# Pharmacotherapy:- Targets of possible interest



## Nathanael.A. (Apr 16, 2013)

*Pharmacotherapeutic Targets: A Hollistic Biochemical Strategy*

Hello Guys (and girls), after a long break from this site, I thought I'd return to attempt to re-address some new approaches to treating the condition of Depersonalization / Derealization, which in some cases tends to respond well to various pharmacological interventions, whilst in others these kind of treatments only serve as to relieve the sometimes co-occurent secondary ailments which accompany DP/DR and do not serve to ameliorate the primary condition, which in general tends to clear up over time.

The current effectiveness of medicines which are indicated for complex psychological diseases is questionable at the most, obviously depending on the condition and the individual, as well there being a significant overlap between many of these conditions as such. In addition to this, the widespread ignorance of DP/DR as a lone standing primary condition by the psychiatric and therefore the neuropharmacological arena's of R&D, drug design and development has unfortunately more or less entirely abstained from the development of even marginally effective viable medicinal treatments for the condition in question. Nevertheless, there exists a wide foray of possible biological targets for the treatment of the primary condition of DP/DR and the secondary co-morbid conditions which tend to accompany the primary ailment as such, some if not most of which remain on the very fringes of neuropharmacological research if not completely unexplored.

Basically, stress is a very complex thing, it has multiple downstream repercussions in the mind, the brain aswell as in the body. In addition to this, stress is known to play a extremely predominant role in the pathogenesis of these kind of conditions, and therefore treatments aimed at targeting dysfunctions which arise in these conditions should put a large emphasis on physiological mechanisms and biochemical targets, as well as those of a neurological origin.

The brain effects the body and the body effects the brain, therefore biochemical stress factors often extend from the realm of physiological processes, into the realm of neurological, and therefore psychological processes, and vice versa.

I will propose a selection of avenues aimed at ameliorating the negative dysfunctions which occur in the shape of stress reactions in the mind and body, these possible medicinal treatments are based upon a sound base of research I have fielded, and are aimed at treating all possible negative biological so called 'Knee-jerk' stress reactions from a bio-pharmacological holistic standpoint and are as follows:

Some of the major mediators which play roles in transmission of stress signalling:

The Kappa Opioid Receptor-

The Opioid neurotransmitter system is generally thought to be mediated by 3 main receptors. These are known are the Mu-Opioid receptor (The M receptor/ Morphine Receptor), The Delta Opioid receptor and lastly the Kappa opioid receptor (K receptor). Until recent times, the general presumption of function of these three receptors was presumed to be that The Mu receptor, as the name suggests was a binding target for the peptide family of neurotransmitters known as the Endorphins and the Enkenphalines. The neurostransmitters stated prior were and are presently thought are widely thought to mediate sensations of pleasure, relaxation and in extreme circumstances euphoria, coupled with analgesia and other physiological effects. One can infer that circumstantial of the psychological effects these transmitters produce, that compounds which emulated there neurochemical activity would be prime candidates for for drugs which could be developed into Anti-depressants, and it has be subsequently verified time and again that a vast majority of compound which activate this receptor in particular tend to result in an extreme anti-depressant effect in varying degrees. However, since the dawn of the age of pharmacology began, when chemists began extracting and purifying the active components of the flora which bore these psychoactive properties, it became widely accepted that due to the extreme capabilities of compounds of these sorts to induce euphoria and extreme pleasure with little un-wanted side effects, they were also inherently predisposed in a vast majority of peoples to produce the unwanted side-effect of drug addiction and habituation, which, in such individuals who succumbed to such addicitions, it rapidly became apparent that such cycles were extremely hard to break, had a multitude of detrimental effects on the persons life in the long run and in conclusion when attempts were made at stopping the usage of such drugs, due to homeostatic adaptive mechanisms, a horrendous, withdrawal syndrome would be the result.

Therefore, the propensity of these drugs to produce such self-reinforcing usage lead the legitimate pharmaceutical industry at large to avoid utilizing any of these compounds in the clinical treatment of depression, regardless of its severity.

In Descending order much less is known concerning the 2 other varieties of Opioid receptor, the Kappa receptor and the Delta receptor as such. It has increasingly become apparent in recent times that the Kappa opioid receptor plays a major role in nociception, and inducing states of anxiety and distress. Kappa mediated transmission often leads to avoident and depressive-like behavior in animal models, and addition to being a mediator of pain at the most basic level, also mediates sensations of distress at a much more abstract higher level such as psycho-social pain, distress, anxiety and depression. Therefore down to this the Kappa is basically thought to antagonize, and play an inverse role in the experience of subjective consciousness in contrast to the Mu-receptor. Endogenous ligands of the K-receptor are known as dynorphins and as previously noted mediate feelings of stress and anxiety, as well as having downstream effects on inflammatory factors and neuronal mechanisms which lead to the secretion of more physiologically-based stress. It is here where we start to encounter the extremely interconnected overlap of the processes which occur in the mind, the brain and the body.

The role which the Delta opioid receptor plays within the Central nervous system is even less well known than the prior stated receptor. It is currently thought that the Delta Opioid receptor plays some-kind of role as the 'middle-man' between the Mu and the K receptor, but the nature of this role is extremely obscure due to the current lack of Delta-specific agonists.

However in very recent studies it has been shown that selective stimulation of the Delta opioid receptor produces robust anti-depressant like effects in animal models of depression, and so this may be hopeful future target for the treatment of primary depression and conditions of the like. It is currently unknown as to whether the Delta-mediated transmission produces any characteristics which are reminiscent of the negative psychological effects of the Kappa receptor, although it has been found that unlike the Mu receptor, activation of the Delta receptor does not lead to severe respiratory depression, although in some but not all studies of the stimulation of this receptor, some exogenous ligand tended to elicit convulsions in the test subjects, but in addition to this, its robust antidepressant effects were correlated with large increases with brain neurophic factors such as BDNF which are known to play a large role in drugs which produce an anti-depressant effect.

In Summation, although there is a lack of Delta specific agents, many compounds which are known to activate the Mu-opioid receptor also activate the Delta opioid receptor, to varying degrees. Therefore, in an attempt to fine tune this individual neurochemical system, in an attempt to prune out its negative psychological-physiological effects, and to facilitate and potentiate its positive psychological-physiological effects, Pharmacological interventions with the following goals could be attempted:

- Induction of treatment with compounds which have a high binding affinity for the Delta/ Mu- opioid receptor subtypes, whilst having an exceedingly low, if not negligible affinity for the Kappa subtype.

-Attempts at treatment utilizing compounds with the prior stated neurochemical properties should be done utilizing a cost/ benefit/ risk based approach, baring in mind that compounds holding the most benefit with the least amount of drawbacks would be ones with preferentially a mid-low affinity for the Mu-opioid receptor complex when compared with its affinity for the Delta- opioid receptor complex, as well almost non-existant effects at the Kappa-receptor, mainly due to existing state of pharmacological advancement we are in at this time, it is hard to have activation of one receptor without the other, if not all three of them, within varying degrees and ratios concurrent Mu/Delta/Kappa activation.

- In Very recent times Selective antagonists at the Kappa-opioid receptor have been developed and have been shown to have robust-antidepressant effects, with a negligible side effect profile. Although the availability and federal approval of such agents at the governmental level is probably a while away, Antagonism of the Kappa-receptor may be of particular suitability as a theoretical target for the treatment of DP/DR due to psychoactive compounds which positively activivate this receptor being heavily implicated in inducing dissociative effects which are extremely similar to the effects seen in DP/DR disorder, if not sometimes identical. Such positive Kappa ligands exist in the Cannabis plant ( THC), as well as the little known Salvia divinorum herb (Salvinorin A). It also must be taken into account that while many opioid based analgesic mediactions which are presently indicated for the treatment of chronic pain, in addition to there potent activity at the Mu and delta receptor sites, many of them also possess potent activity at the Kappa receptor complex.

Agents with psychoactive properties which I have experience with who's effects have been proven to be due to activity within the aforementioned neurotransmitter system are as follows:

Codeine:

For myself, codeine possess's mild anti-depressant effects, which although when compared to the effects of the much more conventional SSRI's are much weaker, they are much more consistent. While this is taken into consideration, codeine also possess's a noticeable addictive quality within myself, and although tends to result in mild relief, concurrently it severely worsens my DP/DR both during and after the experience, and also I find it vastly decreases my level of functioning, which in my opinion is a significant drawback. Codeine and therefore morphine itself has significant activity at the Kappa-receptor aswell as the two other receptors, and afterwords leaves me feeling extremely spaced, therefore due to these side effects this agent inadequate for the amelioration of my symptoms, for me at least.

Dihydrocodeine:

For me, this agent possess's a ten-fold increase of potency of all the effects of the aforementioned opioid, as well as its side effects. The addictive, reinforcing qualities of this drug are significantly increased when compared to the original agent, aswell as the inherent dissociative qualities and its ability to induce massive deficits in my functional capacity, therefore this agent, is also useless, for me.

The Plant known as 'Kratom' :

Consumption of dosages which are anecdotally considered to be in the mid-large range of this plant, very infrequently, In my opinion, possess some short term beneficial qualities in the treatment of short-term stress and depressive-like symptoms. The main psychoactive constituents contained within the plant itself are known to have potent opioid activity, some more potent than morphine, although the subjective, appreciable effects that this plant produces in myself, I have found to be more significantly different and distinct to all other opioids I have consumed, which to varying minimal degress all felt more or less the same (Tramadol, Dihydrocodeine, Codeine). The psychoactive compounds present are of a distinct chemical class and are differ significantly in their chemical structure in comparison to tradition opioid compounds. In myself, his results in an appreciable but significant attenuation of stress, a mild increase in relaxation, while concurrently also not impairing my functioning, or making me feel over-sedated to any degree. In this regard, this compound which I am currently trialing myself, in my opinion possess's significantly greater potential in a strategy of stress reduction than the two aforementioned compounds, with much reduced side effects, including a significant reduction in addictive qualities in myself. In conjunction with an appreciable reduction of co-occurent secondary symptoms, consumption of the plant has, infrequently, led to a noticeable, significant reduction in my primary dissociative symptoms, which thus far seemed to be treatment-refractory.

Pharmacologically speaking, as far as the research says, it is not known to possess a significant degree of activity at the K- opioid receptor, while in conjunction to this, its main active constituents being known to be active at the Mu- receptor site, one or two of its metabolites have been found to be potent activators of

the Delta- opioid receptor.

In terms of the medical care which is currently available for treatment-resistant depression, only recently has scientific research delved into the usage of opioid-activating compounds, which have been found to be in the majority of the small number of studies conducted quite efficacious in its treatment.

Non-Peptide Stress Hormones- Glucocortoids

A Major player in the domain of biological responses to stress is known to be a chemical class of non-peptide hormones, known as the Glucocorticoids. These are steroidal compounds which are mainly secreted from the Adrenal glands, but also have a multitude of neurochemical effects inside the brain, who's activity, like other chemical compounds which fall under the endocrinal domain, is hinged upon the Hypothalamic-Pituitary-Adrenal axis (HPA Axis). This forms part of the endocrine system whereby neurochemical messengers can filter down and initiate signalling cascades which constitute endocrinal responses which occur in response to various situations. External stressor factors instigate one of the major biochemical components of the endocrine system, who's function goes on to serve a variety of hormonal and neurochemical functions. In ancient times, when in large part our stress-response systems, and neurological systems developed, and whose habits tend to persist into the present day, The primary function of endocrinal-stress system responses was to serve as short term measures to increase chances of survival. But in ancient times this was in serious do or die situations, for instance, you're taking a stroll in the forests with your spear, and you encounter a saber tooth tiger; Immediately your instinct is to flee as fast as you can from the present danger. So, in order to facilitate this, your body releases hormones which shut down all long term construction projects, such as cell division, neurogenesis and the sort, rapidly begins to break down body tissue to provide energy, and initiates adrenergic mechanisms which aid in the release of this energy from your muscles. In the short term this is a necessary measure to survive a possible life threatening situation. But when this occurs in the context of modern day, novel situations, such as stress over getting adequate GCSE or A-level exam grades, these stress responses can prove to be dysfunctional, if not all out detrimental to your outcome altogether. The Primary hormone implicated in the bodies reaction is Cortisol, otherwise known as 6-hydroxycortisone.

In conditions which result in severe levels of stress, chronic release of Cortisol can result. When this happens, over extended periods, this precluded severe negative physiological, neurological and therefore psychological outcomes. Persistent cortisol secretion post-pones, shuts down and eventually reverses any long term constructive and adaptive process's, and when speaking in regards of severe psychological disorders, We have to take into account the consistently proven implications and effects that cortisol has on the survival and differentiation of different brain-cell populations.

One particularly vulnerable region of the brain which we know plays a large role in memory consolidation, emotional memory and mood-states is the Hippocampus. The Hippcampus is the target of the majority of Anti-depressent drugs, due to studies which have shown a shrinkage in size of the Hippocampus in severely depressed patients, and people who suffer from chronic stress. One of the factors thought to be behind this is Cortisol's capability at inducing apoptosis (neuronal cell-death) in hippocampal cells, which tends to lead to a wide foray of neuro-cognitive deficits. One of the most basic principles which underlies cortisol induced cell death is energy availability and metabolism. Whilst cortisol is diverting all your bodies energy reserves away from everywhere else save your muscles, because its under the misconception that its about to be gored by an elephant, in-brain energy supplies also become subsequently depleted. The mechanism which predisposes hippocampal neurons to apoptosis under these circumstances is thought to be behind the fact that when intra and inter-neuronal energy supplies (therefore ATP and glucose availability) are deprived, normal ion carrier mediated transport into, and out of neurons is severely impaired. Therefore this leads to a major influx of calcium ions into neurons which, in conjunction with an Glutamergic NMDAR excitotoxic reaction which I won't go into here, inevitably leads to cell-death. So, while most of the current pharmaceutical drug-based therapies which are aimed at attentuating and reversing this dysfunctional process, are generally accepted to, by design target mainly the Serotonergic monoamine system, where the end-goal and general theorem behind their therapeutic effects which are seen in a significant number of depressive patients is that chronic upregulation of serotonin release theoretically 'somehow' leads to up-regulation of neurotophic agents and peptides which support the survival and proliferation of different neuronal cell populations via a multitude of mechanisms, one being the release of BDNF and its inherent ability to induce neurogenesis and potentiate neuroplasticity, There are other novel neurochemical targets at which we can intervene to prevent this process.

Rather than fighting a one front war,better more persistent and longer lasting clinical outcomes could be achieved by attacking these dysfunctional, negative, self-reinforcing cycles from multiple sides, thereby supporting the brains ability to adapt and survive while increasing the ability of it to break these cycles and perpetuate its own positive function. Of the little research that has been done on DP/DR, it has become widely accepted that one site of dyfunctional activitiy in the body is the HPA-axis, and one of the mechanisms of this dysfunction is thought to be an abnormal regulation of the release cortisol, and thereby the bodies physiological response to it. One recently proposed target, which has been found to provide significant therapeutic benefits when targeted with an agent which was deemed to have the most suitable pharmacological profile, is the Glucocorticoid receptor, or 'GCR'.

The GCR is present ubiquitously throughout the body and brain and has been heavily implicated in the regulation of normal, and abnormal, mood cycles in human beings. Until fairly recently agents specific enough to effectively antagonize the GCR itself, and therefore its inherent biological effects, have been over-looked, due to the fact that compounds that directly inversely agonize the receptor itself have a wildly unsafe side-effect profile, and other agents which are indirectly aimed at antagonizing the effects of the GCR via lowering levels of endogenous cortisol levels via interacting with, and down regulating secondarily acting excretatory hormonal factors, have as a paradoxical side-effect due to subsequent homeostatic mechanisms of the body, led to rapid increases in cortisol levels, and other stress-related hormones/ glucocorticoids.

Nevertheless, The issue at hand when probed and researched into seems to become ever more complex and inter-connected, unsuprisingly. But at this moment in time I believe that contrary to what most believe concerning the effectiveness of current treatment which are indicated for mental-health conditions, we beginning to make and shape out tools from the rocks and pebbles which we have attempted to, sometimes catastrophically, make use of in the distant past. These tools, hopefully, may lead to surprising innovations and rapid advancements in our understanding of the nature of these sorts of conditions, and therefore the means by which to treat them, in the near future.

The Primary therapeutic agent under investigation at this time:

Mifepristone:

Mifepristone is a synthetic steroid-like compound with primarily a progesterone antagonizing effect profile, and therefore, due to this, was brought to market mainly to serve as an Emergency contraceptive, usually in combination with another hormonal derivative, typically known as 'Medabon'. Aside from this, it also has prolific, potent effects as a direct Glucocorticoid receptor antagonist, and is also utilised in treatment-resistent cushing's syndrome ( a from of hyper-cortisolism). It therefore blocks most if not all of Cortisol's abberant effects in the brain, aswell as blocking the negative effects of all the other innumerable glucocorticoid compounds which the endogenous stress response. It has been studied and has been shown to be an effective adjuvant therapy in conjunction with more conventional AD's in treating highly treatment-refractory depression and other stress related disorders. One of its proposed secondary effects is a normalization of cortisol levels and a balancing of aberrant HPA axis dysfunction, and therefore this may also prove to be useful in DP/DR. Alongside this, it has also been shown to increase the capacity for spacial navigation in depressive-subjects, this is generally considered to be a hallmark of improves hippocampal function.

Hormone Therapy:- On a More Positive note..

Among the myriad of different types of hormones that all play a multitude of differing roles within the body, there are some which beg further investigation. Some of these hormones, also known as neurosteroids, are neuroactive and are synthesized within the CNS (One of the most typical neuroactive steroids is Pregnolone, and its metabolic derivatives), and play large roles as neuromodulators, being implicated in mediating neuroplasticity, axonal body myelination, the consolidation of short and longer term memory and as modulators of the stress response and mediators of endogenous responses to it. Indeed, it's becoming increasingly discovered that deficits in certain neurosteroidal systems exist in a wide variety of psychiatric disorders, some disorders certain neurosteroids being underactive, and other disorders certain neurosteroids being over-active. However, the due to the multiple roles that neurosteroids play in a wide variety of different neurochemical systems, attempting to base any theoretical concept of treatment by 'increasing the effects of one' or say for instance 'decreasing the effects of another' would be extremely naive, due to the widely known fact that the role that any one neurosteroid in the variety of systems it is likely to interactive is not exactly clear cut, as well as neurosteroids when trialled sparingly in the past have displayed wildly non-linear dosage curves in terms of their effects when attempts have been made in trialling these steroid compounds in the treatment of psychiatric conditions.

Nevertheless, we can look elsewhere within the body, for more sound hormonal targets which have been previously delved into scientifically out of curiosity as to whether they provide any benefit in conditions of this sort.

One of the most well-researched hormonal compounds which have been utilized in conjunction with conventional AD's as an adjunctive treatment is a thyroid hormone, commonly known as T3, or Triiodothyronine . This widely researched hormone has, in the context of the treatment of states of a depressive nature, been consistently shown that when utilized as an augmentation therapy alongside SSRI's, tends to provide extended and sustained improvement in symptoms and quality of life over an average timespan of Two- years in sufferers of treatment-refractory depression. This effectiveness of this therapeutic approach was further emphasized and proven in a retrospective analysis of 100 + patients who did not respond to a mean of 14 other conventional AD medications, which resulted in the findings that a large majority of study-participants, generally given to be 80%+ of the individuals who partook in the study experienced sustained improvement, whilst 33% of such patients experienced full- remission of their depressive symptoms.

Novel Drugs Currently Under Investigation: Neuropsychopharmacology at the Bow Shock;

Tianeptine:

Having experienced this drug-therapy first hand (fairly recently), I have only good things to say about it. It provides rapid relief from intense-stress and other depressive-like symptoms, in contrast to other conventional SSRI's where (for me anyway) I had to wait around for weeks at first, where I actually felt a thousand times worst, until finally the beneficial effects kicked in. But these for me at least, were extremely short lasting. Nevertheless I do consider SSRI's to be an effective therapy for alot of sub types of stress/ anxiety and deppressive like conditions, but in conjunction to this while undertaking longer term treatment there are reports of a wide-variety of unwanted side-effects. Tianeptine, in contrast, works straight from the get-go, has more or less an extremely low incidence of side-effects, and is still extremely effective in treating a large majority of stress-related conditions, ranging from generalised anxiety, atypical depression aswell as severe treatment resistant depression.

Its Primary mechanism of action is still a matter of debate, with the initial idea being that the benefits which it displayed in patients with conditions as such were down to some sort of increase of 5-HT receptor

sensitivity to the action of Serotonin, due to Tianeptines apparently ability to increase serotonin uptake and therefore decrease intrasynaptic 5-HT levels; This however has since been called into question, with more recent findings pointing towards a combination of differing neurochemical mechanisms being proposed, but none being elicited as the predominant cause of its subjective effects. Some which have more recently been put forward and are under-investigation are: Purported modulation and positive interactions at Glutamate AMPAR and NMDAR sites, leading to downstream neurotrophic effects, BDNF release and increased neuroplasticity, Tianeptine being an efficacious positive ligand for the Mu-Opioid receptor. There are reports of addiction, abuse, tolerance, and withdrawal syndromes to varying to degrees, but some of these properties can also be result of conventional Anti-depressant treatment.

For me tianeptine worked, it was somehow relaxing and yet stimulating at the same time, didnt impair by ability to do things, didn't feel like any opioid i'd ever taken, but It wouldn't suprise me if that was one of its positive contributing factors, It increases longer term potentiation (LTP) in the Hippocampus and memory consolidation, This is generally accepted to be a marker of broader neurophic activity in general.

NSI-189:

Under investigation for the treatment of Major Depressive Disorder, as well as PTSD. In animal studies it has been shown to have potent effects on stimulating neurogenesis in mouse hippocampus, rounding up to around increases of size of up to around 20%, which, when compared with the most effective of anti-depressant drugs available today which result in an increase of hippocampal volume of around up to 2%, this avenue of treatment beckons further investigation. I will be doing some myself, which I have been post-poning up until the present due to several factors, the main one being the arrival of several other possible purported adjuvant treatments; I will be testing this compound in some rodent behavior models and will report back accordingly.

7, 8-Dihydroxyflavone:

A purported ligand at the TrkB receptor, whose activation precipitates the expression and upregulation of mRNA which in turn leads to the upregulation of the production of neurotrophic factors, peptide transmitters which support and promote the survival and differentiation of select neuronal cell populations, aswell as stimulation neurogenesis and synaptic plasticity; This compound, being a direct ligand at the purported TrkB receptor, which has been heavily implicated in the antidepressant effects of drugs used to treat the condition, bypasses the rate-limiting step of BDNF release, which is the predominant endogenous ligand for this receptor, and instead directly positively activates it itself. As with the previously stated NSI-189 statement, I am also currently postponing rodent behaviour trials with this as well, due to the aforementioned reasons.

Putative, Psychopharmacological Targets of the Future..

Antagonists of the Kappa Opioid/ Nociceptin Receptor subtypes:

Seeing as Kappa activation induces anxiety and stress, and avoidant-like behaviour in animal models, it would make sense that the blockade of this receptor would reduce subjective sensations of the aforementioned mental-states, if not lead to and provide an anti-depressant, mood-lifting quality altogether. Until very recently,unfortunately there did not exist any such Kappa-selective antagonistic agents to explore such theoretical perspectives. At the present moment, however, Selective Kappa-Opioid Receptor antagonists are in the works, and preliminary results have shown K-receptor blockade to be a promising direction of future drug treatment, which may produce robust mood-lifting/ anxiolytic effects, in conjunction with a theorized benefit to those who suffer from the Primary disorder in question, DP/DR, due to other Mixed-Opioid receptor antagonists having been shown to be effective in providing some appreciable relief in a majority of participants in a small number of studies. This studies however utilised mixed-opioid antagonists which inversely agonized not only the Kappa, but also the Mu-opioid and probably the Delta- opioid receptor heterodimers in combination, henceforth it is therefore difficult to deduce whether the ameliorative effect the study-participants felt on their dissociative symptoms was down either a antagonistic action at a combination of these receptors, or one lone receptor, and/or if due to the beneficial effects being seen was down to the blockade at one of those particular receptors, which of those receptors when antagonized would provide the purported relief from the primary dissociative symptoms experienced by the subjects of any such study performed.

Nevertheless, recent scientific publications provide insight into the possible benefits of Kappa selective antagonists, the agents with the aforementioned specificity of action are along way away from widespread clinical usage and are only used in pre-clinical trials as of yet.

Other methodological approaches seek to circumvent this issue via the administration of a a mixed-opioid agonist/antagonist, usually Buprenorphine which is a potent antagonist at the Kappa-opioid receptor site, but also a a potent agonist at the Mu-opioid receptor site, in conjunction with selective antagonist of the Mu-opioid receptor, in an attempt to minimize or completely nullify the highly addictive qualities of the primary active agent (Buprenorphine), whilst preserving its activity as a potent antagonist of the K- Receptor. This approach serves to crudely emulate what a solely Kappa specific antagonist would do, via the administration of two counter-acting opioid-ergic agents in an attempt the fine tune the pharmacology of both to produce a more or less, purely kappa selective blockade.

Nevertheless results involving the conjunctive use of the aforementioned method in combination with conventional SSRI's proved to be extremely effective in reducing , and in some cases ameliorating altogether depressive symptoms in Treatment-resistant depressive patients, in comparison to conventional standalone treatment with either SSRI's or SNRI's.

Other anecdotal accounts report the usage of Buprepnorphine as a stand-alone drug-therapy in an attempt to treat DP/DR; However this approach is highly questionable due to Buprenorphine's primary, major active metabolite, Norbuprenorphine,being a high affinity Kappa-Opioid receptor positive agonist.

Other Ones to Watch...

In the treatment of DP/DR, generally a major component of treatment should be aimed at treating the co-existing anxiety and depressive disorders which accompany the primary condition, seeing clinically this has alot of the time been found to produce global improvement in symptomatology.

Harking back to the scientifically purported 'Happy Hormone', Treatment of the secondary depressive and anxiogenic disorders which commonly appear alongside Severe neurocognitive dysfunctions, from a Serotonergic standpoint, may not be completely fruitless.

Due to the rapid realisation that the first purported agent to selectively target the 5-HT-1A (serotonin) receptor subtype, which was first thought to theoretically hold unending potential in the treatment of conditions akin to the disorder in-question, namely Buspirone, was completely ineffective and basically inert, in a number of select places around the globe much research was done pursuing the question of Buspirone's apparently in-effectivity at treating the disorders in question. In places such as Japan, and France, they seemed to have the right idea.

The abundant evidence from all the research undertaken hinted that to fully exploit the therapeutic potential which the 5-HT1a receptor held, selective agonists which were developed for it needed to have a high level of intrinsic activity and efficacy, aswell as potency. To put this into context, Buspirone's ability to elicit the maximal pharmacological output relative to that of serotonin (the primary endogenous ligand), hence its intrinsic activity, is ~30%. After thorough research into the matter an intrinsic activity of around 55-85% was found to be needed to result in an appreciable therapeutic benefit, while maximal benefit is seen with compounds that display the same intrinsic activity as serotonin itself (nigh-on 100%) and even greater clinical benefits have been seen with compounds that are full agonists at the 5-HT1a receptor wich are full agonists and/or 'Super'-agonists, basicaly compounds which elicit an effect and an intrinsic activity greater than serotonin itself, (around 124%). Such compounds have been found to elicit analgesic activity equal to or greater than opioid compounds, but without the slew of negative side-effects, including any addictive qualities whatsoever. Other benefits of such 'Super-agonists' of the 5-HT1a receptor include attentuation of dissociative-drug induced memory deficits, and therefore an improvement in neurocognitive functioning.

In addition to this, positive modulators of Glycine, and therefore NMDAR function have been shown to provide significant conditions of this sort. Subsequently, Positive AMPAR modulation may also hold further promise, and compounds which facilitate the functioning of these neurochemical systems and aim to ameliorate the underlying causes of conditions of this sort are of potential, novel, therapeutic approaches of the future.

Other more naturally occuring supplements which may be of benefit include:

- Sarcosine

- D-Serine

- Piracetam

- Aniracetam

- Centrophenoxine

- IDRA-21

- DAO-Inhibitors: Sodium benzoate

- Coluracetam

- Sunifiram

- Uridine


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## Nathanael.A. (Apr 16, 2013)

MDMA is a major contributor to DP/DR; please be well-informed before posting comments/ opinions.

Regards'

Nath


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## nabber (Feb 13, 2009)

I was on bupe for years, it's not worth going down that road. Kratom though, is great. Good post, very informative .


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## clockwork8 (May 9, 2013)

You seem highly knowledgeable of pharmacology and neuroscience, or at least you seem to have the ability to collect a much larger array of useful information than me.

Have you found anything more than what you mentioned about the involvement of NMDA receptors? I'm asking this because I first got intense panic attacks and DP/DR when I consumed a large dose of DXM. I always attributed this to the NMDA receptor activity, but now I'm not so sure... since it's also a K-opioid agonist, and many other substances which purportedly have similar effects are also K-opiod agonists, I'm not sure anymore. I've never taken a k-opioid antagonist, as like you said they seem pretty hard to come by. I have taken oxycodone and hydrocodone, but I am unsure if they had any measurable impact in my DP/DR, or other stress responses. I wasn't particularly stressed or DP'd at the times I took them. But they definitely didn't make it worse either, perhaps I felt mildly more pleasant.

Also do you have any further information explaining how MDMA is a major contributor? I'm assuming it's purely due to the serotonin release, as I've never really heard of anyone getting DP/DR from meth which would have released more dopamine but not serotonin. As far as I know the dopamine and serotonin release are the main components of the action of MDMA. I'm actually kind of unsure what role exactly serotonin plays in stress or in DP/DR. I don't understand why SSRIs are prescribed for anxiety. I took an SSRI once, and I felt DP'd the first day and nearly had a panic attack... didn't take it again. I took a very small dose of MDMA (30 mg) a few weeks ago and I felt very tense after about 1 hour. Then for 2 hours hours after that I had an increase in clarity of vision, that's about it. It doesn't seem like 30 mg of MDMA should cause any perceptible effects from what I've read about it, do you think the tension could partially be a placebo effect where I caused the stress for myself just in anticipation?

I'm not trying to cure my DP/DR with MDMA or anything, I just acquired some because I was curious about its effects. And yes I'll be careful with it. Anyway, I don't know what else to say for the moment. Thanks for the long post.


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## Nathanael.A. (Apr 16, 2013)

Not too sure in all honesty, its kind of abit more simpler to think bout the monoamines (dopamine, serotonin, noradrenaline) in regards to their function than it is with glutamate, just cos glutamate is more widely used in the brain, itmore or less mediates around about everything to varying degrees lol, in conjunction with sumin else called gaba, they're knd of 50/50 in terms of the ratio of how widespread they're use is in the CNS. In contrast, the monoamines r like the by standers and only play a minor role in 'modulating' the activity of the other two main neurochemicals.

To give u an example, drugs which both increase and decrease glutamate levels r being developed as anti-depressants. In regards to your NMDA question, IME the drugs which ive found most beneficial tend to increase glutamate levels or signalling in myself, and therefore NMDA activation, somehow I think memory seems to play a key role in all of these kind of things, and glutamate is heavily implicated in memory processing so..

And when it comes to MDMA, is abit complicated. The post about md I made was in response to another comment some person posted talking about ecstacy which was kind of inappropriate hence it got deleted.

But yh, erm I dont think mdma would help in any kind of situation imo, its interesting i'll give u that but we dont have a clue about how it actually works becos its illegal which tends to result in no research bein done on the drug itself, so yeah, I'd tread carefully if I were you. There are other legal, all be it prescription stimulants which ive taken to using which serve the same purpose as MD pretty well in social (club/ rave) situations which I'd say feel alot more benign imo, generally because their mechanism of action is alot more well known. In general mdma is neurotoxic in high doses, causes very large increases in serotonin/dopamine, which leads to depleted levels afterwards and the down regulation of receptors, so maybe thats why it leads to DP in alot of cases; its basicly too much of a good thing for your body, more or less. Thats my take on it, anyway.

Just to add in regards to NMDA and glutamate, too high levels can actually lead to neuron death, which probably forms some kind of fundamental basis for the body's reaction to stress somehow, so I think raising serotonin levels probably leads to more positive outcomes in conjunction to aiding glutamate function which might even out the cost/ benefit ratio of doing either one or the other, well thats the approach ive used anyway.


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