SSAO (Semicarbazide-Sensitive Amine Oxidase) Inhibitors

PEA is maybe a sigma agonist ? ive just read that DMT is a sigma ligand :D

-qwer27

Amphetamine dxm dmt morphine pcp are ligands , ive hallucinate on those coumpound yes morphine in high dosage can produce visuals maybe it was mental fatigue or the dopamine release form opiod receptor but its pretty unique

Its mechanism of action is not well understood, but ketamine can block NMDA receptors (receptors, N-methyl-D-aspartate) and may interact with sigma receptors.

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression.

-http://www.ncbi.nlm.nih.gov/pubmed/20373470

CLINICAL SIGNIFICANCE OF SIGMA RECEPTORS

Sigma receptors, discovered in 1976 (Martin et al.,1976), have a unique pharmacological profile (Su and Hayashi, 2003) and are located in the cell membrane, although they are also dynamic endoplasmic reticulum (ER) proteins thought to affect intracellular second messenger systems, particularly calcium mobilisation. Sigma-1 receptors are found mainly in regions of the cerebellum, cingulate nucleus, hippocampus, hypothalamus and pones (Stahl, 2005). A recent study by Hayashi and Su (2007) identified the sigma-1 receptor as a novel ER chaperone. Sigma-1 receptors are predominantly expressed at the mitochondrial-associated ER membrane, thereby regulating the IP3 receptor-mediated Ca2þ influx from the ER to the mitochondria (Hayashi and Su, 2007). Because mitochondrial Ca2þ originating fromthe ER is a key activator of three dehydrogenases in the tricyclic acid (TCA) cycle, the sigma-1 receptors are assumed to serve as a regulator of ATP production and
bioenergetics within the cell (Hayashi and Stahl, 2009). Sigma-1 receptors have been shown to regulate a number of neurotransmitter systems, including the glutamatergic, dopaminergic, serotonergic, noradrenergic, and cholinergic systems. Glutamate modulation has the effect of promoting neurogenesis via nerve growth factor which initiated adaptive neural plasticity as a protection or reaction to stress (Takebayashi et al., 2002; Nishimura et al., 2008). The accumulated evidence also suggests that the activation/up regulation of sigma-1 receptors promotes neuronal differentiations well as a robust anti-apoptotic action (Hayashi and Su, 2008). As reviewed by Stahl (2005), sigma-1 receptor ligands have been linked to the improvement of memory and learning processes (Debonnel and de Montigny, 1996; John et al., 1997; Waterhouse et al., 1997; Takebayashi et al., 2002; Guitart et al., 2004; Hashimoto et al., 2007), depression (Senda et al., 1996; Phan et al., 2002; Urani et al., 2002;Wang et al., 2003; Ishikawa and Hashimoto, 2010), anxiety (Ucar et al., 2002; Ishikawa and Hashimoto, 2010), psychosis (Kamei et al., 1998; Urani et al., 2002; Ishikawa and Hashimoto, 2010), stress (Bergeron and Debonnel, 1997; Maurice and Lockhart, 1997; Maurice et al., 2001), aggression (Phan et al., 2002) and pharmacodependence (Ucar et al., 1997; Maurice et al., 2001; Phan et al., 2002).

The action of sigma-1 receptor agonists on the function via NMDA receptors may be important as another mechanism of enhancement of glutamatergic function. It is known that sigma-1 receptor agonists do not bind to the glycine site on the NMDA receptors (located on post-synaptic neurons) because sigma-1 receptors located on the ER. However, it is well known that sigma-1 receptors might play a role in the central nervous system (CNS) as a modulator of signal transduction in neurotransmitter systems such as NMDA receptors (Hashimoto and Ishiwata, 2006).
 
Thus, it seems that sigma-1 receptors might have important roles in glutamatergic function indirectly via NMDA receptors. Various sigma-ligands have been investigated over the years for potential clinical applications. Preclinical and clinical studies have encompassed, for example, functional diarrhoea as a model of somatoform disorder (involving igmesine [also known as JO, 1784], a potent and selective ligand and one of the earliest tested [Roman et al., 1990]), depression (igmesine, opipramol), anxiety (opipramol, siramisine), schizophrenia (panamasine, rimcazole) and somatoform disorders (opipramol). In many cases, however, further development of these agents was stopped for commercial reasons (Volz and Stoll, 2004). Clinical investigations into the potential sigma receptor-related effects of fluvoxamine, however, continue.

Full paper on longecity: http://www.longecity.org/forum/topic/58918-do-antidepressants-do-more-harm-than-good/

Amphetamine dxm dmt morphine pcp are ligands , ive hallucinate on those coumpound yes morphine in high dosage can produce visuals maybe it was mental fatigue or the dopamine release form opiod receptor but its pretty unique

-qwer27

could be the kappa agonism you would experience at that dose, or it could effect D1 this is possible

Sigma-1 receptors have been shown to regulate a number of neurotransmitter systems, including the glutamatergic, dopaminergic, serotonergic, noradrenergic, and cholinergic systems. Glutamate modulation has the effect of promoting neurogenesis via nerve growth factor which initiated adaptive neural plasticity as a protection or reaction to stress. The accumulated evidence also suggests that the activation/up regulation of sigma-1 receptors promotes neuronal differentiations well as a robust anti-apoptotic action (Hayashi and Su, 2008). As reviewed by Stahl (2005), sigma-1 receptor ligands have been linked to the improvement of memory and learning processes

PEA is maybe a sigma agonist ? ive just read that DMT is a sigma ligand :D

-qwer27

What would make you think that PEA is a Sigma agonist? I am just curious what indicated this to you?

I have no idea what Sigma agonism by itself exactly feels like. Sigma agonism has been linked to hallucinogenic and psychotic effects. And I remember reading somewhere that Sigma receptors are closely associated with acetylcholine receptors and that agonizing Sigma receptors can lead to anticholinergic-like delirium.

There is also a theory that the Sigma receptor agonist effects of DXM are largely responsible for the effects felt on a 2nd plateau dose. But other receptors (PCP2, NMDA, etc.) are also effected at this plateau, so it is hard to tell exactly what effect this receptor has.

The 2nd plateau of DXM is more sedative than the first. It is more visual with more changes in cognition and coordination. This does seem like it could be described as similar to the traditional definition of psychosis.

Then there is also a plateau referred to as "Plateau Sigma" that is reached by taking a 2nd plateau dose, followed 3hr later by another 2nd plateau dose, and followed 3hr later by a 3rd plateau dose. After the normal effects of the DXM wear off, the user experiences extremely powerful visual and auditory hallucinations that cannot be distinguished from reality and strange delusions. Entity contact has often been reported.

The theory is that this semi-psychotic state occurs due to the long period of non-stop Sigma receptors agonization.

So it seems like Sigma agonization leads to highly abstract thought processes, delusions, and visuals and can cause delirium. Ever since I learned about Sigma receptors, I have considered them to be another psychedelic receptor.

''What would make you think that PEA is a Sigma agonist? I am just curious what indicated this to you?''

''That feeling sounds to me like it might be due to NMDA antagonism. I get this feeling from many NMDA antagonists and especially with DXM. Perhaps SSAO is what destroys Endopsychosin, the body's endogenous version of PCP. Or maybe it is effecting some other endogenous NMDA antagonist.-powerfulmedicine

It feels similar but different. I wouldn't call it NMDA antagonism... it is something else. Sort of dissociative but not mentally, and not bodily NMDA antagonism either... I don't know how to describe its difference.''

SSOA, phenethylamine, sigma ; linked :D  + amphetamine are a sigma ligand....
Might not be horsecrap afterall.

''The theory is that this semi-psychotic state occurs due to the long period of non-stop Sigma receptors agonization. ''

''As reviewed by Stahl (2005), sigma-1 receptor ligands have been linked to the improvement of memory and learning processes''

''And I remember reading somewhere that Sigma receptors are closely associated with acetylcholine receptors and that agonizing Sigma receptors can lead to anticholinergic-like delirium.''

i love the link between glutamate and acetylcholine in the first article but psychotic state do not improve memory and learning, especially anticholinergics.

Could phenethylamine be a D2 agonist they dissociate the mind alright but the visual effect are wayyy too obvious. Its surely the neuromodulation witch modulate other things that make the magic,could be the neurotransmission acting but it look like this compound have a lots of cards to show ; euphoric, sedative,stimulant.... so might be neuromodulation showing different grades of color.

The fact that DMT is an agonist at sigma receptors has me very intrigued. I would like to be able to isolate its feeling from the other effects of DMT...

Do we know of any easily available selective sigma agonists? How about agonists that have other effects that are easy to filter out, like GABAergics? I doubt I'd be able to differentiate between DMT's other effects and its sigma agonism.

Ibogaine :D NMDA antag.  kappa agonist and 5HT2A agonist + sigma :D filter it out eheh
Ibogaine is more sigma 2 than 1 but DMT is only sigma 1 eheh gotta check it out there is a seller of iboga in my ''province'' ,its a must for anyone passionate about trans-dimensional mind expansion.

5HT2A is the only serotonin receptor activated just pure fun.
Ibogaine:4.00 Sigma2,3.57 SERT, 3.02 DAT, 3.01 NMDA,2.88 KOR, 2.67 MOR, 2.55 Sigma1, 2.22 M3, 2.16 5ht2a, 1.96M1, 1.72 M2, 1.47 D3; its from the Psychedelics and the Human Receptorome PDF these are not dissociation constent at all, data below 2 are not perceivable...f*cking depend on dosage :D

Do we know of any easily available selective sigma agonists? How about agonists that have other effects that are easy to filter out, like GABAergics? I doubt I'd be able to differentiate between DMT's other effects and its sigma agonism.

-toastus

Cocaine is also a Sigma-1 agonist, but once again it would probably be hard to pick out the effects of this receptor from other receptors. And I doubt that most people would want to use this drug for such a purpose.

DXM is probably your best bet, since the prevalence of Sigma-1 agonism is supposed to be what  differentiates the 1st and 2nd plateau. This also isn't a perfect solution though due to the other receptors that are effected. And it should also be noted that DXM effects both Sigma-1 and Sigma-2.

I am pretty sure that there are no easily available sigma agonists that don't also effect a ton of other receptors. There are a few obscure research chemicals that have high affinity and selectivity though. Cocaine is also a Sigma-1 agonist, but once again it would probably be hard to pick out the effects of this receptor from other receptors. And I doubt that most people would want to use this drug for such a purpose.
DXM is probably your best bet, since the prevalence of Sigma-1 agonism is supposed to be what  differentiates the 1st and 2nd plateau. This also isn't a perfect solution though due to the other receptors that are effected. And it should also be noted that DXM effects both Sigma-1 and Sigma-2.

-powerfulmedicine

DXM would be harder since it's an NMDA antagonist which would hamper thoughts. also an acetylcholine antagonist

''As reviewed by Stahl (2005), sigma-1 receptor ligands have been linked to the improvement of memory and learning processes''

''And I remember reading somewhere that Sigma receptors are closely associated with acetylcholine receptors and that agonizing Sigma receptors can lead to anticholinergic-like delirium.''

i love the link between glutamate and acetylcholine in the first article but psychotic state do not improve memory and learning, especially anticholinergics.

-qwer27

The psychedelic state would classically be described as a psychotic state. Also the psychedelic state is initially anticholinergic, just not to the point of delirium. And anticholinergics do cause upregulation of acetylcholine receptors after the effects wear off. So a psychotic state could ultimately improve memory and learning.

Sigma over-agonization has been linked with schizophrenia. And a major component of schizophrenia is hallucinations and increases in free association. Ideas become inexplicably linked in the mind. The mind becomes overly stimulated. The psychotic state experienced during "Plateau Sigma" is also a result of overstimulation of Sigma rectors.

But it seems plausible that when this receptor is agonized, but not excessively, it could have nootropic effects. Free association and mental stimulation is a good thing up to a point. For instance, the increase in mental effects on the 2nd plateau of DXM may very well be due to Sigma agonism.

So Sigma agonists are probably very useful up to a point.

DXM would be harder since it's an NMDA antagonist which would hamper thoughts. also an acetylcholine antagonist

-toastus

The anticholinergic effects of DXM are pretty weak, but I could see how it still might make the mind less sharp in some ways with its NMDA antagonist effects. Though it is possible to sort of pick out the Sigma effects if you have a lot of experience with this drug.

Oh well. I guess you'll have to keep looking.

Good thing i turn the SSAO topic into a sigma agonist ahah, Great knowlegde thx powerfulmedicine for details on sigmas. I just love them more :D

''Free association and mental stimulation is a good thing up to a point.'' You could say that again :D

'' Ideas become inexplicably linked in the mind. The mind becomes overly stimulated.'' i spend last year on amphetamine so yeah i know that feeling really really well, its like a instant absolute understanding , there is no logic of words, you feel it. Intellectual transcendence. too much cause psychosis not really psychosis but extra focus on concepts or void i might say.  Ibogaine and dmt have that absoluteness.

I just found that I had a whole bunch of Glucosamine hydrochloride tablets hidden in the back of a cabinet in my bathroom, so soon this thread will be a bit more back on track.

The Glucosamine that I have is intended to promote joint health and includes 2g of gelatin per tablet as an active ingredient. I want to experiment with activating PEA using Glucosamine, but I hope that the gelatin does not interfere with the PEA. I'm not sure if the gelatin will expand in the stomach and slow down the absorption. I know that eating before taking PEA can make it inactive sometimes.

Also, the recommended dose is 6g daily according to the stuff I have, so it seems like this compound is very safe at the doses that have been tested so far.

Yeah I'm making a new thread for Sigma Receptor discussion, which I would like to continue. Let's get this thread back on track.

Soon I will test cranesbill root at doses lower than a gram for its potency at inhibiting SSAO.

i have some glucosamine and will be testing various things.

has anyone found it better before, or during the experience?

Ibogaine :D NMDA antag.  kappa agonist and 5HT2A agonist + sigma :D filter it out eheh
Ibogaine is more sigma 2 than 1 but DMT is only sigma 1 eheh gotta check it out there is a seller of iboga in my ''province'' ,its a must for anyone passionate about trans-dimensional mind expansion.
5HT2A is the only serotonin receptor activated just pure fun.
Ibogaine:4.00 Sigma2,3.57 SERT, 3.02 DAT, 3.01 NMDA,2.88 KOR, 2.67 MOR, 2.55 Sigma1, 2.22 M3, 2.16 5ht2a, 1.96M1, 1.72 M2, 1.47 D3; its from the Psychedelics and the Human Receptorome PDF these are not dissociation constent at all, data below 2 are not perceivable...f*cking depend on dosage :D

-qwer27

iboga has a complex synergy between its various actions, it appears to be strongest in chronic micro dose ware you occasionally take a full dose, if the right dose is used it is reverse tolerant.

SRI - when wears off enhanced serotonin firing
NMDA antagonist - upregulates D2
KOR - upregulates D2 and MOR
MOR upregulates KOR
5HT2A - downstream D2 agonist - strongly synergizes with most above

toastus that mix i was talking to you about? it seem like iboga is practically got it already set up, i imagine it could be improved though.

L-lysine is an SSAO inhibitor!

Here are two abstracts:

Interaction of L-lysine and soluble elastin with the semicarbazide-sensitive amine oxidase in the context of its vascular-adhesion and tissue maturation functions.

Olivieri A, O'Sullivan J, Fortuny LR, Vives IL, Tipton KF.

Abstract

The copper-containing quinoenzyme semicarbazide-sensitive amine oxidase (EC 1.4.3.21; SSAO) is a multifunctional protein. In some tissues, such as the endothelium, it also acts as vascular-adhesion protein 1 (VAP-1), which is involved in inflammatory responses and in the chemotaxis of leukocytes. Earlier work had suggested that lysine might function as a recognition molecule for SSAO/VAP-1. The present work reports the kinetics of the interaction of L-lysine and some of its derivatives with SSAO. Binding was shown to be saturable, time-dependent but reversible and to cause uncompetitive inhibition with respect to the amine substrate. It was also specific, since D-lysine, L-lysine ethyl ester and epsilon-acetyl-L-lysine, for example, did not bind to the enzyme. The lysine-rich protein soluble elastin bound to the enzyme relatively tightly, which may have relevance to the reported roles of SSAO in maintaining the extracellular matrix (ECM) and in the maturation of elastin. Our data show that lysyl residues are not oxidized by SSAO, but they bind tightly to the enzyme in the presence of hydrogen peroxide. This suggests that binding in vivo of SSAO to lysyl residues in physiological targets might be regulated in the presence of H(2)O(2), formed during the oxidation of a physiological SSAO substrate, yet to be identified.

L-lysine as a recognition molecule for the VAP-1 function of SSAO

A. Olivieri, K. Tipton, J. O’Sullivan

Summary

Semicarbazide-sensitive amine oxidase (EC 1.4.3.6) acts as a vascular-adhesion protein (VAP-1), mediating the adhesion of lymphocytes to vascular endothelial cells under inflammatory conditions. The relationship between the adhesive and the enzymatic functions of SSAO have not yet been fully defined. Previous studies from this laboratory showed aminohexoses, which were neither substrates nor direct inhibitors of SSAO, bound to the enzyme as reversible inhibitors in the presence of H2O2 generated during substrate oxidation. The possibility that surface l-lysine could act similarly has been investigated in the present study. The presence of l-lysine during the oxidation of benzylamine resulted in time- and dose-dependent inhibition of SSAO activity, in a process that was dependent on the H2O2 formed during benzylamine oxidation. The possible implications of this in terms of the therapeutic uses of lysine are discussed.

Someone should test this out. L-lysine may not be effective though, since it seems like Hydrogen peroxide must be present in order for L-lysine to inhibit SSAO. But Hydrogen peroxide is present in the body and is a product of the break down of some SSAO substrates according to these studies, so maybe it will work.