# NALTREXONE or NALOXONE for derealization? Expiriences.



## phaeton

Hallo! I'm a doctor and I live with my DD for at least 10 years. I tried many medications, but they just help me to cope with my comorbid depressive simptoms, leaving derealization intact...

I'm going to try naltrexon, because It makes sense from patophisiological point of view!

*In Pub Med I've found the only few articles*

Expert Rev Neurother. 2008 Jan;8(1):19-26.
Depersonalization disorder: pharmacological approaches.

Sierra M.
Depersonalization Research Unit, Institute of Psychiatry, King's College, Section of Neuropsychiatry P068, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. [email protected]

Depersonalization disorder (DPD) is a chronic and distressing condition with a prevalence in the general population between 0.8 and 2%. Several neurobiological studies in the last decade have shown that patients have suppressed limbic activation to emotional stimuli. Such findings are in line with a model which suggests that the condition is generated by an anxiety-triggered, 'hard-wired' inhibitory response to threat. Such a mechanism would ensure the preservation of adaptive behavior, during situations normally associated with overwhelming and potentially disorganizing anxiety. In DPD, such a response would become chronic and dysfunctional. Depersonalization remains a condition for which no definitive treatment exists, and for which conventional medications, such as antidepressants or antipsychotics, have been found to be of little value. Fortunately, a few promising lines of pharmacological treatment have emerged in recent years, although more rigorous studies are needed. For example, a number of studies suggest that opioid receptor antagonists such as naltrexone and naloxone are useful in at least a subgroup of patients. In spite of initial expectations, the use of lamotrigine as a sole medication has not been found useful. However, open-label trials suggest that its use as an add-on treatment with selective serotonin reuptake inhibitors (SSRIs) is beneficial in a substantial number of patients. Similarly, the use of clonazepam, particularly in conjunction with SSRI antidepressants, appears to be beneficial in patients with high levels of background anxiety. In line with the stress-related model of depersonalization, those neurotransmitter systems of relevance to depersonalization are known to play important inhibitory roles in the regulation of the stress response.
PMID: 18088198 [PubMed - indexed for MEDLINE]
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J Clin Psychopharmacol. 2005 Jun;25(3):267-70
An open trial of naltrexone in the treatment of depersonalization disorder.
Simeon D, Knutelska M.
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. [email protected]

Depersonalization disorder (DPD) remains one of the few disorders in modern psychiatry for which no treatments are established that are even partially effective, whether pharmacological or psychotherapeutic. Depersonalization disorder is a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition dissociative disorder characterized by a pervasive subjective sense of unreality and detachment with intact reality testing. Two recent controlled medication trials, one with lamotrigine and one with fluoxetine, failed to show efficacy. There is some evidence for dysregulation of endogenous opioid systems in depersonalization, and a few studies have suggested that opioid antagonists may have efficacy in the treatment of dissociation and depersonalization symptoms. In this prospective open treatment trial, 14 subjects were recruited and treated with naltrexone for 6 weeks to a maximum dose of 100 mg/d (first 7 subjects) or 10 weeks to a maximum dose of 250 mg/d (next 7 subjects). Mean naltrexone dose was 120 mg/d. There was an average 30% reduction of symptoms with treatment, as measured by 3 validated dissociation scales. Three patients were very much improved, and 1 patient was much improved with naltrexone treatment. These findings are potentially promising in a highly treatment-refractory disorder for which no treatment guidelines exist and warrant a randomized controlled trial.
PMID: 15876908 [PubMed - indexed for MEDLINE]
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J Psychopharmacol. 2001 Jun;15(2):93-5. - 
Effect of naloxone therapy on depersonalization: a pilot 
study.Nuller YL, Morozova MG, Kushnir ON, Hamper N.
Bekhterev Psychoneurological Research Institute, St-Petersburg, Russia. [email protected]

To test the hypothesis of the role for the opioid system in the pathogenesis of depersonalization, the effect of naloxone (an opioid receptor blocker) on the symptoms and corticosteroids secretion was studied in patients with depersonalization syndrome. Fourteen depersonalization patients were treated with naloxone: 11 patients received single doses (1.6 or 4 mg i.v.) and three others received multiple infusions, with the maximal dosage being 10 mg, and the effect of naloxone on symptom severity was determined. In eight patients, the cortisol, cortisone and corticosterone content in the blood plasma was determined prior to and after the 4 mg naloxone infusion. A reversed-phase microcolumn high-performance liquid chromatography with ultraviolet detection was applied for assessment of glucocorticoids. In three of 14 patients, depersonalization symptoms disappeared entirely and seven patients showed a marked improvement. The therapeutic effect of naloxone provides evidence for the role of the endogenous opioid system in the pathogenesis of depersonalization.
PMID: 11448093 [PubMed - indexed for MEDLINE]
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J Clin Psychiatry. 1999 Sep;60(9):598-603.
Naltrexone in the treatment of dissociative symptoms in patients with borderline personality disorder: an open-label trial

Bohus MJ, Landwehrmeyer GB, Stiglmayr CE, Limberger MF, B?hme R, Schmahl CG.
Department of Psychiatry, University of Freiburg, Freiburg im Breisgau, Germany. [email protected]

BACKGROUND: Dissociative phenomena, including flashbacks, are common in patients with borderline personality disorder and posttraumatic stress disorder (PTSD). Although dissociative symptoms can be severe and may interfere with psychotherapy, there is no established pharmacotherapy for these symptoms. Evidence suggests that alterations of the endogenous opiate system contribute to dissociative symptoms in patients with borderline personality disorder and PTSD. METHOD: We treated 2 groups of female borderline personality disorder patients (N = 13, with an overlap of 5 patients between the 2 groups; all met the diagnostic criteria of DSM-IV and the revised Diagnostic Interview for Borderline Patients) who experienced prominent dissociative phenomena including flashbacks with the nonselective opiate receptor antagonist naltrexone, 25 to 100 mg q.i.d., for at least 2 weeks. A self-rated questionnaire measuring dissociation, analgesia, tonic immobility, and tension (DAISS) was applied to 9 patients, who completed it for 7 consecutive days before and during treatment with naltrexone. In addition, 9 patients (with an overlap of 5 patients from the other group) completed a flashback protocol. RESULTS: DAISS scores reflected a highly significant reduction of the duration and the intensity of dissociative phenomena and tonic immobility as well as a marked reduction in analgesia during treatment with naltrexone. Six of 9 patients reported a decrease in the mean number of flashbacks per day. CONCLUSION: These observations support the hypothesis that an increased activity of the opioid system contributes to dissociative symptoms, including flashbacks, in borderline personality disorder and suggest that these symptoms may respond to treatment with opiate antagonists. In view of these results, a placebo-controlled, double-blind study to assess the potential benefit of naltrexone in a more rigorous way appears justified.
PMID: 10520978 [PubMed - indexed for MEDLINE]


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## phaeton

Please if anyone tried Naltrexone or any other opiod antagonist in treatment of depersonalisation, share your expirience here.

As soon as I have myself tried this medication, I report the results here


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## nabber

Hey Dr. Phaeton,

I was just prescribed naltrexone 3.5mg , I'm going to start it next week. I'll keep you , and everyone updated on how it works.
It's a really low dosage so i'm skeptical , but might as well give it a try eh? Pick up a copy of 'Feeling Unreal.' It's written by
one of the leading psychiatric experts concerning Depersonalization in the U.S. There's a paragraph
of two case studies where they had 14 patients given 120mg per day of Naltrexone over a two week period and it worked well
for 3 of them.


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## phaeton

Thanks a lot for your intention to keep us updated! 

I will try to start with 25mg/d of Naltrexone, or maybe Naloxone injection of 0,4 mg...

I suppose Naltrexone or Naloxone monotherapy is not usefull.

I can quote Nuller that Naloxon exacerbated anxiety and depression. So it seems reasonable to take opioid antagonists only in combination with anxiolytics and antidepressants.

I also have a very positive personal experience of using mirtazapine (30mg/d) + milnacipran (100-150mg/d) as a very potent long-term antidepressive combination, that prevents seasonal rise in severity of my derealization/depersonalization symptoms. This combination is unic and is much better tallerated than each medication in monotherepy.


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## phaeton

nabber said:


> I was just prescribed naltrexone 3.5mg..... It's a really low dosage so i'm skeptical , but might as well give it a try eh?...


I suppose your doctor will observe your progress and titrate the dose untill it works...


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## nabber

phaeton said:


> nabber said:
> 
> 
> 
> I was just prescribed naltrexone 3.5mg..... It's a really low dosage so i'm skeptical , but might as well give it a try eh?...
> 
> 
> 
> I suppose your doctor will observe your progress and titrate the dose untill it works...
Click to expand...

Yeah , that's the plan. I will go back in a month and see her, and see if it has had any effects at all. I take Xanax XR, Lamictal, and Lexapro right now. Seems to 
be a good combo, but I'm sort of in a rut right now with the economy being so bad I think I spend to much time focusing on negative things. Yeah the Nalaxone
only lasts 30-40 minutes I think, i'm no expert at all when it comes to meds. But I hear it works really well, I'd go in for just one shot of it, just a glimpse of reality
would be overwhelming.I wish you well, keep me updated on the 25mg and we can trade notes , and see if the higher dose has a better effect.


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## Johnny Dep

nabber said:


> Hey Dr. Phaeton,
> 
> I was just prescribed naltrexone 3.5mg , I'm going to start it next week. I'll keep you , and everyone updated on how it works.
> It's a really low dosage so i'm skeptical , but might as well give it a try eh? Pick up a copy of 'Feeling Unreal.' It's written by
> one of the leading psychiatric experts concerning Depersonalization in the U.S. There's a paragraph
> of two case studies where they had 14 patients given 120mg per day of Naltrexone over a two week period and it worked well
> for 3 of them.


I think 50mg a day is how much you need to block opiates for the entire day, thats how much they give opiate addicts. This is from memory, maybe I'm wrong on that. Even at the doses they give opiate addicts this is a very safe drug, I don't know they are so reluctant to give full doses. Its safer than aspirin. Anyway, I'm personally intrigued by the use of Naltrexone for DP, I tried Kratom, which is legal where I live, and it did remind me of the way I feel when I separate from painful reality during difficult experiences. The endorphin addiction hypothesis does make sense to me, at least worth further investigation. Unfortunately I don't think Low Dose Naltrexone is really the answer, its only enough to block endorphins/opiates for a few hours. I also think some of the doctors promoting LDN for things like cancer, people like Dr. Bihari, are quacks and financially benefiting from a fraud. If you have cancer and do a "phone consultation" with Bihari for a $500 "donation" to his research he will mail you a prescription for LDN. These phone consults last a few minutes and at these doses the chances of someone getting hurt from the drug is microscopically low. Scam.


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## nabber

Johnny Dep said:


> I think 50mg a day is how much you need to block opiates for the entire day, thats how much they give opiate addicts. This is from memory, maybe I'm wrong on that. Even at the doses they give opiate addicts this is a very safe drug, I don't know they are so reluctant to give full doses. Its safer than aspirin. Anyway, I'm personally intrigued by the use of Naltrexone for DP, I tried Kratom, which is legal where I live, and it did remind me of the way I feel when I separate from painful reality during difficult experiences. The endorphin addiction hypothesis does make sense to me, at least worth further investigation. Unfortunately I don't think Low Dose Naltrexone is really the answer, its only enough to block endorphins/opiates for a few hours. I also think some of the doctors promoting LDN for things like cancer, people like Dr. Bihari, are quacks and financially benefiting from a fraud. If you have cancer and do a "phone consultation" with Bihari for a $500 "donation" to his research he will mail you a prescription for LDN. These phone consults last a few minutes and at these doses the chances of someone getting hurt from the drug is microscopically low. Scam.


Thanks for the reply, I guess I'll give the 3mgx2 daily a month trial then see about titration. The biggest drawback I see to Naltrexone is local pharmacies dont have it, you have to special order it from an outside pharmacy, and I'm not sure if my insurance will cover it. 3mgx60 is 25 dollars. I hope the 50mgx30 isn't insanely overpriced.

I've never heard of Kratom, sounds interesting..

"Kratom also has a yohimbe-like stimulant activity, and uncaria-like immunostimulant activity. Kratom is said to produce a sense of well-being, with users reporting anti-depressant, anti-anxiety, analgesic, and even euphorigenic effects. It is paradoxically a stimulant and depressant, used to aid work and also able to contribute to rest and sleep."


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## Johnny Dep

Kratom is chemically distinct from opiates, but connects to opiate receptors in the same way. Its really just weak heroin. The only reason it hasn't been outlawed yet is because its new, only known outside Thailand for a few years. I don't recommend it, it reinforces negative tendencies within withdrawn, depersonalized people.


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## phaeton

*Naloxone ? trip to reality?*

Today was the 1st session of trying to cope with my transient derealization. 
I started with 0,4mg of Naloxone i/m injection. In 20 min I felt a little bit sad, and paid attention on that the colors became more vivid and objects edges became more distinct. But I was not shure that was not a placebo reaction, so I decided to inject 1,6mg. In about 30 min I felt very relaxed, peaceful and lazy. I did not want to contact to anyone, so I decided to lay into bed for a while. I took one banana and went to my room. It was unusually tasty and fragrant. I was feeling rather comfortable. My attempts of introspection met inner feeling of like I was bored to death with that permanent selfanalisis. It was rather discomfortable for me to think of myself. I can compare this feeling with ideational (thinking) laziness. Sometimes it seemed to me that I don?t want to think at all. Than I detected a lot of unusually intensive spark-like wishes, that disappeared quickly after origination. But the most amazing for me was one distinct and intensive feeling. It was like that I realized my genuine potential to experience happiness. This feeling was originating from inside the depth of my soul. Topically this feeling localized somewhere in the ?inner core? of my chest. The depth of my chest seemed inconceivable. I have never guessed that such place exists. It was so pleasant and in the same time so natural! When I entered another room I found my perception to be objectively changed. The term that came to my mind to describe that was ?naturalness?. I did not find happening to be strange. Everything was familiar. But I'd expected something another. Now I realize that I?d experienced really a great thing. The experience was so much unusual or so much forgotten for me?

It a little bit reminded me of 45mg/d Mirtazapine or benzodiazepines. But these course me to experience demoralizing indifference. In the case of Naloxone there was relaxation and peace in my sole, and naturalness of my psychic condition.

Else I found funny to meet my personality! And I liked my character and my voice (it was so unusual to have a voice!). I found a person ? a new person in my body! 
(Before, when I was alone in the room, I understood ?there is no one here, including myself?) 
You know, I found that person to be grown up already, it was a feeling like when you don?t see your friend for 10 years and one day u meet him and realize he is grown up.

But I can not say that Naloxone1,6mg completely reduced my derealization and repersonalized me?

In 4 hours after injection there was no sense of reality again? (((((

In few days I'm going to try 25mg/d Naltrexone


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## Surfingisfun001

...wow


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## phaeton

Next day after Naloxon.

I was more depressed than usual, feeling of self loss, indifference (hypopathy), lack of energy and motivation were more distinct, although I was on Milnacipran 100mg + Mirtazapine 15mg. May be this partially because of piracetam (3,2g/d) was withdrawn 2 days ago, or of some other reasosns (coffeine, biorhythm etc).

in the evening I took 25mg of Naltrexone orally. In about 2h after that I found myself even more derealized. I experienced a short period of ambivalent emotions, felt a slight restlessness. After that I concluded that I felt a very slight euphoria with apparent slight psychic anesthesia.

The effect did not remind me Naloxone much, but the feeling of beeing calm, a little relaxed, carefree and light-hearted that came much later was the same (in about 4 hours after ingestion).

I found Naltrexone to be interresting for further studying, so before going to bed I took 25mg of Naltrexone + 15mg of Mirtazapine + 3 mg of Melatonine.

I found some interesting information on Naltrexone single 50mg oral dose:
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In healthy adults 50 mg produces fatigue, sleepiness, lightheadedness, nausea, sweating, feeling of unreality, recurrent penile erections, and elevations of plasma luteinizing hormone. Other reactions have been suggestive of opiate agonist effects, including decreased respiratory rate, pupillary constriction, decreased oral temperature, and dysphoria. In maintenance treatment, naltrexone has induced aversive effects such as changes in mood, concentration, alertness, and motor coordination. Depression and abdominal pain have also been observed. 
[Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 761]
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Because naltrexone may inhibit the effects of endogenous endorphins and decreased concentrations of endorphins in the CNS have been associated with fasting and starvation, it has been suggested that the drug may be useful as an appetite suppressant in the treatment of obesity. ... Naltrexone also may be useful in reducing the frequency of binging and purging in patients with bulimina. ... Naltrexone has been used in dosages up to 800 mg daily for the treatment of schizophrenic disorder ... . /Uses are not currently in the labeling approved by the FDA/ 
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 1183]
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## wael

Yeah this is interesting stuff! since i have dp/dr I am interested in Naltrexone/nalexone. But finding a psy that prescripes it for me is not easy. 
But so cool that you are trying both naltrex/nalex and that it has it results! Keep up the good work. You are a doctor, so do you prescripe it to yourself or does somebody else do it for you? And can i get some...  
The article i read was about naltrexone and they were taking 120 -200 mg for about 6 weeks, and it was quite succesful.
But keep us informed!

good luck and greetings


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## phaeton

Today is the day after Naltrexone use. 
During the whole night I have vivid dreams. In the morning there was the feeling of light neusea and sleep deprivation. My condition remainded me also of acute SSRI effect - yawning and stretching a lot. I was calm. I had better mood. It was much easier for me to do little things, but it was steel difficult to find motivation for great deels - I experienced lack of inspiration. There was no psychic anecthesia. But reality still remains undetectible. Now I'm a little bit sceptic towards Naltrexone can "repersonalize" me and help to "realize" reality. High doses of Naltrexone (150mg) maybe may be more beneficial, but... I can not organize my motivation to try...

If I do not receive a good effect of Naltrexone within next few days (after 50 mg/d steady serum concentration is achieved) I will remain on doses of milnaciprane (150) + mirtazapine (30).


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## phaeton

wael said:


> ... do you prescripe it to yourself or does somebody else do it for you?


Naloxone and Naltrexone are not controlled substances as well as most antidepressants, so prescription is just a formality, any doctor as well as I myself can write a prescription, in some drugstores they don't even ask for a prescription.


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## phaeton

I tried to find out the pharmacodynamic spectrum of Naloxone, Naltrexone and 6-beta-naltrxol.

I have not much comprehended all the material (too much time is needed). But I can do some conclusions.

_________________________________________________________________________________________
*Differentiation of Kappa Opioid Agonist-Induced Antinociception by Naltrexone Apparent pA2 Analysis in Rhesus Monkeys* 
Mei-Chuan Ko, Eduardo R. Butelman3, John R. Traynor and James H. Woods 
Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor, Michigan

Naltrexone (NTX) exhibited approximately 3-fold higher affinity for sites labeled by [3H]U69,593 (putative kappa1-selective ligand) than [3H]bremazocine (non-selective ligand) in the presence of mu and delta receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for kappa1- versus non-kappa1-mediated effects. Six opioid agonists were characterized by NTX apparent pA2 analysis in a 50?C water tail-withdrawal assay in rhesus monkeys. Constrained NTX pA2 values (95% confidence limits) were: alfentanil, 8.66 (8.47-8.85); ethylketocyclazocine, 7.97 (7.93-8.01); U69,593, 7.64 (7.49-7.79); U50,488, 7.55 (7.42-7.67); bremazocine, 6.92 (6.73-7.12); enadoline, 6.87 (6.69-7.05). Pretreatment with clocinnamox, an irreversible mu antagonist, confirmed that mu receptors were not involved in the antinociception produced by the kappa agonists, U69,593, U50,488, bremazocine and enadoline; however, both mu and kappa receptors mediated the antinociceptive effects of ethylketocyclazocine. The apparent NTX pA2 profile of opioid agonists correlated highly with the radioligand binding studies, which indicates that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functional evidence of kappa opioid receptor multiplicity in primates and suggests that NTX may be a useful tool to study this phenomenon in vivo. 
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_1. So Naltrexone is only kappa-1 receptor antagonist _

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*Naltrexone and buprenorphine combination in the treatment of opioid dependence *
by Gerra G, Fantoma A, Zaimovic A.
National Department on Drug Policy, 
Rome, Italy.
J Psychopharmacol. 2006 Jan 9;

ABSTRACT
Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50 mg oral dose) plus buprenorphine (4 mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone + buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p = 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p < 0.05; p < 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving. 
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*An open-label study of a functional opioid kappa antagonist in the treatment of opioid dependence *
by Rothman RB, Gorelick DA, Heishman SJ,
Eichmiller PR, Hill BH, Norbeck J, Liberto JG 
National Institute on Drug Abuse, 
National Institutes of Health, 
5500 Nathan Shock Drive, Baltimore, MD, USA. 
J Subst Abuse Treat 2000 Apr; 18(3):277-81

ABSTRACT
Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria and psychotomimetic effects in humans, suggest that dysfunction of the endogenous kappa opioid system may contribute to opioid and cocaine addiction. The objective of this open-label study was to determine the effectiveness of a functional kappa antagonist as a treatment for opioid dependence. This was accomplished by combining a partial mu agonist/kappa antagonist (buprenorphine, 4 mg, sublingual) with a mu antagonist (naltrexone, 50 mg by mouth), theoretically leaving kappa antagonism as the major medication effect. Subjects were treatment-seeking heroin-dependent (as per Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) men (41 7 years old; 19 8 years heroin use) eligible for methadone maintenance. After inpatient detoxification and a naloxone-challenge test to verify that they were not physically dependent on opioids, subjects received naltrexone. Starting on the fourth day, patients also received liquid buprenorphine. All patients received medication at the clinic 6 days per week and a full program of psychosocial treatment. The major endpoints of the study were: pupil diameter to determine if the &mgr; agonist effects of buprenorphine were blocked by naltrexone, urine toxicology, and retention in treatment. Five patients (33%) completed the 3-month study. Four were abstinent from opioids and cocaine for the entire study, and one was abstinent from opioids and cocaine for the last 9 weeks. Six subjects dropped out due to either minor side effects or disliking the sensation of sublingual buprenorphine. There were no significant changes in pupillary diameter. The positive response to treatment exceeds that expected from naltrexone alone (90% dropout). These promising results suggest that controlled studies of this medication combination should be conducted. 
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_2. so Naltrexone and its metabolite (6-beta-naltrexol) do not exhibit the same clinical effect as full mu+kappa receptor antagonist_

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*Different Effects of Opioid Antagonists on ?-, k-, and d-opioid Receptors with and without Agonist Pretreatment*Journal of Pharmacology And Experimental Therapeutics Fast Forward 
First published on January 31, 2007Opioid receptors display basal signaling (constitutive, agonist-independent activity), which seems to be regulated by agonist exposure. Whereas agonist pretreatment desensitizes receptors to subsequent agonist stimulation, basal signaling of ?-opioid receptor (MOR) was shown to increase. Moreover, agonist pretreatment converts the neutral antagonists naloxone and naltrexone into inverse agonists, suppressing basal signaling, whereas analogs with reduced C6-position, e.g., 6-naltrexol, remain neutral antagonists at MOR under any condition. This study compares the regulation of basal signaling of MOR, -(DOR), and -(KOR) opioid receptors after pretreatment with morphine or receptor-selective agonists, in transfected human embryonic kidney 293 cell membranes. Moreover, naloxone, naltrexone, and related antagonists were compared for binding potency and effect on basal and agonist-stimulated receptor signaling, measuring guanosine 5'-O-(3-[35S]thio)triphosphate binding. The results demonstrate basal activity for each opioid receptor, which is modulated by pretreatment with agonists. *Even closely related opioid antagonists display distinct patterns of neutral and inverse effects before and after agonist pretreatment, including distinct efficacies between naloxone and naltrexone at agonist-pretreated DOR and KOR.* Pretreatment with different agonists has varying effects on inverse and neutral activities of some analogs tested. These results demonstrate that antagonist efficacy is context-dependent, possibly accounting for paradoxical pharmacological effects. Activity profiles at the three opioid receptors under different conditions could lead to antagonists with optimal clinical properties in treatment of addiction and adverse opioid effects.
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_3. so Naloxone, Naltrexone and it's metabolite are farmacologically and clinically different compounds and one should not wait that Naltrexone will have the same effect as other compounds._

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*Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats *
by Mague SD, Pliakas AM, Todtenkopf MS, 
Tomasiewicz HC, Zhang Y, Stevens WC Jr,
Jones RM, Portoghese PS, Carlezon WA Jr.
Behavioral Genetics Laboratory,
Department of Psychiatry,
Harvard Medical School, 
McLean Hospital, Belmont,
Massachusetts 02478, USA. 
J Pharmacol Exp Ther. 2003 Apr;305(1):323-30

ABSTRACT
We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.
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*The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. *
by Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C.
Department of Pharmacology,
University of Washington, Seattle, 
Washington 98195-7280, USA. 
J Neurosci. 2008 Jan 9;28(2):407-14.

ABSTRACT
Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a kappa-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2 receptor antagonist antisauvigine-30, but not by the CRF1 receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2 receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes kappa-receptor antagonists as promising therapeutics. 
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*Anxiolytic-Like Effects of {kappa}-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats *
by
Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA.
McLean Hospital.
J Pharmacol Exp Ther. 2007 Sep 6;

ABSTRACT
Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia, but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here we examined if KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms, and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (~24 hr) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine (norBNI) and JDTic. Rats received an intraperitoneal (IP) injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 hr before EPM testing. One day later they were tested in the OF, and five and seven days later they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects, and suggest that this class of drugs may be particularly effective for the treatment of co-morbid depressive and anxiety disorders. 
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*Central kappa-opioid receptor-mediated antidepressant-like effects of nor-Binaltorphimine: Behavioral and BDNF mRNA expression studies *
by
Zhang H, Shi YG, Woods JH, Watson SJ, Ko MC.
Department of Pharmacology, University of Michigan Medical School, 
Ann Arbor, MI, USA; Department of Biomedical Engineering,
College of Engineering, University of Michigan, Ann Arbor, MI, USA. 
Eur J Pharmacol. 2007 Sep 10;570(1-3):89-96.

ABSTRACT
Kappa-opioid receptor antagonists such as nor-Binaltorphimine (nor-BNI) have been shown to produce antidepressant-like behavioral effects in animal models of depression. The aim of this study was to investigate further the duration of centrally administered nor-BNI-induced antidepressant-like actions measured by both behavior and brain-derived neurotrophic factor (BDNF) gene expression. In addition, antagonist studies were conducted to determine the role of opioid receptor subtypes and the time course of nor-BNI's pharmacological actions. Antidepressant-like behavioral effects were measured by decreased immobility in the rat forced swim test and BDNF mRNA expression was determined by in situ hybridization. Centrally administered nor-BNI (20 mug, i.c.v.) decreased immobility and increased BDNF mRNA expression in the hippocampus on day 1, not on days 3-14, post-administration. Systemic administration of selective mu-, delta- and kappa-opioid receptor antagonists did not block nor-BNI-induced antidepressant-like effects. In contrast, i.c.v. administration of nor-BNI 7 or 14 days earlier significantly blocked subsequent nor-BNI-induced decreased immobility and upregulation of BDNF mRNA expression. Although the duration of nor-BNI's antidepressant-like effects did not synchronize with that of its kappa-opioid receptor antagonist effects, this study is the first to show that centrally administered nor-BNI, like most clinically used antidepressants, can upregulate BDNF mRNA expression in the rat hippocampus. These findings further demonstrate that central kappa-opioid receptor mediates antidepressant-like effects of nor-BNI measured by both behavior and BDNF gene expression. 
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*{kappa} opioids selectively control dopaminergic neurons projecting to the prefrontal cortex *
by
Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL.
Ernest Gallo Clinic and Research Center,
University of California at San Francisco, Emeryville, CA 94608; 
Integrative Neuroscience Section,
National Institute on Drug Abuse Intramural Research Program, 
National Institutes of Health, 
5500 Nathan Shock Drive, Baltimore, MD 21224.
Proc Natl Acad Sci U S A. 2006 Feb 13;

ABSTRACT
Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC. 
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_4. so, theoretically, endogenous opioids may course depression and through kappa system can course lack of motivation and apathy (prefrontal cortex) as well as psychosis_
so different types of kappa antagonists may have a potential in therapy of DD... and not only... thats promissing!


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## phaeton

One interresting observation: the periods of my seasonal psychic anesthesia are usually accompanied by marked irritability and agressivness towards things. Can it be because of higher level of Dynorphin? It seems to be reasonable...


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## wael

"any doctor as well as I myself can write a prescription"

It is difficult to convince my psy or doctor to prescribe naltrexone. First, because the knowledge of dp/dr is still limited and not institutionalised in current healthcare. Second, as a result, the do not know a lot about potential drugs to reduce or eliminate dp/dr except for anti-psychotics and ssri's.
I want to be a doctor too :roll: 
We will see,
Keep us updated and hopefully you can experience some positive results!


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## Angela2006

Hello. Do you have any more information on Naltrexone. I only see posts from March. Anything new you can share?


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