![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 25 to 49 of 84. Go back in thread:
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...
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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.
Posted by Larry Hoover on April 24, 2003, at 19:26:32
In reply to Re: What are the best Natural Serotonin enhancers?, posted by stjames on April 23, 2003, at 11:54:42
> 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.For an insightful (but lengthy) review of the effect of the "chemical imbalance" model on clinical practice, go to:
http://www.geocities.com/ss06470/index.htm
Lar
Posted by Dinah on April 24, 2003, at 20:58:29
In reply to Re: about the chemical imbalance concept » stjames, posted by Larry Hoover on April 24, 2003, at 19:26:32
I've printed out that article. Thanks so much! It really describes how I had actually experienced SSRI's. I think I'll sit down and try to figure out what psychological states my various meds might have induced.
Posted by McPac on April 25, 2003, at 0:57:58
In reply to Re: What are the best Natural Serotonin enhancers? » McPac, posted by Ron Hill on April 23, 2003, at 2:41:41
"Hi McPac,
>>>>>>>>>>>>Hi Ron. Sometimes I'll post and then not even be around here for days/weeks at a time. Sometimes I'm gone for months so don't feel bad if you don't see a response.
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?
>>>>>>>>>>>bipolar (mostly terrible depression) AND OCD (plus the usual anxiety that tags along as well)
What meds (and at what dosages) are you currently taking?
Zoloft (100 mg/day is my "best" dose but I'm trying to see if 50 will do) AND lithium (just 1 a day, very low dose) AND 7.5 mg Remeron (very low dose for insomnia)
What meds have you tried in the past and what were the primary effects each of the medications had on you?
Wow, let me think....I've been on Zoloft for 10+ years..it works for my dep/ocd but lots of side effects...the side effect I detest is it makes me VERY angry/irritable...Prozac was a NIGHTMARE for me!...same thing only WORSE (RAGE!ANGER!IRRITABILITY!)....I really believe that one reason, the MAIN reason, that I have to take the lithium is BECAUSE OF the Zoloft!!! Without the lithium I don't think I could ever manage on Zoloft...the lithium balances the rage...and I am NOT an angry/rageful/high-tempered person WITHOUT the Zoloft...YET I'm on it because 1) It works for my ocd 2) It works for my depression 3) It's HELL to get off!......I'm in a bind because I can't just choose ANY anti-dep---I HAVE to have one that will work for OCD as well and the ssri's dominate the choices for ocd...Anafranil for ocd worked but terrible side effects (terrible sedation (felt comatose), terrible sweating (you wouldn't believe how bad), totally ended all thoughts of sex (my "member" was a member of the D.O.A.C.---Dead On Arrival Club....Here is a question Ron: Remeron has been used by some to work for ocd...I tried to switch the Zoloft w/Remeron except my GP increased my Remeron from a tiny 7.5 mg to a MUCH higher 45 mg IN ONE JUMP...made my heart pound out of my chest/terrible adrenaline effect, very nervous/jumpy (but see, I was NOT angry though!) I really think the SSRI's cause this anger/rage/irrit. in me and I'm forced to counter that w/ lithium.......NOT a lot of choices (that I'm aware of due to my ocd..most AD's won't help that)...so it's a very, very frustrating dilemma!....have you heard of many folks that the SSRI's cause to have a terrible temper/anger? Is this even a little common?
About 15-20 years ago I took meds like Nardil (worked great but the diet thing scared me, I was always fearful of eating something wrong)...took imipramine way back when (can't remember if it was powerful enough for me; not sure if it worked well enough...Desyrl (years ago) was too weak and inneffective...BUT, the one thing I always say is that THOSE meds caused little, minor side effects---dry mouth, slight dizziness when standing up..minor stuff compared to the God-Awful major side effects of the SSRI's!!! Folks have been brainwashed by the MASS Marketing that tells them that the reverse is true! The 'old' AD's had trivial, minor, few s/e's....Ron, I'm thinking of possibly trying this: 1) perhaps SLOWLY increase my Remeron (could that make a difference if I increase it SLOWLY, as opposed to the BIG jump my GP did last time? I think so....AND, IMPORTANTLY, I may not even need the full 45 mg (Remeron IS very activating for most at that dose; I may try to see if perhaps 30 mg could be enough to do the job and it may not be too activating for me...that's what I've been seriously considering just recently...it would be AWESOME to get rid of the Zoloft!...so you see, I could handle the older AD's MUCH better...NO RAGE/TEMPER prob's!...(but the older ones weren't nearly as good for my ocd...though, IF I recall correctly I believe the Nardil did a pretty decent job for my ocd).How much do you exercise and at what intensity level?
Ron, Worked out at the gym tonight...I always played sports in my younger days...have weightlifted for years...lift weights very hard (my heart is PUMPING when I work out)...bench-pressed almost 400 lbs a few years back...run somewhat but not often (occassionally I'll go on a LONG run)...so mostly vigorously lift weights now (but when I'm feeling depressed/anxious I often don't work out simply because I feel too shitty).
I REALLY appreciate ANY/all thoughts that you and anybody else here can give me. I've never been too proud to take good advice from other people. I appreciate anybody's responses here. Just don't feel bad if I "disappear" a lot from this board (I'll definitely read all replies to this post though, for sure)....there are times when I've disappeared for many weeks, even many months when my schedule gets crazy....best of health to you and everyone else here Ron! I'll be looking for your reply!!!! McPac
Posted by McPac on April 25, 2003, at 1:14:02
In reply to Re: about the chemical imbalance concept » stjames, posted by Larry Hoover on April 24, 2003, at 19:26:32
Larry, first off, THANK YOU for ALL of your previous replies to me over the past week or so! I appreciate IMMENSELY every reply of yours (most have been saved on my computer for future reference).
From the article that you just posted here,.........."Thirty mg. of dextroamphetamine was found to ameliorate OCD symptoms (Joffe 1991)".
What is dextroamphetamine? (Is this a legal or illegal drug?) THANKS!
Posted by Caleb462 on April 25, 2003, at 2:28:55
In reply to Larry, Re: about the chemical imbalance concept, posted by McPac on April 25, 2003, at 1:14:02
> Larry, first off, THANK YOU for ALL of your previous replies to me over the past week or so! I appreciate IMMENSELY every reply of yours (most have been saved on my computer for future reference).
>
> From the article that you just posted here,.........."Thirty mg. of dextroamphetamine was found to ameliorate OCD symptoms (Joffe 1991)".
>
> What is dextroamphetamine? (Is this a legal or illegal drug?) THANKS!
Dextroamphetamine is a so-called psychostimulant. Amphetamines are probably the most well-known and most used and abused psychostimulants around. There's dextroamphetamine, levoamphetamine, methamphetamine, methylenedioxy-methamphetamine (ecstasy), and so on.The basic action of dextroamphetamine is to cause the release of the neurotransmitters dopamine and noradreaniline. This "speeds up" the mind and body. Increases energy, increases stamina, helps with concentration and cognition, decreases hunger and fatigue, brightens mood and induces euphoria (at higher doses), etc.
Dextroamphetamine is a Schedule 2 drug, meaning it's legal if prescribed to you by an MD. Without a prescription or liscence, it is illegal.
I've never heard of amphetamines helping OCD until I read that, so I wanna check out that study. Large doses of amphetamines can CAUSE obsessive-compulsive behavior, so it is somewhat suprising.
Posted by Ron Hill on April 25, 2003, at 9:42:20
In reply to Ron Hill, Natural Serotonin enhancers?, posted by McPac on April 25, 2003, at 0:57:58
Hi McPac,
Wow, thanks for the detailed response. You have a rather complicated case, huh? The topic at the top of this thread is "natural serotonin enhancers" and after reading your Rx history, my gut reaction is that the natural supplements might not have enough power to keep your OCD under control (just a guess). Have you ever tried 5-HTP? What about SAM-e? St. John’s Wort?
I find it very interesting and unusual that SSRI's induce irritability for you. The SSRI's do just the opposite for me. Initially, they make me happy-go-lucky, content, laid-back, and they take away my somewhat “anal” personality trait. However, over time they adversely affect my dopaminergic pathways and cause apathy, low motivation, and emotional blunting.
McPac, hypothetically speaking, if you were not taking any ADs, what symptoms would best characterize your depression? For example, the depressive phase of my bipolar disorder is best characterized as atypical depression since my symptoms include anergy, anhedonia, hypersomnia, and etc. What about you; how would you characterize your depressive symptoms?
I’m glad to see that you workout as hard as you do. That’s got to help manage your depression and OCD, right?
Other than the basics, I don’t know much about Remeron. Just a thought, but have you ever considered Serzone? I don’t know how good it is for OCD. Maybe you could talk to Ace about medications for your OCD. He has been trying several things lately and he might have some insight for you.
-- Ron
Posted by Larry Hoover on April 25, 2003, at 9:56:30
In reply to Larry, Re: about the chemical imbalance concept, posted by McPac on April 25, 2003, at 1:14:02
> Larry, first off, THANK YOU for ALL of your previous replies to me over the past week or so! I appreciate IMMENSELY every reply of yours (most have been saved on my computer for future reference).
Does that mean I don't get to change my mind? <sarcasm>
Since I've got your attention here, I'd just like to emphasize (as was presented so well in this article) that nutritional treatment for depression depends on there having been a nutritional component in the etiology of the disorder itself. I could probably give you 100's of different biochemical disruptions that might lead to depression, many of which have nothing whatsoever to do with diet. You just have to figure out whether diet is a factor in your mood disorder, and learn what you can do about it. The bonus is that many of the suggested dietary interventions are also good for you in other ways. For example, omega-3 fatty acids cut the risk of coronary artery disease, and reduce the likelihood of senility. If your mood is more stable too, bonus.
> From the article that you just posted here,.........."Thirty mg. of dextroamphetamine was found to ameliorate OCD symptoms (Joffe 1991)".
>
> What is dextroamphetamine? (Is this a legal or illegal drug?) THANKS!Dextroamphetamine is one enantiomer, or one of the mirror-image pair of molecules, in racemic amphetamine. The dextro-/levo- and +/- designations are old nomenclature, having been replaced by R-/S- (e.g. escitalopram (Lexapro) for the S-enantiomer of citalopram).
It is a street drug, but it also a prescribed medication, often used for ADD/ADHD. One brand is Adderal.
The Joffe study was a preliminary study, with only 11 subjects. Dextroamphetamine was compared with methylphenidate (Ritalin). I'd say the results were interesting, but inconclusive. I see no evidence of any follow-up, by Joffe, or anybody else.
Lar
Posted by Larry Hoover on April 25, 2003, at 10:49:10
In reply to Re: Thank you! » Larry Hoover, posted by Dinah on April 24, 2003, at 20:58:29
> I've printed out that article. Thanks so much! It really describes how I had actually experienced SSRI's. I think I'll sit down and try to figure out what psychological states my various meds might have induced.
You're welcome, Diana.
What I found most powerful about this essay was how he brought out the effect of assumptions on treatment protocols. I think it's human nature to extrapolate from assumptions. Then, we use our observations to "prove" our assumptions. So, you end up with a theory chasing itself, a logical fallacy known as petitio principii, or begging the question.
The best example I have ever seen of this is the modelling of stomach ulcers. Back in the '70s, everybody knew that stress caused ulcers. They were associated with Type A personalities. Treatment involved acid reduction and the bland ulcer diet. The problem was, nobody ever got cured.
Then along came a courageous Australian doctor who proposed that ulcers were caused by a bacterial infection. Presenting his ideas at conferences, he was vocally ridiculed. Everybody knew that stomach acid would kill any bacteria! (Aside: food poisoning is proof of the contrary.) But now, we all know that Helicobacter pylori infection causes ulcers. And, the so-called genetic tendency to ulcers, once taken as proof of the Type A influence, can be better explained by transmission of infection between family members.
My own odyssey towards wellness has been motivated by the failure of standard antidepressant therapy. If they had worked, I doubt I'd be on this board right now. I was forced to think outside the standard assumptions. My success has led my care-givers to ask me what I'm doing (outside the box).
Lar
Posted by sapphiredragon on April 25, 2003, at 11:38:34
In reply to Re: Larry, Re: about the chemical imbalance concept » McPac, posted by Larry Hoover on April 25, 2003, at 9:56:30
Thanks to all who have posted on this thread. I would like to especially thank Larry for posting the link to Sobo's article.
There is multi-generational mental illness in my family: bipolar (with psychotic mania), suicidal depression and various forms of anxiety disorders.
Our 24 y.o. son has been seriously depressed since his late teens. He has passionately researched many possibilities for his physical and mental symptoms, and tried out a number of nutritional supplements (including the Pffeifer Center). Some of these were modestly helpful, but none were, in and of themselves, the "magic bullet" he was seeking.
Recently, his depression deepened and my husband and I had to call the police to intercept our son's suicide attempt. We got to him in time and he agreed to hospitalization. For the first time, he was willing to try antidepressant drugs, and within 2 weeks we saw a remarkable improvement. (For the record, he is on 20 mg Lexapro and 10 mg Adderall & uses Ambien as needed for sleep).
It has been almost two months since his hospitalization now, and he said that he feels like the meds give him "space" so that he feels less constricted by the kind of compulsive negative thinking that predominated in his depression. He has begun to venture out socially again, and also has begun an unpaid job internship.
But he's has been continuing to "tweak" his nutritional supplements, and interestingly, like Larry, has found fish oil, vitamin B6 and digestive enzymes to be particularly helpful.
We are fortunate to be working with a psychiatrist who is knowledgeable about the nutritional factors contributing to mental illness. He has been very supportive to our son and respectful of his independent thinking.
I have also really appreciated the PB posters who are exploring multi-faceted approaches to living with mental illness.
Please keep sharing!
Posted by Ron Hill on April 25, 2003, at 11:55:59
In reply to Re: Larry, Re: about the chemical imbalance concept, posted by Caleb462 on April 25, 2003, at 2:28:55
> I've never heard of amphetamines helping OCD until I read that, so I wanna check out that study. Large doses of amphetamines can CAUSE obsessive-compulsive behavior, so it is somewhat suprising.
Caleb and McPac,
Yeah, that's the same reaction I had when I read it. However, if the study is correct and pstims do in fact help OCD, and if one wants to use a natural supplement treatment approach (as previously indicated by McPac), then Enada NADH might be worth a trial. As I understand it, the primary neurochemical action of both Enada NADH and the pstims is along dopaminergic pathways.
I take several supplements, but (as it stands right now) Enada NADH is at the core of my "natural-Rx" for the treatment of the atypical depressive side of my bipolar II disorder.
-- Ron
Posted by Larry Hoover on April 25, 2003, at 12:12:38
In reply to Re: Pstims for OCD?? Really? McPac and » Caleb462, posted by Ron Hill on April 25, 2003, at 11:55:59
> > I've never heard of amphetamines helping OCD until I read that, so I wanna check out that study. Large doses of amphetamines can CAUSE obsessive-compulsive behavior, so it is somewhat suprising.
>
> Caleb and McPac,
>
> Yeah, that's the same reaction I had when I read it. However, if the study is correct and pstims do in fact help OCD, and if one wants to use a natural supplement treatment approach (as previously indicated by McPac), then Enada NADH might be worth a trial. As I understand it, the primary neurochemical action of both Enada NADH and the pstims is along dopaminergic pathways.Lots of if's there, Ron. Here's the study abstract:
J Clin Psychopharmacol 1991 Aug;11(4):237-41
Acute psychostimulant challenge in primary obsessive-compulsive disorder.
Joffe RT, Swinson RP, Levitt AJ.
Department of Psychiatry, Toronto General Hospital, Ontario, Canada.
The effects of acute oral administration of methylphenidate 40 mg versus dextroamphetamine 30 mg versus matched placebo were compared in 11 patients with primary obsessive-compulsive disorder. Dextroamphetamine but not methylphenidate had a significantly greater antiobsessive-compulsive effect as measured by the Comprehensive Psychiatric Rating Scale--Obsessive-Compulsive Subscale, as compared with placebo. This effect appeared unrelated to their effect on depression although a differential effect of the two psychostimulants on anxiety was observed. Although both these stimulants affect serotonin, the differences noted between dextroamphetamine and methylphenidate suggest that catecholamines may be implicated in the pathophysiology of obsessive-compulsive disorder.
The following abstract shows dopamine agonism is indeed a potential *cause* of OCD-like behaviour in laboratory animals.
Pol J Pharmacol 1999 Jan-Feb;51(1):55-61
Role of dopamine systems in obsessive-compulsive disorder (OCD): implications from a novel psychostimulant-induced animal model.
Szechtman H, Culver K, Eilam D.
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Ontario, Canada.
OCD was once considered a rare psychiatric disorder, but recent studies estimate that, in the general population, the lifetime prevalence of OCD is 1 to 2%, twice that of schizophrenia or panic disorder. The most common form of OCD is compulsive checking. Our studies show that the behavior of rats treated chronically with the dopamine agonist, quinpirole, meets the ethological criteria of compulsive checking in OCD; may have a similar motivational basis as compulsive checking in the human; and is partially attenuated by the anti-OCD drug, clomipramine. Thus, the behavioral changes induced by chronic treatment with quinpirole may constitute an animal model of OCD checking. Since behavioral sensitization is an associated effect of quinpirole treatment, the induction of compulsive checking by quinpirole may involve the same mechanisms as the induction of drug-induced sensitization. In this respect, we demonstrated that the MAO inhibitor clorgyline, not only prevented the development of locomotor sensitization to quinpirole, but also reversed it in sensitized rats. To the extent that the quinpirole treatment is an animal model of OCD with strong face validity, it strengthens the hypothesis that dopamine systems play a role in OCD and raises the possibility that MAO inhibitors, which are used clinically for OCD, may exert their effects by acting at the MAO inhibitor displaceable quinpirole binding site.
> I take several supplements, but (as it stands right now) Enada NADH is at the core of my "natural-Rx" for the treatment of the atypical depressive side of my bipolar II disorder.
>
> -- RonSo, is your pattern still the same, with respect to the NADH?
My response has kind of settled into the following pattern. The day I take it, I feel somewhat unwell, though I'd have trouble defining that. I just don't feel motivated. After maybe 12 hours, that wears off, and I feel enhanced cognitive clarity and motivation.
By and large, and notwithstanding the serious illness I've recently endured, I would say that I did not have my fatigue/crash last month. That breaks a pattern that has existed for 18 months. I go back on the road next week, so it will be extremely interesting to me to see how I do in June. I *love* doing experiments, particularly when they seem to go well. <grinnage>
Lar
Posted by McPac on April 25, 2003, at 12:38:27
In reply to Re: Natural Serotonin enhancers? » McPac, posted by Ron Hill on April 25, 2003, at 9:42:20
You have a rather complicated case, huh?
>>>Sure seems that way at times.
....my gut reaction is that the natural supplements might not have enough power to keep your OCD under control (just a guess). Have you ever tried 5-HTP? What about SAM-e? St. John’s Wort?
>>>>>> While I haven't tried those particular supp's, I am being treated by a very highly regarded treatment center that specializes in natural treatments (so far though their plan has had little effect on me...we'll see in time how that all goes)
I find it very interesting and unusual that SSRI's induce irritability for you.
>>>>> Let's just say that after being put on Prozac especially (Zoloft too to a lesser degree), I COMPLETELY understand the cases from time to time in the past about Prozac causing a certain population of people to go ballistic...it definitely had that effect on me, without question.
McPac, hypothetically speaking, if you were not taking any ADs, what symptoms would best characterize your depression? For example, the depressive phase of my bipolar disorder is best characterized as atypical depression since my symptoms include anergy, anhedonia, hypersomnia, and etc. What about you; how would you characterize your depressive symptoms?
>>>>>>>>>My ocd would become unbearable, which would cause extreme agitation, panicky feelings....as for the depression, I wouldn't eat a thing, I wouldn't sleep, wouldn't feel like even moving at all (my ocd & depression---see how they cause 2 completely different types of feelings? ocd---NERVOUS, panicky...depression---lifeless
I’m glad to see that you workout as hard as you do. That’s got to help manage your depression and OCD, right?
>>>>>>It helps
Other than the basics, I don’t know much about Remeron. Just a thought, but have you ever considered Serzone?
>>>>I've heard of it...but don't know anything about it...is it an AD? (DON'T want ANY neuroleptics (AP's)
I don’t know how good it is for OCD.
>>>>Unfortunately, the SSRI's DOMINATE the meds that work for OCD, there isn't much else to choose from....I may try increasing the Remeron in an attempt to ditch the Zoloft...not many other things I could try....
Maybe you could talk to Ace about medications for your OCD.
>>>>>Ace is too cool! Yes, we've chatted. I really wish him well.
Posted by McPac on April 25, 2003, at 12:56:48
In reply to Re: Larry, Re: about the chemical imbalance concept » McPac, posted by Larry Hoover on April 25, 2003, at 9:56:30
Since I've got your attention here, I'd just like to emphasize (as was presented so well in this article) that nutritional treatment for depression depends on there having been a nutritional component in the etiology of the disorder itself.
>>>>>Exactly! That's been my feeling all along. I was HOPING that I WOULD have a simple nutritional deficiency (i.e. magnesium) that, upon taking the supplement, would be the "missing ingredient" that would solve my situation.....however, I NEVER thought I'd be so lucky!
I could probably give you 100's of different biochemical disruptions that might lead to depression, many of which have nothing whatsoever to do with diet. You just have to figure out whether diet is a factor in your mood disorder, and learn what you can do about it.>>>>>Yep...again, I wish it were a dietary problem because I'd have no problem avoiding the foods that were the culprit....in my case it's more likely that something in my brain is flipping when it should be flopping and zigging when it should be zagging, lol....how do you like that incredibly scientific explanation!
The bonus is that many of the suggested dietary interventions are also good for you in other ways. For example, omega-3 fatty acids cut the risk of coronary artery disease, and reduce the likelihood of senility. If your mood is more stable too, bonus.
>>>>Yep....the fish oil may well help me keep a much more even "keel"...hard to say due to many various factors...
Dextroamphetamine is one enantiomer, or one of the mirror-image pair of molecules, in racemic amphetamine. The dextro-/levo- and +/- designations are old nomenclature, having been replaced by R-/S- (e.g. escitalopram (Lexapro) for the S-enantiomer of citalopram).>>>>>>>Wow-----just off the top of my head that is EXACTLY what I thought it was!! <<<LOL!! joking! After reading that I STILL wonder what it is, lol!
Thanks Lar!
Posted by McPac on April 25, 2003, at 13:09:04
In reply to thinking outside the box, posted by sapphiredragon on April 25, 2003, at 11:38:34
Our 24 y.o. son has been seriously depressed since his late teens. He has passionately researched many possibilities for his physical and mental symptoms, and tried out a number of nutritional supplements (including the Pffeifer Center).
>>>>>>I am going to Pfeiffer myself. So they didn't help him too much, huh?
(For the record, he is on 20 mg Lexapro and 10 mg Adderall & uses Ambien as needed for sleep).>>>>>>Just for future reference, if the Ambien ever loses its ability as a sleep aid for him, he could try LOW-DOSE Remeron (7.5 mg). It works great for terrible insomnia.
But he's has been continuing to "tweak" his nutritional supplements, and interestingly, like Larry, has found fish oil, vitamin B6 and digestive enzymes to be particularly helpful.
>>>>>>Fish oil seems to help me too and I'm also taking vitamin B-6. What specific digestive enzymes does he take?
Thanks!
Posted by Larry Hoover on April 25, 2003, at 13:13:37
In reply to Ron, Re: Natural Serotonin enhancers?, posted by McPac on April 25, 2003, at 12:38:27
I'm going to hijack this thread a bit, if you don't mind.
The question of the utility of 5-HTP and/or tryptophan as antidpressant therapies came up, and it would seem that poor quality research has been the norm. If you use the stringent criteria employed in the following meta-analyis, only 2 0f 108 relevant studies provide meaningful outcomes. Nonetheless, it would seem that serotonin precursors are effective, based on limited data.
Cochrane Database Syst Rev 2002;(1):CD003198
Update of:
Cochrane Database Syst Rev. 2001;(3):CD003198.Tryptophan and 5-hydroxytryptophan for depression.
Shaw K, Turner J, Del Mar C.
School of Population Health, University of Queensland, Public Health Building, Herston Rd, Herston, Queensland, Australia, 4006. k.shaw@sph.uq.edu.au
BACKGROUND: 5 Hydroxytryptophan (5-HTP) and tryptophan are so-called natural alternatives to traditional antidepressants, used to treat unipolar depression and dysthymia. OBJECTIVES: To determine whether 5-HTP and tryptophan are more effective than placebo, and whether they are safe to use to treat depressive disorders in adults. SEARCH STRATEGY: Trials were searched in computerized general (Medline, Psychlit, and Embase) and specialized databases (Cochrane Controlled Clinical Trials Register, Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trial Register); by checking reference lists of relevant articles; by handsearching relevant specialist journals; and by contacting relevant authors where appropriate. Publications in all languages were sought. SELECTION CRITERIA: Trials were included if they were randomized, included patients with unipolar depression or dysthymia, compared preparations of 5-HTP or tryptophan with placebo, and included clinical outcomes assessed by scales assessing depressive symptoms. DATA COLLECTION AND ANALYSIS: Data was extracted independently by the three reviewers, onto data collection forms. Inclusion criteria were applied to all potential studies independently and a coefficient of agreement (Kappa) was calculated for them. Disagreement was resolved by reaching consensus. Trial quality was scored according to risk of bias. Analysis for 5-HTP and tryptophan were combined due to the small number of included trials. MAIN RESULTS: 108 trials were located using the specified search strategy. Of these, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive. REVIEWER'S CONCLUSIONS: A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluate the efficacy and safety of 5-HTP and tryptophan before their widespread use can be recommended. The possible association between these substances and the potentially fatal Eosinophilia-Myalgia Syndrome has not been elucidated. Because alternative antidepressants exist which have been proven to be effective and safe the clinical usefulness of 5-HTP and tryptophan is limited at present.
Posted by McPac on April 25, 2003, at 13:35:35
In reply to Re: Ron, Re: Natural Serotonin enhancers? » McPac, posted by Larry Hoover on April 25, 2003, at 13:13:37
"I'm going to hijack this thread a bit, if you don't mind".
>>>PLEASE respond whenever you can/wish to---your responses are always appreciated by me!
I thought that Pfeiffer might try trytophan with me (I read about a safety issue w/ regards to 5HTP).....I've got a lot of questions to ask Pfeiffer when I go back to them....Take care!
Posted by Ron Hill on April 25, 2003, at 15:09:40
In reply to Re: Pstims for OCD?? Really? Not!, posted by Larry Hoover on April 25, 2003, at 12:12:38
> So, is your pattern still the same, with respect to the NADH?
Larry,
I've wanted to find time to post to you and give you an update. Some of your writings prompted me to do some reading on TMG (betaine) and several days ago I started taking about 250 mg/day of it. I'll write more at a later date, but the short version is that TMG seems to work in a favorable synergistic way with the Enada NADH. As a result, I am now taking 2.5 mg of Enada NADH only once per week. It’s too early to know how this will all shake out, but so far so (very) good.
As you know, Enada NADH has been very beneficial in the treatment of the atypical depressive side of my BP II. But when I was taking 2.5 mg every four days without the TMG I would get irritable on the day I took it and begin to lose my motivation and become depressed on day four of the dosing schedule. Further, it seemed that as time passed the irritability on the front-end and the depression on the tail-end both were getting worse. The recent addition of the TMG has solved this problem (at least for now).
I also have added a few milligrams of 5-HTP administered sublingually on a PRN basis for treatment of any breakthrough irritability. I don't seem to need the 5-HTP very often, and certainly not every day, but when I do need it, it seems to take the edge off nicely. I have adopted the position that one of the keys to using supplements successfully is to minimize the dose and to take periodic "supplement holidays".
By the way, when I was at the nutritional store purchasing the TMG, I bought a bag full of other supplements that you and others refer to regularly (e.g., Borage oil, R(+)-lipoic acid (kinda spendee stuff), pregnenolone, DMAE, choline, etc). My plan is to add-on one at a time very slowly so that I can determine which one does what to my mood disorder and my general wellbeing.
Thanks for your willingness to share your expertise with so many of us here in pbabbleland. I'm glad to hear that your periodic crash has apparently taken a sabbatical as of late.
-- Ron
Posted by McPac on April 25, 2003, at 15:27:31
In reply to Re: Pstims for OCD?? Really? Not!, posted by Larry Hoover on April 25, 2003, at 12:12:38
"the differences noted between dextroamphetamine and methylphenidate suggest that catecholamines may be implicated in the pathophysiology of obsessive-compulsive disorder".
>>>>>>What kinds of natural treatments might affect these catecholamines in a way that would be good for someone w/ ocd?
Posted by McPac on April 25, 2003, at 15:38:00
In reply to Re: Serotonin:good for some depressions,bad for others, posted by linkadge on April 23, 2003, at 14:36:46
You mentioned that Remeron made you worse...how so?
thnx
Posted by sapphiredragon on April 25, 2003, at 16:13:42
In reply to sapphiredragon, Re: thinking outside the box, posted by McPac on April 25, 2003, at 13:09:04
The Pfeiffer Center's treatment didn't do much to alleviate my son's very deep depression. He went through a lot of preliminary testing, and they found a few nutritional deficiencies, but nothing dramatic. He tried out their supplements for a month or so, but after noting little effect, decided to stop buying their special vitamins.
As a previous poster said, if nutritional factors are not the primary cause(s) of mental disturbances, nutritional supplementation alone won't solve the problem.
My son was not able to overcome the suicidal thinking of his depressed state until he started on the SSRI and Adderal.
Re your question about digestive enzymes: For general digestion, my son takes betaine HCl and pancreatin. For helping with the assimilation of the fish oil, he has been using an ox bile supplement. Without the ox bile, the fish oil makes him nauseous, he says.
Posted by Larry Hoover on April 25, 2003, at 17:03:54
In reply to Lar, Re: Ron, Re: Natural Serotonin enhancers?, posted by McPac on April 25, 2003, at 13:35:35
> "I'm going to hijack this thread a bit, if you don't mind".
>
> >>>PLEASE respond whenever you can/wish to---your responses are always appreciated by me!
>
> I thought that Pfeiffer might try trytophan with me (I read about a safety issue w/ regards to 5HTP).....I've got a lot of questions to ask Pfeiffer when I go back to them....Take care!Well, if your mare is really skittish, and difficult to breed, you may want to try some supplemental tryptophan to calm her down. Go to:
http://www.buygpdirect.com/gpefeed.htmYou can get fish oil for about $14 a gallon, too.
Lar
>
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