# Everything I know about social anxiety / social phobia



## TouchyBoy (Apr 20, 2010)

*.*

.


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## crayzyMed (Nov 2, 2006)

Very interesting post TouchyBoy, good work!

Low 5HT1A density has also been associated with social anxiety, a strong 5HT1A agonist would also be effective for social anxiety.

Did you read my topic about lisuride?
http://www.socialanxietysupport.com/forum/f30/intrest-in-lisuride-90293/

Lisuride is a:
5HT1A agonist
5HT1B agonist
5HT2A agonist
5HT2C agonist
5HT6 agonist
5HT7 antagonist
5HT5A didnt find yet
D2 agonist 
D4 agonist

And weaker as:
5ht1e
D5
H2
D3

I personally do not beleive that 5HT2A antagonism is good, while 5HT2A increases anxiety in some brainarea's, it increases dopamine in the mesolimbic area's (the area's important for us).

Indeed, lisuride while also being a 5HT2A and C agonist, is anxiolytic as a whole:


> [Anxiolytic effects of lisuride and its agonistic action to central 5-HT1A receptors]
> [Article in Japanese]
> 
> Akai T, Takahashi M, Nakada Y, Ohnishi R, Ikoma Y, Yamaguchi M.
> ...


Tandospirone, a potent 5HT1A agonist has potential too.


> Dosage
> 
> Tandospirone is typically used at a dose of 30 mg/daily[6] taken in divided doses of 10 mg three times per day due to its short half-life. Though originally considered a relatively weak anxiolytic agent,[6] a clinical study found that doubling the dose to 60 mg/daily resulted in a "remarkable anxiolytic effect with an early onset of action, and without significant adverse effects", as well as "excellent anxiolytic efficacy that is comparable to that of the benzodiazepines".[6] [7]


Unfortionally its not available in the western world.

Memantine is usefull as it upregulates D2, high glutamate has also been associated with social anxiety, in this regard memantine can be usefull too.

Nicotine upregulates D3 in the nucleus accumbens, wich causes the severe craving for it, D3 upregulation in this particular brain area isnt usefull.

The problem with rasagiline and deprenyl is that they wont raise dopamine in the mesolimbic regio's (dont have a ref at hand now).


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## mark555666 (May 1, 2008)

crayzyMed said:


> [..]
> 
> The problem with rasagiline and deprenyl is that they wont raise dopamine in the mesolimbic regio's (dont have a ref at hand now).


If rasagiline and deprenyl don't raise dopamine mesolimbic pathway then I can assume MAOI's like Parnate/Nardil don't do that either?


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## crayzyMed (Nov 2, 2006)

Freesix88 said:


> If rasagiline and deprenyl don't raise dopamine mesolimbic pathway then I can assume MAOI's like Parnate/Nardil don't do that either?


According to rocknroll they do, but i think i remember a study showing that parnate does not raise dopamine there.

I was mostly referring to MAOB selective dosages regarding deprenyl and rasagaline.


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## crayzyMed (Nov 2, 2006)

I think i remember seeing a study that nmda antagonists also increase 5HT1A density (like they do with D2), so memantine will be usefull for that too.

About oxytocin, both 5HT1A agonism and D2 agonism increase it, look at this thread for more info regarding D2 and oxytocin:
http://www.socialanxietysupport.com...uces-oxytocin-secretion-in-rodents-and-86668/

Will go further in your post later today or tomorrow, watching lost atm.


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## mike8803 (Feb 21, 2010)

i pity the foo


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> Maybe, though, that these global effects are only due to the agony of 5HT1A and other receptors that mask the negative effects of 5HT2a and 5HT2C? What do you think?


I think that is true, and i also think that is exactly what you want to happen, especially regarding some dopamine receptors, lets take a look at those studies:



> *Social Anxiety*
> 
> (PMID: 7912934) D1 agonists reduced aggression in mice bred for aggression and reduced nonagonistic approach in mice bred for low aggression. The rationale is, from the study, "In both cases, this resulted from induction of a marked reactivity to mild social stimulation as measured by increases in behaviors such as escape, reflexive kicking, and vocalizations."
> 
> ...


(Copied from ex_dubio on mind and muscle)

Dopamine is in some brainregio's anxiogenic.

So what does this mean? It may be plausibly to say that the higher density of D2 and D3 is because of a lower ammount of dopamine, and that the low D2 density in social phobics is because of too much dopamine.

But, i dont agree with that theory, i beleive that more dopamine is highly beneficial. Here's my theory of what is going on.

While dopamine is anxiogenic in some brainregio's its prosocial and rewarding in other brainarea's, and the reason why a bigger dopamine density contributes to a higher social status is because its not only dopamine that plays a role, but also 5HT1A in those people, i beleive 5HT1A directly counteracts the increased anxiety by D2/D3 in some brainarea's while not interfering with the benefits of D2 and D3 in other brain area's. (I'm also guessing that amphetamine is a very effective treatment for SA because it only increases dopamine in the "good" area's, while leaving the anxiogenic area's unaffected).

In support of my theory is the fact that lisuride, despite being a dopamine agonist is highly anxiolytic.

Its the interplay between several receptors wich is highly beneficial.

The most important thing to achieve is combined 5HT1A and D2 agonism, D3 agonism too but D3 has several negative effects on reward.

A friend of my who took pramipexole for a whole noticed that it induced anhedonia, this due to its selectivity for D3. This property of pramipexole also causes gambling.


> PLoS ONE. 2008 Jun 25;3(6):e2479.
> Dopamine agonist increases risk taking but blunts reward-related brain activity.
> Riba J, Krämer UM, Heldmann M, Richter S, Münte TF.
> 
> ...


Also:
- Nmda antagonists upregulate 5HT1A and D2
- 5HT1A agonists decrease glutamate (wich should also upregulate 5HT1A and D2, will check wheter this occurs)

Thus i beleive that memantine + 5HT1A agonism + D2 agonism is a highly effective combo without much if any tolerance occuring. While there are no good selective 5HT1A or D2 agonists (well there tandospirone but impossible to get, and bromocriptine wich unfortionally also is a 5HT2B agonist) id say that Memantine+lisuride would be the best combo to achieve this.

About pindolol, its rubbish, it can be used to augment SOME SSRI's but mostly i wouldnt bother with it, the only good available 5HT1A agonist is lisuride, there's also buspar but it has a very poor intrinsic activity.

About COMT and MAOB, i dont know i havent investigated it that much.


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## crayzyMed (Nov 2, 2006)

Indeed one might think this ... but in fact is now known that dopamine is linked to extroversion and social dominance is correlated with elevated levels of dopamine. We also know that the greatest density of dopamine receptors (at least in part) certainly due to the attainment of high status ... surely there are genetic causes for this, but the high density of receptors is a consequence of high social status.

We agree ... is the only possible explanation to justify the fact that (in the medical literature) sometimes referred to as dopamine is linked to anxiety and fear, sometimes as anxiolytic and linked to social ... and this is in agreement with other evidence derived from studies. (If I understand the association between anxiety and metabolimsmo COMT could be explained with this argument ... but I am not sure what I understood)

The receptor agonists 5ht1a is in my opinion very important, as increasing oxytocin is put to rest the neuronal circuit of fear that is triggered by the amygdala.

*Yes, 5HT1A plays a crucial role, as seen with lisuride it counteracts any possible increase in anxiety by 5HT2A, 5HT2C or D2 agonism. 5HT2A agonism also increases dopamine in the mesolimbic area's, wich is a good thing. While 5HT2A causes anxiety in some brain area's, again the 5HT1A agonism counteracts this*

Oh **** ... I thought that pramipexole was a good fight for the anhedonia ... I thought contributed to enjoy life as a dopamine agonist! I knew that pramipexole (as well as other dopaminergic) lead to pathological gambling and other little things from bad guys, but I thought it was a good thing, that is one thing that made more active attitude to life, motivated, bright and happy.

why this effect? agismo the D2/D3 theory should not be a good thing?

*Agonsim of D2 is good but agonism of D3 is bad when it comes to reward D1 also plays a big role in reward, the problem with prami is that its more selective for D3, causing the dopamine system to be out of balance (too much D3 activation compared to D2, wich blunts the reward system)*

Upregulated receptors 5ht1a so as to afford to use every day as an agonist lisuride without causing tolerance? And the same for D2 receptors?

*Yes, in combination with a NMDA antagonist you should be able to take lisuride daily without any tolerance occuring.*

So you think lisuride has an action on D2 receptors important enough to be useful in social anxiety disorder? How effective has over other dopamine agonists?
*Yes definatly, lisuride is a very strong agonist on D2 and D4, D2 is socially important and D4 agonism increases cognition, while only a weak agonist at D3, it definatly wont blunt reward, but instead increase it.

All other dopamine agonists are either selective for D3 or cause fibrosis due to 5HT2B agonism.*

I was very upset to read those things on pramipexole :'( it seemed a good medicine ... read this on wikipedia "Several unusual adverse effects of pramipexole (and related D 3-preferring dopamine agonist medications Such as ropinirole) May include compulsive gambling, hypersexuality "I light up the eyes because it seems a good thing ... but anhedonia is not at all 

PS: anyone knows clarify my doubts about these two questions?:

1) "About MAO-B inhibitors ... I read that could reduce the production of dopamine to levels lower than the original ... can be true?"

2) "someone to do research on the metabolism of COMT, I may have made mistakes in understanding the significance of the studies. I understood that "high-activity COMT = high extraversion, low neuroticism (good for us)" and "low-activity COMT = low extraversion, high neuroticism (bad for us)." Can you check?"


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## crayzyMed (Nov 2, 2006)

Yeah youll need to adapt to it as it will reduce dopaminergic transmission like all the other dopamine agonists. However as its also a alpha2 antagonist its possible that it wont induce sedation during the adaptation period as with trivastal.

I'm really excited to see a report regarding lisuride, it looks perfect on paper (it also doesnt appear to be a 5HT2C agonist in humans). So if you try it keep me updated.


> Titre du Document
> Tianeptine decreases both serotonin transporter mRNA and binding sites in rat brain
> Auteur(s)
> KURODA Y. ; WATANABE Y. ; MCEWEN B. S.
> ...


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## podizzle (Nov 11, 2003)

ill be using some 4-hydroxyandrostenedione to help with my strength training this summer so I will be able to report back on any decrease in social anxiety. awesome thread!


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> http://www.mdma.net/mdmaeff.htm


In rats they use huge doses wich deplete serotonin with 40%, this reduction of serotonine upregulates 5HT1A, but as mdma doesnt significantly deplete serotonin in humans, this wont be relevant for us (unless you take a huge neurotoxic dose, wich would be counterproductive).


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> I was thinking one thing ... if, like any other
> compound lisuride in chronic subrules receptors that
> dying (nullifying conclusion its effects) and whether
> memantine actually able to increase receptor
> ...


Hmm, cant say exact numbers, but i beleive that in combination with memantine those receptors will stay sensitive enough so you wont notice a big drop in effiacy.

Ive had a study about NMDA antagonists in general, let me dig them up.


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## crayzyMed (Nov 2, 2006)

...



> Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat
> 
> G Micheletti, B Lannes, C Haby, E Borrelli, E Kempf, JM Warter, J Zwiller
> 
> ...





> Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.
> Author: Mele, A : Cabib, S : Oliverio, A
> Citation: Psychopharmacology-(Berl). 1995 Feb; 117(3): 313-7
> Abstract: The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.





> Summary. Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31 mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [3H]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [3H]MK-801 binding in the frontal cortex by 40.3%. *The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%*. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D2 receptor expression.





> Decreased striatal dopamine-receptor binding in sporadic ALS: Glutamate hyperactivity?
> 
> O. J. M. Vogels, MD, PhD, W. J. G. Oyen, MD, PhD, B. G. M. van Engelen, MD, PhD, G. W. A. M. Padberg, MD, PhD and M. W. I. M. Horstink, MD, PhD
> From the Departments of Neurology (Drs. Vogels, van Engelen, Padberg, and Horstink) and Nuclear Medicine (Dr. Oyen), University Hospital Nijmegen, the Netherlands.
> ...





> Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
> Rogóz Z, Dlaboga D, Dziedzicka-Wasylewska M.
> 
> Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. [email protected]
> In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, *we can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain, *and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.


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## crayzyMed (Nov 2, 2006)

> Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
> Nair VD, Savelli JE, Mishra RK.
> 
> Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
> The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. I*n the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP.* The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.





> J Mol Neurosci. 1998 Oct;11(2):121-6.
> Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
> Nair VD, Savelli JE, Mishra RK.
> 
> ...


And about 5HT1A:


> *Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brain*
> 
> K. Wdzony*, M. Ma
> 
> ...


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> http://www.ncbi.nlm.nih.gov/pubmed/1714897
> 
> It seems that forskolin stimulates the activity of serotonin transporter ... perhaps it might be helpful to avoid adaptation to Tianeptine also using a day one day and another.
> 
> It would be one more reason to take over the fact that forskolin increases D2 receptor. Anybody know what doses should be used?


Not sure about what dose of forskolin you need to take, but i tought you may find this report interesting about the memantine and tianeptine combo.



> My experimenting continues!
> 
> Today I have restarted Memantine @20mg and 2 hours later I ingested 12.5mg of Tianeptine. I was expecting this combination to knock me out but it has worked surprisingly well. I no longer get much stimulation from 20mg of Memantine but the addition of Tianeptine so far looks very promising. But more importantly I am not feeling dull and slow through my dose of Tianeptine and my cognition feels completely normal - and the magic of Tianeptine is still there. So this combination looks promising at the moment.
> Whether I have suddenly become more tolerant to the dulling cognitive effects I don't know. I find it strange that this could happen in just one day? Or this could be the effect of Memantine somehow counteracting this annoying side effect of Tianeptine? In all honesty I just don't know.
> I know from reading and studying www.tianeptine.com that Tianeptine much like Piracetam helps modulate the NMDA receptor and from my own experience Piracetam works with Memantine (so in theory there isn't any strange reason why Tianeptine wouldn't work with Memantine)


http://www.imminst.org/forum/If-only-I-could-dodge-Tianeptine-side-effects-t41193.html
(Read the whole thread for more info).

(Hope you dont mind for copying your experience here thorsten).


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## PiecesFalling (Jan 31, 2010)

I get the feeling there's a lot of useful information here but it all looks like jargon to me. :|


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## soaringfalcon11 (Jun 7, 2009)

I don't think SA is a brain disorder, but rathe a mind disorder. I'm thinking this because I used to have SA, but not anymore. And even when I had it, if I was around a certain people, it would go away completely. It's our thoughts which give us SA. Maybe nuerotransmitter and whatnot are part of it, but I think it's definitely a lot deeper than a "chemical imbalance."


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## crayzyMed (Nov 2, 2006)

soaringfalcon11 said:


> I don't think SA is a brain disorder, but rathe a mind disorder. I'm thinking this because I used to have SA, but not anymore. And even when I had it, if I was around a certain people, it would go away completely. It's our thoughts which give us SA. Maybe nuerotransmitter and whatnot are part of it, but I think it's definitely a lot deeper than a "chemical imbalance."


I disagree, i actually think thats the opposite around, you seem to be someone were it was a problem in the mind but not a chemical imbalance, however i beleive that for the majority of ppl therapy is useless and medication is the key.

For example, the most terrible part about social anxiety for me is that no matter how much i expose myself or go out with my friends, i will allways feel the same anxiety, i went to a friend of me allmost daily, and years later i still have the same ammount of anxiety. I have confidence enough too.

SA also involves reward problems.


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## crayzyMed (Nov 2, 2006)

> Y Zhang, D K Raap, L D van de Kar, A Javed, T S Gray, F Serres
> 5-Ht2a receptors stimulate acth, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic crf and oxytocin-expressing cells
> JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, THE , 21(10):3572-3579 2001
> "MDL 100,907 produced a dose-dependent inhibition (ED(50) congruent with 0.001 mg/kg) of the effect of DOI on plasma levels of ACTH, corticosterone, oxytocin, prolactin, and renin without altering basal hormone levels." [Full Text]


5HT2A agonism also increases oxytocin.

So we know that 5HT1A, 5HT2A and D2 increase it.


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## crayzyMed (Nov 2, 2006)

> Pharmacopsychiatry. 1997 Sep;30 Suppl 2:113-6.
> Effects of long-term administration of hypericum extracts on the affinity and density of the central serotonergic 5-HT1 A and 5-HT2 A receptors.
> 
> Teufel-Mayer R, Gleitz J.
> ...


St johns worth upregulates 5HT1A and 5HT2A.


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## Ehsan (Mar 21, 2009)

> COMT - the idea that I did read various studies is that: low-activity COMT (met / met) is associated with low extraversion, increased anxiety and neuroticism, while the high activity with low neuroticism and high extraversion (but also schizophrenia) ... However, please read you also studies to see if indeed I be so wrong to interpret or
> 
> Possible solutions: SAMe (should promote the activity of COMT) inhibitors of the enzyme aromatase drugs (estrogen reduces COMT and that's why women have higher probability of suffering from the anxiety disorders including social anxiety) The two AI I know are the 6-oxo (androstenetrione) and ATD (androstatrienedione), the second of which has a great effectiveness in reducing estrogen (with the pleasant result of increased testosterone), but is unfortunately ' antagonist of that testosterone in the brain, so even if this increases even more testosterone means that probably its psychological effects are reduced), the first you do not have this problem but I do not know whether it is effective as the first and Know about studies.
> 
> ...


I studied some of the above papers quickly but I didn't find consistent results. Also results were not form statistical significance.Second papers say val-val genotypes are more extroverts while the third says val-val genotypes have more phobic anxiety.
======================================================
lisuride
is its effect different from SSRIs?
SSRIs elevate extracellular serotonin and have a simillar agonism effect on all 5-HT receptors but they are almost useless.

LSD and methylergonovine have similar pharmacology. are they useful in SAD?


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## crayzyMed (Nov 2, 2006)

Ehsan said:


> ​I studied some of the above papers quickly but I didn't find consistent results. Also results were not form statistical significance.Second papers say val-val genotypes are more extroverts while the third says val-val genotypes have more phobic anxiety.
> ======================================================
> lisuride
> is its effect different from SSRIs?
> ...


I think it has potential because its a 5HT1A agonist and a 5HT7 antagonist at the same time (5HT7 antagonism enhances the antidepressant response to ssri's).

Lets take a look at what 5HT1A agonism ALONE can do:


> Dosage
> 
> Tandospirone is typically used at a dose of 30 mg/daily[6] taken in divided doses of 10 mg three times per day due to its short half-life. Though originally considered a relatively weak anxiolytic agent,[6] a clinical study found that doubling the dose to 60 mg/daily resulted in a "remarkable anxiolytic effect with an early onset of action, and without significant adverse effects", as well as "excellent anxiolytic efficacy that is comparable to that of the benzodiazepines".[6] [7]


Then we have D2 agonism on top of that (remember the study showing that D2 and D3 are implicated in social status?).

And the rest of its profile doesnt look bad either.

Your question about LSD, well yes, psychedelics tent to kill of depression/anxiety or reduce it in low doses that arent psychedelic, wich is because they have a complex pharmacological profile. For example 5HT2A agonism on its own can decrease dopamine in the frontal cortex while also being anxiogenic, however when combined with 5HT1A agonism none of the negative effects seem to appear (look at lisuride for example) while the benefits of 5HT2A agonism would still be there. (5HT2A plays a crucial role in mesolimbic dopamine release). Its also interacts with several andronergic receptors, so i think it would also be a non sedating dopamine agonist like trivastal (wich also is a alpha 2 antagonist) but i dont know the function of all the other adronergic receptors.

lol i dont wonna sound like lisuride is some kind of wonder potion, as i noticed i kinda do:b but it seems definatly worth a try imo.


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## crayzyMed (Nov 2, 2006)

Interesting studies, thx for those!


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## podizzle (Nov 11, 2003)

So megadose vitamin C to reduce cortisol for increase in 5ht1a?


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## karoloydi (Feb 18, 2010)

I am not sure if the strategy of depleting serotonin to increase dopamine is gonna work.
The connecting factor between dopamine and serotonin is L-amino acid decarboxylase

L-amino acid decarboxylase catalyzes several different decarboxylation reactions:
L-DOPA to dopamine 
5-HTP to serotonin (5-HT) 
Tryptophan to tryptamine.

Does anyone know why theres not an L-amino acid decarboxylase supplement Like L Dopa and 5 HTP?

Heres a quite easy to understand article on dopamine serotonin relationship.
http://www.neuroassist.com/serotonin-dopamine.htm

Here are some quotes from that article that I think will be helpful:



> The serotonin dopamine systems are intertwined to the point that of being one system





> The dopamine precursors tyrosine or levodopa deplete of serotonin. The serotonin precursors 5-HTP or tryptophan deplete dopamine. With the serotonin dopamine system if either becomes depleted enough both systems will no longer work. The serotonin dopamine systems are in balance.





> Serotonin dopamine synthesis is caused by the enzyme "L-amino acid decarboxylase"





> From a clinical standpoint, during long-term use levodopa
> becomes ineffective due to serotonin depletion. In order to prevent this 5-HTP needs to be administered with levodopa
> in proper balance. In medicine when the levodopa
> quits working the approach is to increase the levodopa
> dosing which depletes serotonin even more.





> When only 5-HTP is used in treatment, 5-HTP depletes dopamine, norepinephrine, and epinephrine levels. When dopamine levels drop low enough, 5-HTP becomes ineffective and the side effects of dopamine depletion occur. 5-HTP and dopa must be provided in proper balance to affect optimal serotonin dopamine balance. For years doctors have depleted serotonin levels in Parkinson's Disease patient by prescribing only levodopa


I think I experienced something like this from wellbutrin. When I took wellbutrin on its own I was really irritated and angry and got depressed to the point that I was crying. Normally even if I am upset and I want to cry I cant cry. Its like impossible to me.
Last week I tried taking wellbutrin with 5 HTP and I had none none of those symptoms. Could be a coincidence, but it makes sense that this could be the case.


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## karoloydi (Feb 18, 2010)

Another good article that shows one of the ways NMDA antagonists like memantine prevent tolerance. And also how they increase dopamine. Have a look on my previous post about L-amino acid decarboxylase to see the connection if you cant see it.

Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase.
http://www.ncbi.nlm.nih.gov/pubmed/9871440



> This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia ***** pars reticulata (SNr) and corpus striatum (CS). *The NMDA receptor-ion channel antagonists MK 801, budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS*. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.


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## Selection10 (Oct 7, 2009)

this is a great topic!!!


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## zendog78 (Jan 27, 2010)

There is one thing missing from this thread, once crucial bit of information that puts all this research into perspective. That is:

*Correlation *

*Does *

*Not *

*Imply *

*Causation!*

http://en.wikipedia.org/wiki/Correlation_does_not_imply_causation

I spent years chasing my tail playing amateur Psychoneuroendopharmacologist. 
I became an expert in talking all this **** and together with my background as a Psych nurse was able to scam whatever I wanted out of so many doctors. Weird and wonderful substances augmented, potentiated, mediated and supplimented with other weird and wonderful substances, natural substances, illicet substances. 
I spent years obsessed with pubmed.com, nature reviews, clinical trials and self medication. I was upregulating, downregulating, Sensitizing, Desensitizing... I very nearly killed myself several times.

You know where it all got me?

*Nowhere!*

It makes you feel better doing this because it makes you feel your on a path to discovery. You see all the associations between various conditions, body systems, drug types and effects and it always feels like you are just around the corner from pulling it all together and then finding that magic bullet that fixs everything.

Aint gunna happen.

A single study means nothing. Researchers publish for all kinds of reasons and even the "gold standard" Double blind placebo controlled trials can be conducted poorly. Added to that are studies that are conducted analysed and presented in such a manner that for all intensive purposes they are faked. For political, financial and for reasons of personal gain and prestige.
Similarly, a mouse is not a human being! Their metabolisim, brain and body structure have some parallels to humans but the hypothesis that a change in behaviour in a certain way after being given some drug or another means X change the funtion of their brain and then extrapolated to mean x in humans are all unproven hypothesis. If you add in that our understanding of the workings of the brain is still unproven and just a theory (http://en.wikipedia.org/wiki/Receptor_theory) You are left with a questionable research methods, probably not reproduced = *worthless speculation* on a *hypothesis* on a *hypothesis* on a *hypothesis *on a *hypothesis!*
It is pure speculation, an educated shot in the dark, it gives researchers some food for the mind and maybe when weighed up an analysed with hundreds of other studies it could give a direction for further research; but on its own it is *meaningless!*

Trust me when I say, your wasting your time on a pointless and potentially dangerous search for a holy grail that doesnt exist...at least at this point in time.
If you want to know more about research methodology I highly reccomend you buy or borrow "Bad science" by Dr Ben Goldacre. It is a real eye opener and even if you insist on continuing to read this kind of stuff, it will give you great tools and know how of sorting out what is worth reading.
http://www.badscience.net/

But overall you would be better served using this time to read some autobiographies of people who have suffered in their life for some perspective on your own. Or some therapy or exercise. Stuff that we know helps.

Social anxiety is here for ever. You may be able to control it, suppress it or ignore it for a while but what you really need to do is improve it.
So do what works
Zen


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## crayzyMed (Nov 2, 2006)

zendog78 said:


> You know where it all got me?
> 
> *Nowhere!*
> 
> Zen


The big reason for that is because you forgot one crucial part, and that is, keeping the density of the receptors you activate sensitive, wich in the end caused your MAOI to poop out on you, atleast there are many that have long term succes with MAOI's, its not an issue for everyone.

With selective releasing agents you get a response right away so you can also take breaks whenever its needed, the only issue i have left now is excess euphoria, induced by amphetamine when combined with AMT (i dont get tolerant to it because of the small breaks and memantine) however i should be able to counteract that problem with naltrexone and rimmonabant, wich both also increase cortisol (increased cortisol is beneficial for me).

Personally i know that i cant fix myself without research chemicals, atleast MAOI's could work for me but i'm pretty picky when it comes to meds, i want to be pretty much side effect free and also only want rapid acting meds, the things i play with i wouldnt recommend unless your really treatment resistant.

AMT is excellent, its a serotonine, dopamine releasing agent, ive written about serotonine releasing agents before, see this:

Anyway guys, i beleive in serotonine releasers as the future antidepressants, 2 study's by nichols et al showed that they are superior to sertraline (1) and have a more rapid effect then standard antidepresants (2). SSRI's work by elevating serotonine however the serotonine autoreceptors lower serotonine again untill they downregulate and serotonine is elevated high enough for the patient to notice a antidepressant effect, however many patients are treatment resistant, activity of the 5HT1A autoreceptors has been associated with that atleast according to a study in mice (3). 
Serotonine releasers effectively bypass the autoreceptors by forcing serotonine release resulting in a more robust response.

Some selective serotonine releasers are available as research chemicals however they dont have any research behind them in humans and could carry risk, an exception of this is AMT or alpha methyl tryptamine, it has been in clinical use for 20 years in the sovjet union, besides serotonine release its also a dopamine releaser wich further potentiates the antidepressant effects.

It is true that combined serotonine and dopamine release leads to neurotoxiticy, as seen with MDMA, however with MDMA there are 3 major factors contributing, first oxidative stress caused by massive monoamine release, AMT in low daily doses doesnt cause a massive elevation and oxidative stress will be minimal, hyperthermia if hyperthermia is abolished MDMA's neurotoxiticy is gone too, AMT in low doses doesnt cause any hyperthermia and last the toxic metabolites, wheter AMT has those is unclear (or i'm just not aware of that).

In conclusion i beleive that switching to a SSRI would decrease all benefits ive got up till now, and i beleive that the best strategy would be augmenting AMT.
AMT also lacks the impotence and other side effects seen with SSRI's, and it by itself fixes me up a great deal, so its definatly going to be a keeper.

1. The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats.". Stress. PMID 9787258.
2. Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action. Unfortunately as a research chemical it's legality is subject to change. PMID 10428424.
3. RGS inhibition at Gαi2 selectively potentiates 5-HT1A-mediated antidepressant effects PNAS 107/24/11086

Then the dopamine part keeps my ADHD better at bay then amphetamine itself, its just my SA wich needs an extra push to get into full remission, the only problem is excess euphoria when i combine amp with AMT, a problem that can be fixed tough! 

AMT kept working for me the 2 months i took it, only cross tolerance induced by other recreational substances could made me tolerant to it, however combined with memantine a 2 day break was enough to completely reverse it and back again it works for a long time!


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## crayzyMed (Nov 2, 2006)

When the worthless speculation turns out succesfull in my case, i cant call it speculation anymore.


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## zendog78 (Jan 27, 2010)

How was that a reply to my post? You quoted me then didnt address anything I said in the thread?

Anyway, if you get some sucess thats great but find a treatment that doesnt require constant monitering and adjustment with minimal side effects, is legal, safe and obtainable and that is still working well for you after 12 months, then I will be impressed.

I for one think NMDA antagonists are the future of antidepressants.
My own theory of Social phobia is that it is related to a psychologically stressful situation causing a reduction in frontal lobe activity which sets up a negative feedback loop of increasing anxiety and decreasing higher brain funtion.
I also think there is a big role for stress induced mitocondrial dysfuntion and subsequent apitosis in the brain.
There are various agents you could address with this such as ketamine for amphetamine tollerence but your still always going to be chasing your tail with downregulation and neuroplasticity has its limits, especially when you factor in ageing.

I think it is a biological disorder as I have the same problem in that exposure does not really improve my SA. 
There is some interesting work being done clinically with D-cycloserine but apparently tolerence again is a major issue.
The brain and body always strives for homeostasis which is genetically programed through hereditry and our environment. 
Overcoming that is a damn big fish to fry.


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## crayzyMed (Nov 2, 2006)

I know that in my case i have dopaminergic problems, wich is based on this:


> Here's what doesnt work for my social anxiety at all:
> 
> - Selective serotonine releasers, up to recreational doses, induce euphoria but lack any effect on my social anxiety.
> - Alcohol, induces euphoria but doesnt work either
> ...


Also, anticholinergics wich induce dopamine in more brainarea's then just the reward pathways seemed to abolish my anxety, atleast on a dose that caused a delirium (accidently overdosed on diphyndramine).



> You quoted me then didnt address anything I said in the thread?


Thats because there's no point, its clear i cant convince you.

Overcoming tolerance isnt as hard as you think, there are ppl that have had allready 2 years succes with memantine for amphetamine tolerance.

I personally beleive that dopaminergic problems are the mean issue in social anxiety disorder (ive made a thread about that a while ago) you are having succes with nardil, however downregulation took place so you dont see as much benefits anymore.

Your saying that NMDA antagonists could be the future antidepressants, why dont you try augmenting nardil with memantine? NMDA antagonists upregulate mRNA expression of several dopamine receptors wich is why they work for amphetamine tolerance, however wheter they would work with MAOI's is not clear, because they also tend to upregulate the autoreceptors (wich need to be downregulated before nardil can kick in).


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## zendog78 (Jan 27, 2010)

> Thats because there's no point, its clear i cant convince you.


What? Then why quote me? Confusing again. I would be happy to discuss but not with that superior attitude

Whatever dude, enjoy your thread


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## crayzyMed (Nov 2, 2006)

zendog78 said:


> What? Then why quote me? Confusing again. I would be happy to discuss but not with that superior attitude
> 
> Whatever dude, enjoy your thread


Dude, there's no need to get angry, because you were writing with big letters it did look like you would be very hard to convince, so i immediatly started describing the things i'm looking at myself and what succes i allready booked instead of discussing the points you have brought up as i tought that would end in a never ending yes or no discussion.

I dont feel superior to you in any way btw, srry if i sounded like that.


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## Under17 (May 4, 2010)

Alright, so basically we should stop taking meds that we know works for us, and instead just exercise and read people's autobiographies and live with SA and whatever other mental illnesses we have for life.

GTFO.


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## JohnG (Sep 3, 2010)

Whitout medications it's hard to Expose yourself and learn new social skills. You should ask medical/pharmacological help if SA is making your life impossibile.


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## broflovski (Feb 1, 2011)

Great thread, I've enjoyed reading (but haven't understood the ultimate inference). This all seems overcomplicated.


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## crayzyMed (Nov 2, 2006)

> 3. Decrease dopamine in the striatum during the night (to sensitize the receptors during the day): 5-HT2A inverse agonist (in the striatum decreases / increases in mPFC ... also large numbers of these receptors is associated with lower reactivity of the amygdala and increased excretion of oxytocin), 5-HT3 antagonist (decreases dopamine in the striatum and increases in mPFC ... The 5-HT3 receptor agonists is the major cause of inactivation of the mPFC under MDMA), Inositol (D2 receptors increases ... I do not know if it works as a messenger or decreasing dopamine, so it would be best taken at night).


5HT2A inverse agonism is very bad as that would downregulate the receptor wich is important for sa, there's no need to lower dopamine at night, NMDA antagonists and alpha3beta4 (i think) antagonists upregulate dopamine receptors.


> 4. Lower serotonin* during the day and modulate receptor: Sildenafil (decreases amyloid beta, increases the action of SERT by the rise in cGMP) Tianeptine (increases the action of SERT, however, it appears that the amount of long-term decrease SERT same ... I assumed that since the T an inhibitor of nitric oxide it can increase or decrease the amyloid beta cGMP); Respen-A (reserpine, associated with a calcium supplement would prevent the action on the dopamine and involve then selective serotonin) 5-HT2C antagonist during the night (even if this action results in an increase in dopamine and is contrary to paragraph 3, the antagonism of this receptor is the primary means to increase the wave sleep slow and this is important), 5-ht7 antagonism (both during the day and at night ... is antidepressant, anxiolytic and reduces REM sleep), and perhaps 5-HT 1A antagonism during the night so over-regulate the receptors for day (as for the 5-HT2A a large number of these receptors is associated with lower reactivity of the amygdala and increased secretion of oxytocin ... however, we must ensure that no negative effects on sleep. methysergide should be the example of the favorable side effects ... its physical part of the drug).


Its better to increase serotonine by releasing agents.


> 5. Increase mPFC activity during the night and decrease during the day, decrease the norepinephrine during the day: antagonize alpha-2 receptors during the night to the upregulated day ... during the day then you might want to use an alpha-2 agonist such as guanfacine or clonidine, or a mixed antagonist of alpha-1 + beta-2, while the latter approach, however, affects only the final receptors (probably no effect on dopamine), the use of guanfacine or clonidine results in an overall decrease of norepinephrine released, but also dopaminergic activity in the mPFC.


I beleive NE should be increased during the day.


> 7. Increased androgens, antioxidants and other potentially useful supplements: Carnitine; vitamin E; D-aspartic acid, Glutathione, Vitamin D, Papaya, Omega-3, ZMA, LDN, Alpha Lipoic Acid.


Excess antioxidant activity is bad imo.


> 9. Antagonism of glutamatergic NMDA receptors: antagonism itself (as in the case of memantine) prevents the effects of social defeat reduces the fear conditioning and reduces (in some cases reverse) the tolerance of many substances (such as the dopamine amphetamines, and benzodiazepines). The fact is that a particular substance of this class (ketamine) also has a powerful antidepressant effect independent from the action on NMDA receptors (and reduces the activity of the HPA) ... given that memantine may be taken daily but lacks this effect Positive K's I do not know whether the use of K in order antidepressant can be a substitute for memantine, and then encloses both the effect of memantine that his ability antidepressant. Another thing to consider is that NMDA antagonists appear to decrease vasopressin, and in one study reported that using the vasopressin antagonist blocks the morphine tolerance in the same way that an NMDA antagonist memantine on ... the effect of tolerance could therefore actually be mediated by the reduction of vasopressin ... there is to do more research, but if so you could use a vasopressin antagonist in place of memantine and ketamine antidepressant purposes.


I dont think vasopressing uperegulate D2 and D3.



> 10. GABA-A receptor agonists during the night: while it would be good for anxiety and stress the use during the day, it is not interacting with modafinil (which appears to antagonize the GABA-A receptor and lose its effectiveness with agonists at this receptor), better then use them during the night, low-dose benzodiazepine, Lysine (I seem to convert glutamate into GABA ... maybe that has seen the same action of vitamin B6 at doses need to be careful)


GABAB agonism during daytime.



> With regard to the sex hormones ... we know that social anxiety is more common in women than in man, but you should understand if androgens to decrease the incidence of SA or estrogen to grow and I do not have clear ideas on the subject. For example, estrogen decreases the activity of COMT (negative) but increase GH (positive), of course we know that androgens have positive effects, the only negative I found is that vasopressin increases. If I were sure that (at least in males) estrogen could play a negative effect on SA and angrogeni positive, you could use SERMs such as tamoxifen, which reduces the action of estrogen and can more than double ) theconcentration of androgens (with the known negative effects such as hair loss and acne). They are used in women with breast cancer (because they are antagonists of oestrogens and also reduce GH and IGF-I) and in hypogonadal men (because of the increase in LH and testosterone).


Clomid can be used safely to increase test.


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## broflovski (Feb 1, 2011)

TouchyBoy said:


> What part do you mean? mean that drug interactions are complicated proposals? or the way I wrote the post is complicated? I did the translation from Italian to English with google, if there are parts incomprehensible from the point of view of writing, I can try to translate better.


I mean the former. The way you formulate is ok, and I'm very grateful. But, taking into account the previous CrazyMed's post I'm increasingly discouraged with the situation, that quite opposite inferences may be made from the same data.


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## JohnG (Sep 3, 2010)

5-HT2A agonism, seems to release glutamate also, that doesn`t look so good. But, no time to go into the subject, maybe someone knows better?


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## crayzyMed (Nov 2, 2006)

5HT2A agonists release glutamate in the prefrontal cortex wich is good for cognition, NMDA antagonists excert most of their dopamine upregulation effect in the striatum.


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> Why? does not increase anxiety? I found that the increased transmission of norepinephrine characterizes social anxiety, harm avoidance, fear conditioning ... Furthermore, the use of clonidine decreases the activity in the mPFC


Depends on the cause of social anxiety, is it excess nerveusness or dopamine defiency?


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## crayzyMed (Nov 2, 2006)

I beleive oxytocin is overrated, it increases TRUST in other ppl, but i dont beleive many ppl have sa because they dont trust others or lack empathy.


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## crayzyMed (Nov 2, 2006)

> CLOMID: the doubt remains that the antagonism to estrogen can be anxiety-inducing ... and also decreases the GH ... I must investigate


Its a mixed agonist/antagonist and not anxiety inducing AFAIK, testosterone increase however is anxiolytic.


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## zendog78 (Jan 27, 2010)

Crazymed - you should be over at bluelight talking this kind of stuff because nobody here has the expertise to question your assertions and they need to be questioned.

I don't know if you are are a chemistry student or pharmacy student but I know sure as **** that you are not a qualified researcher or scientist in this field, I don't think you are even an assistant because some proper methodology would have surely rubbed off on you by now.

Nor are you involved in the treatment of mental illness. You're not a doctor or a Psychiatric nurse which is what I am.

Everything you are saying is opinion dressed up as fact and factoids dressed up as knowledge.

"Ampa receptors modulators and glutamate antagonists downregulating dopamine receptors blah blah blah" 

Everything you are talking about addresses so many complex feedback mechanisms for systems we are not even close to understanding and you are trying to follow all the hints to some holy grail of sociability. 

It's bull****.

More to the point, its dangerous bull****.

This is amateur chemopsychonaughtics - 

For every three of these studies you are posting there will be two out there somewhere that come to the exact opposite conclusion.

Show me peer review, show me double blind placebo controlled trials and high quality meta-analysis - the vast majority of what you are posting is just crap, noise, nothing more.

This stuff has no real world application in the therapeutic management of a debilitating condition such as social phobia. Period. 

This is not evidence

And you are putting others at risk by passing yourself off as some sort of guru on here, moderators should be ashamed for letting you do it for so long.

The biggest risk of this isn't getting Parkinson's at 45 or stroking out, no, the biggest danger to this is the loss of time and the wasting of years.

So I'm sorry to tell you, but everything you know about social phobia is SFA mate. Nothing. All this is just factoids masquerading for knowledge. Your wasting your own time and wasting others by perpetuating the myth that consciousness is nothing more than a big bag of chemicals that can be manipulated at will by other chemicals.
Even if this was true, we are nowhere near finding this panacea you are searching for and if it does come, it will come from something like gene therapy not from our primitive chemical therapy.

Stop selling snake oil, stop with your little personality cult on here.

There is no magic bullet to social phobia and anxiety disorders. The solution is a combination of lots of little things, drugs, therapy and just learning and growing not reading obscure journal entries about obscure compounds.


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