![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 4 to 28 of 84. Go back in thread:
Posted by Ron Hill on April 23, 2003, at 2:16:15
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
It can make a grumpy man smile.
-- Ron
Posted by Ron Hill on April 23, 2003, at 2:21:25
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
It can make a social phobic man friendly and outgoing.
-- Ron
Posted by Ron Hill on April 23, 2003, at 2:23:54
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
It can make an anxious man relaxed and calm.
-- Ron
Posted by Ron Hill on April 23, 2003, at 2:29:02
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
It can make an obsessive-compulsive man carefree and content.
-- Ron
Posted by Ron Hill on April 23, 2003, at 2:41:41
In reply to What are the best Natural Serotonin enhancers?, posted by McPac on April 22, 2003, at 23:13:04
> I want to throw my Zoloft where it belongs (in the toilet). I want to inrease my serotonin naturally instead of using this chemical trash. Any ideas? Can you increase it enough with natural methods?
Hi McPac,I hear ya; I threw my SSRI’s away several years ago. There are a couple things that you can try. I can share with you the little I know on the subject, but Larry would know much more.
However, before I say anything, please tell me:
What is your dx?
What meds (and at what dosages) are you currently taking?
What meds have you tried in the past and what were the primary effects each of the medications had on you?
How much do you exercise and at what intensity level?
-- Ron
Posted by Ron Hill on April 23, 2003, at 3:42:06
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
On the downside, however, chief among the brain’s reactions to artificially elevated serotonin levels is a compensatory drop in dopamine which can change a goal oriented, motivated, and ambitious man into a "do nothing boy".
-- Ron
Posted by linkadge on April 23, 2003, at 8:09:17
In reply to Re: What are the best Natural Serotonin enhancers? » stjames, posted by Ron Hill on April 23, 2003, at 3:42:06
I don't know how many millions of people
are swallowing a lot of expensive nothing
if serotonin does not help mental illness.Even if it wasn't serotoin at work, call
it what you want, I swallow these little
white beads, and I feel better in a few
weeks. Maybe not all feel better, but thats
why I am very thankful
Linkadge
Posted by stjames on April 23, 2003, at 10:55:38
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
> Increasing Serotonin does not help mental illness.
>AD's regulate Serotonin. Thhy do not increase it in a traditional sence but hold more of it at the clef, which in turn causes a cascade of effects
up and down the neurotransmition system. In some cases this causes down regulation.When someone says "I want to increase Serotonin"
it seem to me to indicate a very bare understanding of what is going on. Therefore,
picking treatments based on a flawed understanding
yields poor or no results.
Posted by Larry Hoover on April 23, 2003, at 11:04:24
In reply to What are the best Natural Serotonin enhancers?, posted by McPac on April 22, 2003, at 23:13:04
> I want to throw my Zoloft where it belongs (in the toilet). I want to inrease my serotonin naturally instead of using this chemical trash. Any ideas? Can you increase it enough with natural methods?
I think the focus on serotonin with respect to depression is, at its worst, a mistake, and at the least, a distraction. If you want to increase serotonin naturally, buy some tryptophan. You can get it from some sources of veterinary feed supplements.
This isn't the greatest metaphor, but....
Tricyclic antidepressants were discovered totally by accident,what we call in science serendipity. Everyone wanted to know how they worked, and when it was discovered that they block serotonin reuptake, the search then went on to find drugs with a similar action with more benign side-effect profiles. So we got the SSRIs, and on it goes. On to the metaphor.
If you think of a neuron as a loaded gun, and neurotransmitters as fingers on the trigger, tricyclics might be seen as alternative means of pulling the trigger, by way of changing the trigger sensitivity. SSRIs are just different ways of doing the same thing, pulling the trigger. What has been lost in this focussing on a narrow (but observable) effect is that the real change occurs because a bullet is released.
Any time you simplify a complex system, you lose information. I fear that the simplification that declares depression to be the result of an imbalance in serotonin is really meaningless. To focus on just one chemical amidst a soup of other chemicals is wilful blindness. Just think about the blind men and the elephant.
Lar
Posted by stjames on April 23, 2003, at 11:54:42
In reply to Re: What are the best Natural Serotonin enhancers? » McPac, posted by Larry Hoover on April 23, 2003, at 11:04:24
Any time you simplify a complex system, you lose information. I fear that the simplification that declares depression to be the result of an imbalance in serotonin is really meaningless. To focus on just one chemical amidst a soup of other chemicals is wilful blindness. Just think about the blind men and the elephant.
Lar
THANK YOU LAR !!!.
It has been clear to me for years that with complex systems like neurology, simplistic
models like "increasing whatever" are flawed.This is also my consern about this site. People
seem to only leave with the understanding of "Oh, all I need is to increase X". I have been posting for years trying to correct this misconception, but few seem to want to listen and understand.
Posted by linkadge on April 23, 2003, at 13:12:58
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 11:54:42
Most people here know that the sum of all
human happiness is not just Serotonin. We
do know is that SSRI's do two things.
1. Yes they do increase Serotoin, as measured
by spinal metabolite byproduct levels.2. They relieve depression for many.
The drugs may infact, and probably do
do more than that. But we haven't really
discovered what that is. We also
know that low Serotonin metabolites and
chronic cortisol elevations are among
the few measurable indicators of depression,(5HTAA only measurable upon death however)
We know there is a strong correlation between
5HT1 receptor expression and violent suicide,
and 5HT2 and sleep. We can induce depression
by lowering Serotoin with Resterpine, and
we can raise it by blocking serotoinin autoreceptors. We know that violent criminals often have a high testosterone/serotoin ratio. We know that 5HTP, the precursor to serotoin can effectivly treat depression in some. We know that there are very few clinically effective antidepressants that have no effect on Serotonin, and that the ones that do are virtually useless in treating suicidal idealation. We know that ECT has robustly alters Serotonin receptor density. We know that MDMA
(while bad for the brain) is possibly the best drug out there for depression, and it enhances the release of serotonin. Lithium raises serotonin and decreases suicide risk.So, no, thats not all thats going on,
but for goodness sake you'd be a fool
to think that Serotonin doesn't have
a certain deal to do with a whole
lot of peoples problems.Linkadge
Posted by Peter S. on April 23, 2003, at 13:50:59
In reply to What are the best Natural Serotonin enhancers?, posted by McPac on April 22, 2003, at 23:13:04
Has tryptophan or 5HTP ever worked for anyone? I see tons of books and web sites saying that these are effective but have heard very little actual accounts that they work. I have a feeling that this hype from the natural remedy industry. I tried 5HTP and I was sleeping 14 hours per day. I've heard that tryptophan can augment SSRI's but again haven't heard of this working for anyone. I would definitely give tryptophan a try if I thought it would help.
Would love to hear people's experiences or info.
Peter
Posted by stjames on April 23, 2003, at 14:03:37
In reply to Just cuase SSRIs don't work for everyone..., posted by linkadge on April 23, 2003, at 13:12:58
> So, no, thats not all thats going on,
> but for goodness sake you'd be a fool
> to think that Serotonin doesn't have
> a certain deal to do with a whole
> lot of peoples problems.
Please do not call me a fool. I did not
say "Serotonin doesn't have a certain deal to do with a whole lot of peoples problems."
Serotonin does, but not in the "lets just
make more and them we will be better" sence.
Posted by Paulie on April 23, 2003, at 14:28:30
In reply to What are the best Natural Serotonin enhancers?, posted by McPac on April 22, 2003, at 23:13:04
From Depression-anti-aging therapies by James South
Increased brain production of serotonin through tryptophan supplementation does not automatically increase serotonin nerve activity. At low levels of psychobiologic arousal, there will be adequate serotonin to support the correlative low serotonin nerve activity, even when neuron levels of tryptophan and serotonin are low (22). This more apathetic, vegetative quiescent variety of depression ("I'm so depressed I can't even get out of bed") is referred to as the "apathetic-inhibited" type (22). This form of depression represents more of a deficiency of activity of the dopamine/ noradrenalin "yang" "get-up-and-go", activating neural circuits, and so tryptophan/ serotonin may offer little relief to, or even worsen, this type of depression.
At higher levels of arousal, however, the more rapid turnover of serotonin in the synaptic gap will require higher levels of serotonin production to adequately maintain the greater activity of serotonin circuits. Thus Young and Teff suggest that tryptophan will be most effective as an anti-depressant in those suffering from "anxious-agitated" depression, with its high state of stress arousal, combined with the depression (22). Anxious, agitated depression occurs when a person's dopaminergic/ noradrenergic activating ("yang") neural circuits are functioning strongly, without the calming, relaxing, mellowing serotonin circuits ("yin") functioning strongly as a complementary counterbalance.
Paulie
Posted by linkadge on April 23, 2003, at 14:33:37
In reply to Re: Just cuase (sic) SSRIs don't ....., posted by stjames on April 23, 2003, at 14:03:37
There are two sides,those who think Serotonin does everything,
and those who think it does nothing,
I have mistaken you for the latter,I apoligise.
Linkage
Posted by linkadge on April 23, 2003, at 14:36:46
In reply to Serotonin:good for some depressions,bad for others, posted by Paulie on April 23, 2003, at 14:28:30
This is true,
Thats probably where the 40 percent fits
into the gap of Antidepressant nonresponders.If you're going to take the 5HTP route then
add some tyrosine.Linkadge
Posted by stjames on April 23, 2003, at 15:01:13
In reply to Agreed / Sorry, posted by linkadge on April 23, 2003, at 14:33:37
>
> There are two sides,
>
> those who think Serotonin does everything,
> and those who think it does nothing,
> I have mistaken you for the latter,
>
> I apoligise.
>
> LinkageI would say I am in the middle, however I think
Serotonin is *just* one thing we understand. Many
others are involved, so concentrating on Serotonin
as the only agent in anyones illness is a mistake.
Posted by McPac on April 23, 2003, at 19:19:22
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 0:00:23
"Increasing Serotonin does not help mental illness".
"Gonggggg" lol
Posted by Ron Hill on April 24, 2003, at 1:29:47
In reply to Re: What are the best Natural Serotonin enhancers?, posted by McPac on April 23, 2003, at 19:19:22
McPac,
Hey, you didn't answer my questions. :-)
Here, read 'em again (please):
http://www.dr-bob.org/babble/20030417/msgs/221686.html
-- Ron
Posted by Ron Hill on April 24, 2003, at 2:15:44
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 11:54:42
Hi James,
I like you Mr. James Oracle. You were one of the first people I solicited advice from when I arrived at pbabbleland years ago. Keeping in mind that I am your friend, may I offer an opinion? If no, stop here. If yes, keep reading.
> This is also my consern about this site. People
seem to only leave with the understanding of "Oh, all I need is to increase X". I have been posting for years trying to correct this misconception, but few seem to want to listen and understand.Maybe the message is not the problem. Perhaps its the sharp edges on the package used to deliver the message.
-- Ron
P.S. Your stock is starting to make a move to the up side. ORCL closed at $12.00 per share yesterday.
Posted by stjames on April 24, 2003, at 15:04:24
In reply to Re: What are the best Natural Serotonin enhancers? » stjames, posted by Ron Hill on April 24, 2003, at 2:15:44
> Maybe the message is not the problem. Perhaps its the sharp edges on the package used to deliver the message.
Well that is too bad, I like to cut to the chase.
Some do not like it and many seem to appreciate
my bluntness. Plus there are lots of people here to hold hands and say "Poor you". Since this kind of help never did swat for me, in getting well from my illness, and I have bee well for over 20 yrs, I will continue to be blunt.It is either that or assume people are stupid, and I do not want to think like that.
Posted by Bill L on April 24, 2003, at 15:10:20
In reply to What are the best Natural Serotonin enhancers?, posted by McPac on April 22, 2003, at 23:13:04
I didn't read all the follow ups so I might not be adding anything. But the prescription AD's are very safe (for everyone) and very effective for most people. They are more effective than St John's Wort, Valerian, and some of the other natural remedies.
I think the best question to ask is what helps depression rather than asking what increases serotonin. Scientists do not know whether or not SSRI's or other drugs relieve depression by increasing serotonin. It's just a theory.
Posted by Ritchie on April 24, 2003, at 17:31:38
In reply to What's the deal with tryptophan and 5HTP?, posted by Peter S. on April 23, 2003, at 13:50:59
> Has tryptophan or 5HTP ever worked for anyone? I see tons of books and web sites saying that these are effective but have heard very little actual accounts that they work. I have a feeling that this hype from the natural remedy industry. I tried 5HTP and I was sleeping 14 hours per day. I've heard that tryptophan can augment SSRI's but again haven't heard of this working for anyone. I would definitely give tryptophan a try if I thought it would help.
>
> Would love to hear people's experiences or info.
>
> PeterI have been taking 5 HTP for about 2 months now. Besides taking it for sleep, I also take it to even out my mood and to curb carb cravings. I also just started taking Strattera for depression. The combination seems to work well with me. I swear by it but I suppose it doesn't work for every one. My doctor actually recommended it. The thing about HTP is it is rather expensive to take daily. I take 200 mg every night. I wouldn't recommend the 2 together with anyone who has an eating disorder, your appetite just literally disappears.
Hope this helps.
Jax
Posted by jrbecker on April 24, 2003, at 17:43:59
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 11:54:42
In no way am I trying to add further agitation to this interesting thread, but I thought I'd offer some interesting knowledge on what helped me start to first conceptualize the interplay of the neurotransmitter systems, long before I took my first psychopharm and introductory neuroscience courses. Many of you are familiar with the Hedonistic Imperative (http://www.biopsychiatry.com), but for those that aren't, it offers a phenominal vault of information for the novice to start understanding what the heck these meds do. When visiting the site, make sure to scroll down to the "refs" link to look up any of a number of cross-referenced terms. As you'll find, there are many offshoot websites (e.g., HedWeb, Nutritional Psychiatry, The Hedonistic Imperative) that range from scientific to philospical in nature. One of these links which has very recently been updated, is Utopian Pharmacology (http://www.mdma.net). It talks about -- you guessed it -- "ecstasy," its imperfections/shortcomings, but also its utlility as a psychotropic prototype. Anyways, it's an interesting read, not only for its timeliness (since it has recently been updated), but also because it's probably the best single piece of writing I've come accross that helps to explain the complex interplay of the neurotransmitters (yes, that of the dopamine/serotonin relationship in specific!). It's certainly not the most easy-to-comprehend and simplist explanation though, so have some caffeine on hand while you read. I've included an exerpt below. My advice to you in both reading this excerpt and the actual link is to skim brutally...
[
Lifelong ecstatic wonderpills and genetic self-mastery are at best some way off. So which ingredients of MDMA's primal magic are most worth mimicking pharmacologically right away? Preventing tolerance, promoting safety, and indefinitely extending duration are vital. Yet how desirable is inducing more or less euphoria, more or less calmness or behavioural activation, purer empathogenic or entactogenic action, and a greater or lesser hint of trippiness?Pre-treatment studies with receptor antagonists indicate that dopamine D2 antagonists such as haloperidol (Haldol) attenuate MDMA's positive hedonic effects; 5-HT2A antagonists like ketanserin suppress MDMA's residual psychedelic activity; and SSRIs like citalopram, the most selective of the SSRIs, diminish if not abolish the full spectrum of MDMA's psychoactivity. Drug discrimination studies performed on captive rodents may overlook certain subtleties of the MDMA experience. But on present evidence, it's the interplay between the serotonergic and dopaminergic systems that underlies MDMA's discriminative stimulus effects/sublime magic.
The full story is complex and still poorly understood. As the user "comes up", serotonin released into the synaptic cleft activates multiple serotonin receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7), and subpopulations (most notably, 5-HT1B, 5-HT2A and 5-HT2C). The hierarchy of their relative contributions to the subjective and behavioural effects of MDMA use may shift with increasing dosage and the course of the trip. Several of these serotonin receptor subtypes have functionally opposing roles, notably the effects of 5-HT1A and 5-HT2C receptor agonism on anxiety. As well as inducing a synaptic flood of serotonin, taking MDMA indirectly induces the release of extra dopamine in the mesolimbic reward centres. Activation of the serotonin 5-HT1B and 5-HT2A receptors leads to an increase in the vesicular release of dopamine, but dopamine levels are also increased by reuptake inhibition. In addition, dopamine synthesis is increased and turnover reduced. Increased synaptic availability of dopamine in turn inhibits glutamate-evoked firing in the nucleus accumbens. Dopamine released in the shell of the nucleus accumbens inhibits the firing of GABAergic medium spiny projection neurons. Inhibited excitability of the spiny projection neurons in the rostral shell of the nucleus accumbens - whether it's mediated by dopamine, glutamate antagonists or mu opioid agonists - is the neurological signature of euphoric bliss, whatever its guise.
On MDMA, there's much more going on as well. MDMA induces the release of noradrenaline, and inhibits its reuptake. It also triggers the release of acetylcholine. MDMA exerts (weak) binding to the alpha-2 adrenergic and histamine H1 receptors; this binding contributes in unknown degree to behavioural stimulation. Activation of the noradrenaline system causes an acute elevation of blood pressure. Additionally, taking MDMA increases plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA). To thicken the plot further, MDMA triggers the release of hypothalamic arginine-vasopressin and, to a lesser degree, oxytocin (the "cuddle hormone"). These hormonal changes may influence some of MDMA's psychological effects. But the current consensus is that enhanced serotonin and dopamine release are crucial to the magic, even though they don't explain it.
The serotonin system is uniquely complex. A whistlestop tour can't do it justice. The existence of the serotonin molecule in Nature long predates the brain; serotonin is found in both the plant and animal kingdoms. However, the effects exerted by a neurotransmitter on the post-synaptic membrane aren't determined by the chemical itself, but rather by the structure of the post-synaptic receptor subtypes to which it binds. Our serotonin-producing neurons belong to a phylogenetically ancient neurotransmitter system. In the vertebrate CNS, serotonin-producing neurons regulate aggression, impulse-control, mood, anxiety, cognition, temperature, appetite, circadian rhythms, sexual activity, sleep, sensorimotor integration, sensitivity to pain, emotional resilience and romantic love. Serotonin entering the axonal vesicles is released over time in response to action potentials by exocytosis into the synaptic cleft, the narrow gap 10-20 nm across between pre- and post-synaptic neurons. Seven distinct families of serotonin neuronal receptors have been isolated; 14 sub-populations of G-protein-coupled receptors and one family of ligand-gated ion channels (the 5-HT3 receptor) have been cloned. Distribution, density and regulation of the serotonin receptors vary in different areas of the brain. So does both the affinity of serotonin for its different receptor subtypes and the effects of serotonin agonists on second-messenger systems. Only a few hundred thousand of the 100 billion or so neurons in the brain manufacture serotonin. The serotonergic cell bodies are confined to the raphé area in the brainstem, but their projections extend to almost all areas of the brain and spinal cord. Most notably for E-users, serotonergic projections innervate the dopaminergic nigrostriatal and mesocorticolimbic circuits. The serotonin system has co-evolved with dopaminergic projections in the course of primate evolution. Amongst many other roles, the serotonin system helps to regulate a lifetime spent n complex social hierarchies where more ancient fight-or-flight reactions have been offset by the need for an increasingly complex cognitive, emotional and behavioural response. This unique signalling complexity of the serotonin pathways and their multiple receptors ensures we can now be (un)happy in more ways than ever before.
The serotonin/5-hydroxytryptamine molecule itself is an indole amine synthesized from the essential amino acid L-tryptophan through the intermediate 5-hydroxytryptophan. Although some serotonin is present in the cytoplasm of serotonergic cell bodies and nerve terminals, most serotonin in the axonal terminals is sequestered in small membrane-bound sacs, i.e. the synaptic vesicles. This prevents the neurotransmitter from being metabolised by the enzyme MAO. Serotonin is metabolised, mainly by MAO-type A, into the inactive metabolite 5-hydroxyindoleacetic acid (5-HIAA). Numerous studies have shown self-destructive violence, aggression, poor impulse-control, reduced social status, suicide, and some types of depression are associated with low concentrations of cerebrospinal fluid 5-HIAA. Consequently, these conditions are often conceived as disorders of "low serotonin function". Firing of the serotonin neurons causes exocytosis, a rapid calcium-dependent process of neurotransmitter release. Depolarisation of the axon induces opening of voltage-sensitive calcium channels; the resultant calcium influx causes synaptic vesicles to fuse with the plasma membrane, where they empty their load of serotonin into the synaptic cleft. In the synapse, serotonin exerts an action on both pre- and post-synaptic receptor sites. Extracellular serotonin is then normally taken back up into the serotonergic neuron via the highly efficient presynaptic transport pump. The structure of the transporter protein determines how it couples ion gradients to substrate transport in ways that still need to be clarified.
Whatever the precise details, taking MDMA causes a remarkable role-reversal of normal transporter function. The MDMA molecule binds with high affinity to the serotonin transporter and enters the presynaptic axon terminal. Current theory suggests that MDMA causes serotonin release via a diffusion exchange mechanism involving the serotonin transporter, not by calcium-dependent exocytosis of the serotonin-containing secretory vesicles. MDMA taken up into the presynaptic terminal unbinds from the uptake transporter, triggering a reconfiguration of the transporter so it binds to serotonin inside the cytoplasm of the nerve terminal. The reconfigured transporter then reverse-pumps the newly-bound intracellular serotonin out of the cell, changes configuration again, dumps the serotonin into the extracellular space, and then takes up MDMA once more, repeating the process of depletion rather than recycling the neurotransmitter.
The ensuing flood of serotonin in the user's synapses sets the MDMA magic rolling. The neurotransmitter binds to multiple serotonin receptor subtypes. The subtypes play different excitatory and inhibitory roles. So which receptor subtypes are of most long-term therapeutic and social-recreational interest to the paradise-engineer? Like the proverbial drunkard who searches for his lost keys only under a lamp-post "because that's where the light is", investigators focus first on wherever they can probe most easily. The receptor-based account below will soon be superseded by something deeper. But it probably at least offers clues to the full story.
Serotonin 5-HT1 agonists, sometimes termed serenics, show pronounced anti-aggressive properties. Aggressive behaviour is modulated in by the 5-HT1B receptors in particular. The presynaptic 5-HT1B terminal autoreceptors form a vital part of a feedback mechanism regulating serotonin synthesis and release. Receptor knock-out mice lacking the 5-HT1B receptor are superficially normal in appearance, feeding patterns and breeding behaviour; but they are ferocious, and highly reactive. Such knockout mice are also unusually partial to alcohol and supersensitive to the effects of cocaine, though these traits may reflect a compensatory enhancement of the dopamine system rather than offer a direct pharmacological model of 5-HT1B receptor function. By contrast, 5-HT1B receptor agonists such as the drug anpirtoline exert "serenic" effects. In "animal models", 5-HT1B receptor agonists diminish alcohol-heightened aggression. Surprisingly, perhaps, there is substantial evidence to suggest that some endogenous serotonergic pathways normally activate rather than suppress motor output. Acute activation of 5-HT1B receptors is known to play a role in MDMA-induced locomotor activity: 5-HT1B agonists and MDMA show cross-tolerance, suggestive of a common mechanism of action. 5-HT1B antagonists restrain the hyperlocomotion that rodents and clubbers typically undergo on serotonin-releasers like MDMA. Perhaps with this crude behavioural measure in mind, some "unlicensed" psychonauts try combining a supposedly 5-HT1B-selective agonist such as the piperazine derivative TFMPP [1(3-trifluoromethylphenyl)piperazine monohydrochloride] with dopaminergic psychostimulants to try and replicate the acute effects of MDMA. The results are mixed. It is now known that TFMPP binds at multiple serotonin receptors with only limited selectivity. Taken on its own in the absence of a dopaminergic psychostimulant, TFMPP does not feel MDMA-like. Even combined with a dopaminergic, TFMPP's activation of the 5-HT2C receptors makes some users feel anxious. The MDMA effect is hard to emulate: MDMA is "a multifaceted jewel", not a cheap-and-cheerful euphoriant.
There are further subtleties in the way of replicating MDMA's acute effects, and even more obstacles to sustaining the magic indefinitely. The serotonergic system has both 5-HT1B autoreceptors and post-synaptic 5-HT1B heteroreceptors; they play different functional roles. 5-HT1B receptors acting as autoreceptors regulate serotonin release via inhibitory feedback at the presynaptic terminals of serotonergic neurons; turnover and release of serotonin are typically increased under conditions of acute stress. 5-HT1B heteroreceptors are located on the terminals of nonserotonergic neurons. Thus 5-HT1B heteroreceptors regulate the release of other neurotransmitters. A single serotonin neuron can modulate different brain functions and multiple cellular targets in virtue of the thousands of non-synaptic varicosities on its axonal branches that project to multiple areas and neurotransmitter systems. 5-HT1B receptors within the ventral tegmental areas (VTA), for instance, function as heteroreceptors to inhibit GABA release. Since the GABA terminals in the VTA and substantia nigra exert a tonic inhibitory influence on dopamine function, inhibition of GABA by inhibitory 5-HT1B heteroreceptors leads to the disinhibition of dopamine activity. Thus agents acting directly or indirectly as 5-HT1B agonists can cause the release of dopamine in the striatum and nucleus accumbens. Indirectly again, dopamine release is also regulated by 5-HT1B heteroreceptors within the glutamatergic hippocampo-accumbens pathways. Regulation of 5-HT1B receptor function itself is under the control of 5-HT-moduline, an endogenous tetrapeptide that controls 5-HT1B receptor efficacy. 5-HT-moduline is a so-called allosteric modulator. Allosteric modulators bind to a different binding site from the natural agonist and can, potentially, circumvent the development of tolerance. 5-HT-moduline is released from adrenal medulla in response to acute stress. 5-HT-moduline plays a pivotal role in synchronising the serotonergic signalling activity of the different terminals of individual neurons, coordinating their effects on a variety of different cerebral functions. Rationally designed synthetic drugs that recognize the 5-HT-moduline binding-site on the 5-HT1B receptors, and act on the 5-HT1B receptors as allosteric modulators themselves, may potentially exert long-term serenic, anxiolytic and mood-brightening effects by increasing serotonin release.
In general, however, care must be taken in describing serotonin 5-HT1 agonists as "serenics", even if such agents induce a syndrome outwardly suggestive of inner tranquillity. The demeanour that an animal exhibits after "serenic" administration may indeed be submissive, passive and timid - in contrast to the fierce, assertive and aggressive behaviour of 5-HT1B knockouts. Yet "serenity" tends to connote an inner E-like peace that may be lacking - and not just in the unfortunate laboratory rodent. In fact some so-called "serenics" may enhance fear/anxiety reactions: it's only their use in combination with dopamine-releasing euphoriants that makes such agents especially interesting to the psychonaut. Indeed supersensitive 5-HT1B autoreceptors are implicated in depression and obsessive compulsive disorder. By introducing extra copies of the gene for 5-HT1B receptors into serotonin neurons, researchers can breed passive and depressive rats that show signs of abject misery [i.e. "learned helplessness" and "behavioural despair"]. The syndrome of learned helplessness is associated with excess production of 5-HT1B receptors that are churned out in greater profusion by the depressive brain. This isn't to deny that 5-HT1B agonists may have therapeutic potential, whether in bipolar disorder, autism, alcoholism or disorders of impulse-control and aggression. Thus the triptans, serotonin 5-HT1B/1D receptor agonists, are clinically effective for treating migraines; they can also curb aggression. But 5-HT1B antagonists and inverse agonists such as SB-236057-A are under investigation for possible clinical use as long-term and relatively fast-acting antidepressants. Acute 5-HT1B autoreceptor blockade can increase serotonin release. Cognitive function is affected by their use too. Whereas 5-HT1B agonists may adversely affect memory via inhibition of acetylcholine release in the hippocampus, antagonists and inverse agonists of the 5-HT1B receptor can improve the consolidation of learning. This simplified outline of the neurobehavioural role of a single family of serotonin receptor subtype illustrates how inducing lifelong E-like states - as distinct from "mere" raw bliss - is going to be a formidable technical challenge. In this case, the possible existence of multiple subpopulations of 5-HT1B autoreceptors and heteroreceptors makes inadequate selectivity of ligands even more of a problem, especially for seekers of precision-tools rather than chemical coshes.Whereas serotonin 5-HT1B receptor knockout animals are aggressive by nature, 5-HT1A knockouts are timid, anxiety-ridden creatures. Whereas serotonin 5-HT1B receptors are found mainly on terminal processes, 5-HT1A receptors are located solely on serotonergic nerve cell bodies within the dorsal raphé nucleus. The role of the 5-HT1A receptors in MDMA's acute subjective effects still isn't clear. Taken over a prolonged period, selective 5-HT1A receptor agonists exert a delayed-onset anxiolytic as well as (sometimes) a mood-brightening activity. Their (modest) therapeutic efficacy relies on an adaptive neuronal response. Acute activation of the presynaptic 5-HT1A receptor on the raphé nuclei tends to reduce both the rate of firing of serotonin neurons and the corresponding release of serotonin from the nerve terminals; chronic activation causes the receptors to desensitise, leading serotonergic neuronal activity to rebound. Clinically, buspirone (Buspar), a 5-HT1A partial agonist, is licensed for generalised anxiety disorder. Similar agents like gepirone (Ariza), flesinoxan, tandospirone and ipsapirone are under investigation. Alas taking them doesn't remotely engender the extraordinary sense of inner peace induced by MDMA. In rats at least, 5-HT1A agonists facilitate male sexual behaviour, hypotension, increased food intake and produce hypothermia, none of which are prominent sequelae of MDMA use. In general, 5-HT1A agonists are well tolerated. But they may also on occasion induce dizziness, nausea, and headaches, probably linked to their postsynaptic receptor action rather than presynaptic anxiolytic effect. Buspirone itself is also a dopamine D2 antagonist, albeit a weak one. This may explain why it's never been wildly popular with patients. It's also very slow to work. Gepirone, on the other hand, allegedly lacks significant activity at the dopamine D2 receptors. Gepirone acts as an agonist at the presynaptic 5-HT1A receptors and a partial agonist at the post-synaptic 5-HT1A receptors. Hopefully, gepirone will prove a clinically useful anxiolytic and antidepressant. However, though 5-HT1A antagonists reduce discrimination of MDMA in animal models, the role of 5-HT1A receptor activation in MDMA's effects needs elucidation via more first-person experimental studies.
The MDMA molecule, especially the dextrorotatory "+" isomer, has only a low affinity for the 5-HT2 receptor. This is why taking the drug within the normal dose-range typically induces only minor perceptual changes. If prompted, many Ecstasy users report altered time perception, but any visual distortions are usually mild: the N-methyl group of the MDMA molecule prevents it from fitting as comfortably into the 5-HT2A receptor as does the trippier (-)-MDA enantiomer of its structural parent. Experiments with human as well as non-human animals show a correlation between a drug's psychedelic potency and 5-HT2A receptor binding affinity. Activation of the 5-HT2A receptors is a prerequisite of the "classic" hallucinogenic effects exerted by tryptamine psychedelics such as LSD and phenethylamine psychedelics like DOM. Conversely, 5-HT2A receptor inverse agonists act as antipsychotics.
None of this neurobabble should disguise the fact that psychedelia is still scientifically uncharted. It's often too weirdly exotic for words. Materialistic neuroscience has failed to close the ontological gulf between neural porridge and consciousness - whether "ordinary" or "altered" states. Some psychonauts, understandably enough, feel the neurobabblers have lost the plot. Most of today's storytelling about altered states and the chemistry of mind will doubtless seem no less archaic to our descendants than the Greek humoral psychology of classical antiquity strikes the contemporary molecular biologist. Yet fortunately for the engineering purposes of inducing sustainable E-like bliss, we need manufacture only the sufficient neural conditions for beautiful states of consciousness. We don't need a deep understanding of how and why consciousness is generated (or alternatively, some philosophers allege, its fundamental immanence in the world). We can guess even less about the possible altered states of consciousness of our redesigned successors. We don't know whether the "explanatory gap" between the physical facts and phenomenal mind can ever be closed. But either way, our emotionally invincible descendants should be able to explore entheogens, and map out even the most outlandish reaches of psychedelia, in safety. Unlike us, our genetically enriched descendants may revel in the assurance that bad trips are inconceivable, and psychological damage is impossible. This is because their obnoxious molecular substrates will have been edited out. .Alas our own less robust minds are psychologically vulnerable to even "physically" harmless psychedelics that aren't also euphoriants. Dual-action dopamine- and serotonin-releasers like MDMA are the latter, though they aren't always harmless. With MDMA, as with so many psychoactive drugs, very often "less is more". This piety is easy to intone but hard to practise, especially when taking fast-onset euphoriants. The lucidity of the entactogenic effect of MDMA may be especially pronounced at low-to-moderate dosages. "Optimal" dosage of psychotropic agents taken for "non-approved" purposes is most often empirically determined by the user investigating what level induces maximal enjoyment. Yet the effects of lower, "sub-optimal" dosages that more subtly modulate consciousness may be of greater value for facilitating personal growth. Low-to-moderate dosage E-experience may be easier to integrate into the rest of one's E-less life. Nonetheless at higher, quite possibly neurotoxic doses of 200mg or so, MDMA can itself sometimes deliver psychedelic euphoria, entheogenic rapture, and some very interesting exotica indeed. Alas the unique effects of such doses [and likewise higher doses of other stellar phenethylamines] cannot safely be investigated in depth until the neurotoxicity of MDMA's metabolites and/or toxic free radicals can be prevented.
In the meantime, if the user desires a completely clear sensorium, then perceptual alterations might seem eliminable altogether, in principle, by taking only the (+)-MDMA enantiomer rather than the standard racemate. Sadly, pure (+)-MDMA is scarce; it's also hard to prepare at home. Thus one unintended consequence of scheduling MDMA has been to widen youthful exposure to psychedelia, albeit psychedelia in its warmest and most gentle introductory guise. (-)-MDMA at normal doses is only minimally active at the "psychedelic" 5-HT2A receptor owing to its (comparatively) bulky methyl group. By contrast, MDA (which lacks it) is an all-in-one cocktail that can be hallucinogenic as well as empathetic and slightly speedy.
Alternatively, if uncomplicated perceptual clarity is sought then a 5-HT2 antagonist such as ketanserin or the 5-HT2A selective MDL-11939 might help preserve total lucidity. 5-HT2A antagonists have the additional advantage of preventing MDMA-induced hyperthermia that exacerbates toxicity. Neurotoxic hydroxyl radical formation is temperature-mediated; conversely, hypothermia-inducing agents enhance neuroprotection.
However, there are complications. Stimulation of the serotonin 5-HT2A receptors contributes to the rewarding effects of MDMA, or at least plays a permissive role in dopamine release. So trying to eliminate perceptual alterations completely while retaining the full-blooded E-magic may be difficult. MDMA is often reckoned a "serotonergic" drug. Compared to amphetamine this is true: MDMA's affinity for the serotonin transporter is greater, and its ratio of serotonin to dopamine release is higher, than amphetamine. Even MDMA's extra release of dopamine partly depends on its activation of the 5-HT2A receptors. But serotonin-releasing agents [e.g. the halogenated amphetamine appetite-suppressant fenfluramine (Pondimin)], taken on their own, aren't notably rewarding or entactogenic/empathetic, at least at ordinary dosages. The enhanced release and reuptake inhibition of dopamine is essential to MDMA's tendency to promote blissful well-being and to colour its entactogenic-empathetic effect.
Convergent strands of evidence indicate that dopamine release is critical to the MDMA magic. Dopaminergic activity in the brain and motor behaviour may be crudely interpreted as under the inhibitory control of the serotonin system. Yet the multiple serotonin pathways play functionally different roles. According to one hypothesis, the extra serotonin released by MDMA stimulates 5-HT2A receptors located on inhibitory gamma-aminobutyric acid (GABA) striatonigral neurons. VTA dopaminergic neurons in the brain's reward centres are under continuous inhibition by GABA. Stimulation of the 5-HT2A receptors inhibits these GABA neurons, thereby allowing the disinhibition of dopamine biosynthesis. Post-E levels of dopamine in the mesolimbic reward circuitry are far higher than would be explained by MDMA's relatively weak additional release of dopamine via the uptake carrier.
Animal drug discrimination studies, and the human behavioural evidence, tend to support this dopaminergic account. Although some MDMA users prefer reflective tranquillity and intimate group hug-ins, many loved-up clubbers opt to dance for hours at raves - a form of hyperlocomotion one would expect from Peruvian marching-powder rather than a serotonergic agent.
However, this account is still simplistic. The release of serotonin following an MDMA-induced reversal of the reuptake pump results in a stimulation of the 5-HT1B receptors and, at higher doses, increasingly of the 5-HT2A receptors as well. Such receptor stimulation can trigger marked hyperactivity, especially in young MDMA users who rave. At lower doses, MDMA-induced locomotor activity is caused mainly by the released serotonin's preferential activation of the 5-HT1B receptor. This is because serotonin has a somewhat higher affinity for the 5-HT1 receptors than the 5-HT2 receptors. The greater flood of serotonin in the synapses triggered by higher doses of MDMA promotes locomotor activity via 5-HT2A receptor-mediated dopamine stimulation as well. To complicate matters, MDMA may itself bind, albeit weakly, to the 5-HT2A receptor. A further complicating factor is that MDMA-induced release of serotonin stimulates the 5-HT2C receptors. Activation of the 5-HT2C receptors serves to mask expression of MDMA-induced hyperactivity, sometimes evidently more effectively than others. The various subpopulations of 5-HT2C receptor located on GABAergic neurons in the ventral tegmental area and the substantia nigra tend to exert a tonic inhibitory influence over the mesolimbic dopamine system. Thus 5-HT2C receptors tonically inhibit dopamine release in the nucleus accumbens, mostly it seems in virtue of their constitutive activity i.e. entering the activated receptor state in the absence of an agonist. Other things being equal, activation of 5-HT2C receptors is anxiogenic, demotivating and generally unpleasant. Certainly the stimulant effects of MDMA are greatly enhanced following treatment with a 5-HT2C antagonist. Sustained antagonism of the 5-HT2C receptors might well we harnessed to intensify the hedonic properties of long-lasting E-like consciousness. Less speculatively, 5-HT2C antagonists such as agomelatine are under investigation as potential clinical antidepressants.
As usual, there are complications: all 5-HT2C receptors are not the same. Numerous 5-HT2C receptor isoforms are produced as a result of RNA editing, and their individual roles in modulating the MDMA effect aren't properly understood. In general, the receptor story illustrates at the molecular level that being blissful isn't the same as being blissed out. To sustain empathetic love, simply banishing all capacity for social anxiety isn't going to work. Specific and selective 5-HT2C receptor antagonism may well prove a worthwhile goal; but it's too early to say what the MDMA experience may gain or lose in consequence, whether socially or subjectively. Empathy entails caring about others, not lacking a care in the world. Thus the MDMA-induced disinhibition from social anxiety, and the lowering of psychological defensive barriers, is radically distinct from the sort of anxiolysis induced by SSRIs or the benzodiazepines - or indeed by alcohol or opiates. With none of these drugs or drug categories is a reduction in the user's social anxiety matched by an E-like upwelling of empathy or sensitivity to the feelings of others - in fact quite the reverse. There are subtleties of the MDMA experience that haven't yet been explored.If acute serotonin-mediated enhanced dopamine-release is indeed essential to the magic of MDMA, then a wide range of safe long-acting dopaminergics are already on offer to augment any hypothetical subtype-selective "serotonergic" therapies. Compared to our descendants, we're probably all anhedonic. So some form of dopaminergic augmentation is a therapeutic step in the right direction. "Dual-deficit" models of everyday E-less malaise are plausible; and they naturally invite dual-action remedies. Clearly, inhibition of glutamate-evoked firing in the nucleus accumbens is an ingredient of the E-magic: it is known that firing-inhibition depends on both dopamine and serotonin release; and this process is mediated by both dopamine and serotonin receptors. But beyond these superficial generalities, working out how to replicate sustainably at the molecular level the precise neurochemical signature of peak experiences will be hard. Until the dawning of the era of wholesale genomic rewrites and true designer babies, using a cocktail of subtype selective serotonin agonists and gentle dopaminergic psychostimulants still looks like the easiest way to mimic and enhance the entactogenic-empathogenic effect induced by MDMA-like compounds. However, there are many pitfalls in choosing the right dopaminergic for the job.
In contrast with intracranial electrical stimulation, a direct chemical assault on the hedonic treadmill rarely works. This failure is witnessed by the unsatisfying and usually counterproductive effects of using catecholamine-depleting psychostimulants. Darwinian-era mood and motivation is regulated via a multitude of indirect mechanisms of feedback-inhibition. So it's worth reviewing how and why the substrates of human well-being are held in check; and what can be done about it. First, an unavoidably fast-and-furious tour of the dopamine system is in order. The CNS has three main dopaminergic pathways. They regulate movement, hormonal secretion, and emotion. Each projects from dopaminergic cell groups in the midbrain. 1) The nigrostriatal pathways extend from the substantia nigra pars compacta to the striatum. This pathway is critical to the control of involuntary motor movement; its dysfunction is implicated in the tremor, rigidity and akinesia of the "dopamine deficiency disorder" Parkinson's disease, and several other neuropsychiatric disorders such as Tourette's Syndrome. 2) The tuberoinfundibular system extends from the hypothalamus to the pituitary gland. It's involved in prolactin- and growth hormone-secretion, and the regulation of lactation and fertility. 3) The mesocorticolimbic pathway extends from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex. The mesocorticolimbic system is central to emotion, motivation, willed action and, more subtly, the modulation of thought-processes. In crude terms again, dopamine is critical to sensorimotor integration; appetitive behaviour of all kinds; the capacity to switch from one course of behaviour to another; and the orchestration and activation of the motor output system. Dopamine has also traditionally been described as the brain's "pleasure chemical", cueing potentially (Darwinian) fitness-enhancing stimuli so they can acquire control over an organism's behaviour. Certainly, consistent with the dopamine theory of reward, electrically or pharmacologically stimulating microcircuits in the rostral shell of the nucleus accumbens produces intense pleasure in the absence of any goal-seeking behaviour. But this formulation can be misleading. The mesolimbic dopamine system mediates "wanting" more than "liking"; and its drug-induced or electrical stimulation may increase incentive-salience rather than the raw intensity of pleasure itself. Dopaminergic neurotransmission is critical to incentive-motivation and all forms of purposeful behaviour. Dopamine levels tend to rise if one is anticipating a rewarding event; and levels then tend to fall if the anticipated reward fails to materialise. Couched in the language of psychology rather than neuroscience, enhanced dopamine release in the pleasure centres imparts a sense of urgency, significance and a feeling of things-to-be-done. The molecular substrates of pure pleasure are still elusive.
At the cellular level, the dopamine system doesn't quite rival the molecular, pharmacological and functional diversity of the serotonin system; but the two "classic" types of dopamine receptor (D1-like and D2-like receptors) have several subtypes and alternate splice-forms. Further, the number of different messenger RNA and dopamine binding sites substantially exceeds the five dopamine receptor genes of the human genome, a diversity that reflects the genetic polymorphism and alternative splicing events in normal dopamine gene-expression. However, each type of dopamine receptor belongs to the superfamily of G-protein-coupled receptors that activates or inhibits different forms of adenylyl cyclase inside the cell. Intriguingly, the presence or absence of variant alleles of dopamine receptor subtypes and their signal-transduction mechanisms is correlated with variants of human behaviour and personality. For example, individuals with genotypes containing the seven-repeat allele of the dopamine D4 16-amino acid repeat polymorphism tend to exhibit the personality trait of "novelty-seeking". This trait is characterised by a tendency to impulsiveness, risk-taking, exploration, excitability, and an optimistic mood, though alas not a loving, E-like temperament. For better or worse, within a few decades prospective parents will be able to select such alleles and their rationally redesigned enhancements when choosing the parameters of their future offspring. Such naturally loved-up kids may prove more easily adorable than today's Darwinian default-models.Like the other catecholamine neurotransmitters, dopamine itself is synthesised from the non-essential amino acid L-tyrosine. L-tyrosine is transported across the blood-brain barrier into the dopaminergic nerve cell. L-tyrosine is converted to L-dopa by the enzyme tyrosine hydroxylase. L-dopa is then rapidly converted to dopamine by L-amino acid decarboxylase. Next dopamine is sequestered in synaptic vesicles by a dopamine transporter. At the synapse, the dopamine nerve terminal displays high-affinity uptake sites. They rapidly terminate the action of the neurotransmitter on the receptors if it isn't metabolised by the MAO or COMT enzymes. Depending on concentration gradient, the dopamine carrier can transport dopamine back into the nerve cell, recycling it as normal, or alternatively, after a user has taken a classic amphetamine, the carrier can transport dopamine from the cell terminals into the synaptic cleft. In common with amphetamine, MDMA inhibits the neuronal reuptake of dopamine, albeit more weakly than MDA. Further, increased post-E administration activity of the serotonin 5-HT1B and 5-HT2A receptors causes the dopaminergic neurons themselves to fire more rapidly. This higher impulse-frequency causes increased dopamine-release via exocytosis of the dopamine-containing vesicles in the normal manner.
So what leaves so many "normal" Darwinian people - who are neither clinically depressed nor loved-up on MDMA - comparatively anhedonic and hypodopaminergic? The dopamine neurotransmitter is under powerful homeostatic control. So is the density and signal-transduction efficiency of the receptors to which it binds. Feedback-inhibition of dopamine synthesis, dopamine release and spontaneous action-potential generation in dopamine-producing cells is modulated by a variety of functionally distinct dopamine autoreceptors that regulate membrane excitability. The dopamine neurotransmitter itself functions as an end-product inhibitor of tyrosine hydroxylase, the rate-limiting step in dopamine production. Dopamine plays this role by competing with a tetrahydrobiopterin co-factor for a binding site on the enzyme. Dopamine synthesis is also modulated by the rate of impulse-flow from the nigrostriatal pathway. In addition, presynaptic dopamine receptors modulate the rate of tyrosine hydroxylation; and most mesolimbic dopamine neurons possess cholecystokinin-autoreceptors and neurotensin-autoreceptors that regulate dopamine function as well. Indeed activity of the mesocorticolimbic dopamine system is regulated by multiple neuronal pathways containing different neurotransmitters, notably serotonin, opioids, GABA and glutamate. Precisely what dopamine actually does in the all-important dopamine-sensitive shell of the nucleus accumbens is unclear. The main effect of its release seems to be the inhibition of the GABAergic medium spiny projection neurons (MSNs). These neurons come in two types. One subtype expresses dopamine D2 receptors and enkephalin. This sort of GABAergic medium spiny cell projects from the nucleus accumbens to the ventral pallidum. It is activated by "reward stimulation" of the ventral tegmental area. The other subtype of GABAergic medium spiny projection neuron co-expresses substance P, dynorphin and dopamine D1 receptors. This subtype projects directly back to the ventral tegmental area. It regulates motivation and pleasure, or our deficit thereof.
So how can this cruel and complex web of inhibitory feedback mechanisms best be modified? If our aim were pure-and-simple cloud nine euphoria, then better drugs to decrease glutamate and GABA currents in the critical medium spiny neurons of the nucleus accumbens might be adequate - at least until new genes and gene networks can be more readily inserted in the genome, and the regulation of old ones improved. But well-controlled, high-functioning euphoria is more elusive than mind-blowing rapture. Crude "natural" interventions to enrich dopamine function aren't effective. For instance, some psychonauts, clubbers and alternative therapists alike have explored taking free-form amino acid supplements of L-tyrosine and L-phenylalanine in a bid to boost native dopamine levels or reanimate a drug-frazzled brain. But tyrosine hydroxylase is normally saturated. So unlike tryptophan-loading and/or 5-HTP-loading to increase neural levels of serotonin production, this "dopaminergic" precursor strategy typically doesn't work. On the other hand, taking L-dopa does increase synaptic dopamine levels. This is especially so when L-dopa is combined (as in Sinemet for Parkinsonians) with a peripheral decarboxylase inhibitor such as carbidopa to prevent its metabolism outside the brain, At least for a minority of "normal" subjects, taking L-dopa can be an effective motivator, libido-enhancer and mood-brightener. In a more controlled setting, rodents engineered so they can't synthesize dopamine initially develop quite normally, only to die miserably a few weeks after birth following a failure to eat, drink or do very much in this world at all. Yet when such dopamine knock-out mice are abundantly maintained on L-dopa, they can flourish. Indeed L-dopa-maintained dopamine knock-out mice become hyperactive and sexually vigorous. This manipulation has not yet been attempted in dopamine knock-out humans. Augmentation should in any case be tried only cautiously and in controlled-release preparations (e.g. Sinemet SR) since high levels of L-dopa may increase oxidative stress. Whatever the mechanism, simply increasing raw dopamine levels per se is not enough. For instance, an agent such as alpha-methylparatyrosine that inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, might be expected to produce a state of melancholic depression; but in non-depressives it doesn't reliably do so. This complicates any simplistic catecholamine-depletion theory of retarded depression. Nevertheless, dopamine-releasing agents demonstrably tend to induce euphoria. By contrast, dopamine receptor antagonists like haloperidol are dulling and dysphoric. All the classical dopamine D2-blocking neuroleptics blunt will-power and flatten emotion. Administering dopamine D2-blockers tends to induce apathy and anhedonia, and ruins the MDMA magic. Nasty but instructive, such magic-prevention experiments are an important pointer to what's needed to sustain the MDMA spectrum of consciousness. It's known that stimulation of the dopamine D2-like receptor causes an increase in phosphatidylinositol hydrolysis by activating enzyme phospholipase C. Enhanced phosphatidylinositol hydrolysis is implicated in euphoric mania. Conversely, the lithium used to treat "uncontrolled" euphoria inhibits the phosphatidylinositol second messenger system and darkens mood in nondepressed "euthymic" people. Understanding the principles behind the pharmacological induction of controllable non-stop euphoria will be a first step on the route to designing lifelong variations of the subtler forms of magic.
In the meantime, dopamine antagonists like amisulpride (Solian) can be used at low doses preferentially to antagonise the synthesis-, release- and impulse-modulating presynaptic dopamine D2/D3 autoreceptors. Thus a regimen of low-dose amisulpride may potentially enhance dopamine release and boost mood and motivation, whereas many dopamine reuptake inhibitors [e.g. vanoxerine, bupropion, nomifensine] "adaptively" diminish the neuronal release of dopamine over time, even though their action on reuptake inhibition increases the neurotransmitter's synaptic availability. Unfortunately, pre-treatment with high doses of dopamine reuptake inhibitors blunts MDMA-induced release of dopamine, though not to the same degree as SSRIs blunt MDMA-induced release of serotonin. Other crude strategies to augment dopamine function involve taking dopaminergic agents such as the dopamine agonists pergolide (Permax) and bromocriptine (Parlodel); the potent, pro-sexual, long-acting D2 agonist cabergoline (Dostinex); selective D2/D3 agonists such as pramipexole (Mirapex) or ropinirole (Requip); catechol-o-methyltransferase (COMT) inhibitors such as tolcapone (Tasmar); selective MAO-B inhibitors such as selegiline (Eldepryl) or rasagiline; adenosine 2A receptor antagonists; and centrally active nicotinic receptor agonists. Oral, centrally-active dopaminergic "pro-drugs" with higher bioavailability and fewer adverse side-effects are also under investigation. But there are obvious problems. For instance, dopamine-release promoting agents, if fast-acting and taken in the absence of anything subtype selectively "serotonergic", may not induce serenely motivated well-being as distinct from compulsive pleasure-seeking, thought disturbances or manic excitement. Any tendency to cause uncontrolled dose-escalation is likely to cause toxicity, florid psychoses and abuse. Regrettably, these worries about the "abuse-potential" of psychostimulants frequently generalise in mainstream wisdom to an unwarranted fear of all "dopaminergic" antidepressants/mood-brighteners. ]
For more see the link...
Posted by stjames on April 24, 2003, at 18:49:44
In reply to further fodder for the serotonin/dopamine discuss., posted by jrbecker on April 24, 2003, at 17:43:59
Key to understanding some of this is knowing
our neurotransmitters are a few atoms off
of being psychedelics. 5HT and LSD (or any indole
psychedelics) are very close to being alike.
Go forward in thread:
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.