. Neuropsychobiology, Vol 50(4), 2004. pp. 292-295.
5- Chen, Tai-Jui; Yu, Younger W.-Y.; Chen, Ming-Chao; Tsai, Shih-Jen; Hong, Chen-Jee; Association analysis for serotonin transporter promoter polymorphism and auditory evoked potentials for major depression. Neuropsychobiology, Vol 46(2), Aug 2002. pp. 57-60.

 

[nuke]

This study in particular is very enticing:

5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism.

Doleviczényi Z, Vizi ES, Gacsályi I, Pallagi K, Volk B, Hársing LG Jr, Halmos G, Lendvai B, Zelles T.

Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, 1083, Budapest, Hungary.

In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss.

http://www.ncbi.nlm.nih.gov/pubmed/18663573?dopt=Abstract

This covers some of the SARs of these 5-HT6 agonistic compounds:

2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors.

Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK.

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT(6) serotonin agonists. It was found that 5-HT(6) receptors accommodate small alkyl substituents at the indole 2-position and that the resulting compounds can bind with affinities comparable to that of serotonin. In particular, 2-ethyl-5-methoxy-N, N-dimethyltryptamine (8) binds with high affinity at human 5-HT(6) receptors (K(i) = 16 nM) relative to 5-HT (K(i) = 75 nM) and was a full agonist, at least as potent (8: K(act) = 3.6 nM) as serotonin (K(act) = 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT(1A) (K(i) = 170 nM), h5-HT(1D) (K(i) = 290 nM), and h5-HT(7) (K(i) = 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 5-HT(6) agonist reported to date. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retains 5-HT(6) receptor affinity (i.e., 10: K(i) = 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT(6) agonists and antagonists.

http://www.ncbi.nlm.nih.gov/pubmed/10715164

 

[hamhurricane]

wow nuke, thats totally fascinating. i have yet to sample 2-Me-DMT, and i have often wondered exactly how potent its auditory effects are compared to DiPT. if anyone has tried both they should speak up, although its difficult to quantify these sorts of things.

EDIT: based on this new SAR theory could their be an auditory hallucinogen stronger than DiPT, what about something like 2-propyl-DMT?

 

[yaesutom]

http://www.bluelight.ru/vb/showthread.php?t=247064 <--- sorry i was obviously really fucking wired on amphetamine at the time.

hmm.. i thought i tried 2-Me-DMT but maybe not.. don't remember (during a few years i was pretty 'out of it'), but i know i've had alpha,N,N-TMT and it was a major audio distorter at an active dose (100mg+), but not as potent as DiPT (also the way it distorted sound was 'different' but similar)

 

[Doctor Abalaba]

Fucking awesome Nuke!

 

[nuke]

http://www.bluelight.ru/vb/showthread.php?t=247064 <--- sorry i was obviously really fucking wired on amphetamine at the time.

hmm.. i thought i tried 2-Me-DMT but maybe not.. don't remember (during a few years i was pretty 'out of it'), but i know i've had alpha,N,N-TMT and it was a major audio distorter at an active dose (100mg+), but not as potent as DiPT (also the way it distorted sound was 'different' but similar)

Well, that kind of fits with my theory, but I guess there's a third component, which would be n,n-dialkyl substituents as well.

So the dialkyl substituted AMTs might all turn out as audio distorters... maybe.

 

[IGNVS]

http://www.bluelight.ru/vb/showthread.php?t=247064 <--- sorry i was obviously really fucking wired on amphetamine at the time.

hmm.. i thought i tried 2-Me-DMT but maybe not.. don't remember (during a few years i was pretty 'out of it'), but i know i've had alpha,N,N-TMT and it was a major audio distorter at an active dose (100mg+), but not as potent as DiPT (also the way it distorted sound was 'different' but similar)

a,n,n-tmt is what i was looking up when i found bluelight. do you have a trip report on it? where can i get more info (i havnt heard or seen anything about it anywhere but my imagination)?

thanks

 

[hamhurricane]

it would seem there are a large number of 5ht6 antagonist drugs used experimentally, are there any prescription drugs with such an action? if so they could be taken in conjunction with DiPT and part of this theory could be tested...

 

[Doctor Abalaba]

In my research I stumbled upon Carbamazepine. Carbamazepine is an anticonvulsant/mood stabilizers, but it seems that there are case reports indicating that it can cause 'reversible ptich distortion (1,2,3,4).' I didn't pay it much mind then, but I just did some research. So apparently it is thought to exert, at least it's anticonvulsant effects, via GABA and NMDA (5), however, to some degree it is known to be a serotonin releaser (6,7).
Serotonin releasers are very different than 5-HT6 agonist, and this rare side effect would be very difficult to study given it's anomalous nature, but I thought this might be interesting though. It's my opinion that frequently we underestimate the binding potential of a compound. I don't have the particular data for carbamazepine, but a lot of the older pharmacodynamic data were generated in cells other than neurons (for example; 2c-b 5-HT receptor binding was determined in rat hepatocytes- 8.). These data may not be representative of in vivo human binding. I digress, Carbamazepine certainly produces an interesting effect, which sounds to me akin to that of DiPT.



1-Yoshikawa, H., & Abe, T. (2003, March). Carbamazepine-induced abnormal pitch perception. Brain & Development, 25(2), 127-129.
2-Kobayashi, T., Nisijma, K., Ehara, Y., Otsuka, K., & Kato, S. (2001, August). Pitch perception shift: A rare-side effect of carbamazepine. Psychiatry and Clinical Neurosciences, 55(4), 415-417.
Chaloupka, V., Mitchell, S., & Muirhead, R. (1994, July). Observation of a reversible, medication-induced change in pitch perception. Journal of the Acoustical Society of America, 96(1), 145-149.
3-Miyaoka, T., Seno, H., Itoga, M., & Horiguchi, J. (2000, July). Reversible pitch perception deficit caused by carbamazepine. Clinical Neuropharmacology, 23(4), 219-221.
4-Miyaoka, T., Seno, H., Itoga, M., & Horiguchi, J. (2000, July). Reversible pitch perception deficit caused by carbamazepine. Clinical Neuropharmacology, 23(4), 219-221.
Griffiths, T., Penhune, V., Peretz, I., Dean, J., Patterson, R., & Green, G. (2000, April). Frontal processing and auditory perception. Neuroreport: For Rapid Communication of Neuroscience Research, 11(5), 919-922.
5-Wengel, S., & Folks, D. (2003). Mood stabilizers. Agitation in patients with dementia: A practical guide to diagnosis and management (pp. 149-166). Arlington, VA US: American Psychiatric Publishing, Inc.
6- Elphick, M., Anderson, S., Hallis, K., & Grahame-Smith, D. (1990, January). Effects of carbamazepine on 5-hydroxytryptamine function in rodents. Psychopharmacology, 100(1), 49-53.
7- Schachter, S. (2002, June). Tricyclic anticonvulsants: Mechanisms of action. Epilepsy & Behavior, 3(3), S7-s8. Retrieved February 7, 2009, doi:10.1016/S1525-5050(02)00014-8
8- Kanamori T, Tsujikawa K, Ohmae Y, Iwata YT, Inoue H, Kishi T, Nakahama T, & Inouye Y. (2005). A study of the metabolism of methamphetamine and 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in isolated rat hepatocytes. Forensic Science International. 148 ( 2-3 ), 131-7.

 

[kakti]

Would 5-meo-dipt fit into this proposal? There are massive auditory distortions at the 25mg+ level.

 

[nuke]

Carbamazepine is a very weird drug. Does oxcarbazepine have this effect too?

Would 5-meo-dipt fit into this proposal? There are massive auditory distortions at the 25mg+ level.

Yes, it should, what's interesting is that the 5-MeO doesn't seem to cause any increase in potency for auditory distortion. A halogen in the 5-position seems to enhance the selectivity/potency of 5-HT6 agonists though; 5-X-DiPT would be an interesting assay.

 

[Doctor Abalaba]

I couldn't find any scholarly articles about that effect in oxcarbazepine. Wouldn't be surprised if it did though.

 

[Morninggloryseed]

There is some. I'll admit that I've only tried DiPT once...@ 100mg...but the auditory distortions I experienced off 11mg of 5-MeO-DiPT were quite strong...I don't think 11mg of DiPT would have produced such an effect. There is certainly some increase in potency with regards to the auditory distortion, as well as differences in the ways it distorts auditory perception. 5-MeO-DiPT produces a much more linear sort of distortion, where as DiPT isn't. Shulgin spoke of this in TIHKAL.

what's interesting is that the 5-MeO doesn't seem to cause any increase in potency for auditory distortion.

 

[IGNVS]

does anyone find auditory distortions to be more disturbing than visuals? it definatly throws you off WAY MORE.. alot of times in a very dark way. more of that "loss of control" feel

 

[Hammilton]

That won't be too useful, it blocks multiple serotonin receptors in addition to having all sorts of other effects.

It would be cool to see what would happen with a more selective 5HT6 antagonist would produce though.

 

[MurphyClox]

How could I miss that topic? Extraordinarily interesting!

I have seen some recent works that refer to the 5HT4-receptor as target of DiPT, 5-MeO-DiPT and alike. How is this receptor-subtype distributed in the ears resp. the regions of the brain responsible for hearing?


- Murphy

 

[Phener]

Seems a lot of research has progressed since original post:

The 5-HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[4][5][1] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[5][6][3]

[edit] Function
Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

Despite the 5-HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[13] and agents such as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other dementias.[14][10][15] 5-HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[18][11] Additionally, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

http://en.wikipedia.org/wiki/5-HT6_receptor

Lots of compounds to test the hypothesis with. It's possible polymorphism in receptors involved in the ear? (if this theory still stands) Wonder what the side effects being reported of the agonist and antagonists are.

 

[nuke]

Well, the 5HT6 theory is still kind of up in the air due to the recent study pertaining to a large number of compounds and reporting numerous psychedelics with an affinity for 5HT6 found that DIPT was not a ligand. It may also be 5HT4, as Murphy is alluding to, which was not evaluated.

That paper is here: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009019

 

[atara]

5-ht4 is the target of a number of novel antidepressants and nootropics.

http://en.wikipedia.org/wiki/RS-67333

http://en.wikipedia.org/wiki/SL65.0155

There are also a number of 5-ht4 ligands used to treat gastroesophagal reflux disease, but I assume, since no psychological effects are noted, that these do not cross the blood-brain barrier and instead only act on receptors in the gut.