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Anyone try Ketamine for Depression and/or Anxiety?

ketamine depression anxiety

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#1 Daniel Cooper

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Posted 13 April 2020 - 02:32 PM


IV Ketamine has a great reputation for turning around depression.  More murky with respect to anxiety.

 

I'm looking for someone with first hand experience as a patient or a clinician.

 

 



#2 adamh

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Posted 14 April 2020 - 12:40 AM

Used it but not from a doctor. Approximately 25 - 30mg insufflated did the job. It produced a drunk feeling that lasted about an hour to 3 hours as it tapered off. Afterward it was like being washed out of negativity. Depression was gone and a pleasant relaxed feeling remained, no anxiety. I do not recommend it for habitual use, the benefit seems to fade in that situation and using large amounts for a long time leads to nasty changes in the body but for one-off or rare occasions its great.


 


Edited by adamh, 14 April 2020 - 12:41 AM.


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#3 Daniel Cooper

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Posted 14 April 2020 - 01:14 PM

Were you using it recreationally or were you treating depression/anxiety?

 

Did you seem to get any last benefit from it?



#4 thompson92

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Posted 14 April 2020 - 01:23 PM

 

Used it but not from a doctor. Approximately 25 - 30mg insufflated did the job. It produced a drunk feeling that lasted about an hour to 3 hours as it tapered off. Afterward it was like being washed out of negativity. Depression was gone and a pleasant relaxed feeling remained, no anxiety. I do not recommend it for habitual use, the benefit seems to fade in that situation and using large amounts for a long time leads to nasty changes in the body but for one-off or rare occasions its great.


 

 

How would you view Ketamine as a treatment option for neurogenesis, post concussion syndrome or some kind of mild TBI?



#5 adamh

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Posted 14 April 2020 - 06:32 PM

@thompson92, I have no idea about that. All I know is the depression and any negative feelings felt washed away. I use it maybe once a year at most. The benefit lasts for some time. 



#6 YoungSchizo

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Posted 24 May 2020 - 02:27 PM

Hey guys, I don't want to hijack the thread but I had a question.. After 15 years I'm able to smoke THC without experience psychosis (which is a miracle) should I try (Es)ketamine for depression?



#7 Daniel Cooper

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Posted 29 May 2020 - 03:36 PM

Hey guys, I don't want to hijack the thread but I had a question.. After 15 years I'm able to smoke THC without experience psychosis (which is a miracle) should I try (Es)ketamine for depression?

 

 

I think people are going to tell you that because ketamine is used to create a model of schizophrenia in laboratory animals that it would therefore be dangerous for a person with schizophrenia to take it (the argument does have a certain logic to it).  

 

Now, in the much lower doses being used with nasal esketamine ... would that be a problem?  I don't know.  I'd look to see if anyone had written a paper on dosing schizophrenia patients with ketamine.

 

I'd be shocked if schizophrenia patients haven't been given ketamine in a surgical setting, even if unwittingly.  Having had a surgery in which ketamine was used to induce, I don't recall anyone asking me if I had any mental disorders.


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#8 Daniel Cooper

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Posted 29 May 2020 - 05:58 PM

Here's a nice little article that has a summary of the research on the use of ketamine in patients with psychiatric disorders.
 
Is Ketamine Contraindicated In Patients With Psychiatric Disorders?

 

The test groups were small, but everyone returned to baseline after about 90 minutes. In one test they did not see an increase BPRS scores in schizophrenic patients at a 0.1mg/kg dose, while in another test they saw an increase at a similar dose in healthy controls.  Go figure.

 

 

 

 


Edited by Daniel Cooper, 29 May 2020 - 05:59 PM.

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#9 YoungSchizo

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Posted 30 May 2020 - 12:16 AM

I think people are going to tell you that because ketamine is used to create a model of schizophrenia in laboratory animals that it would therefore be dangerous for a person with schizophrenia to take it (the argument does have a certain logic to it).  

 

Here's a nice little article that has a summary of the research on the use of ketamine in patients with psychiatric disorders.
 
Is Ketamine Contraindicated In Patients With Psychiatric Disorders?

 

The test groups were small, but everyone returned to baseline after about 90 minutes. In one test they did not see an increase BPRS scores in schizophrenic patients at a 0.1mg/kg dose, while in another test they saw an increase at a similar dose in healthy controls.  Go figure.

 

I will most likely hit a huge roadblock with current psychiatrists and considering the 'drugs are bad for schizophrenics mkay' guidelines of current psychiatry in the treatment of depressive symptoms but like with what the article says and with what I experience with alcohol and now weed I think I might hold my ground to push them to try it out.

 

Smoking weed without backfiring schizophrenic/depressive symptoms gave me kinda of confidence in trying (Es)Ketamine like it shows in the study. Weed and ketamine are not the same but what's the same about it is it's the same that in the sense when THC leaves the system ketamine will likely do the same and whatever my symptoms may will be it'll return to baseline after it leaves my body (but maybe with a nice 'trip' that also tackles my depression as a main goal of treatment).

 

Here in Europe the research of schizophrenia in general tends to move towards what now a days is like autism, a broad spectrum which you cannot pin down as simply schizophrenia, that's something really important for the treatment of the heavily stigmatized label of schizophrenics in the future, a personalized treatment.


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#10 StevesPetMacaque

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Posted 30 May 2020 - 08:21 PM

Ketamine's actions are mediated through indirect stimulation of mTOR (many studies); this is in fact a general property shared by NMDA antagonists. High dose magnesium may even provide a similar benefit by inhibiting calcium flux into neurons after NMDA stimulation, effectively acting as an antagonist (personal speculation).

 

My friend is a research scientist in this field; his suspicion is that the rapid synaptic rewiring following NMDA antagonism/mTOR stimulation allows the brain to eliminate learned "loops" (I forget the exact phrase) that maintain various mental illnesses in homeostasis.

 

Rapamycin, an mTORc1 inhibitor, paradoxically increased the benefits of ketamine (granted, single study). Glucosamine is also an mTOR inhibitor, and anecdotally helps with depression and anxiety. My guess would be that these antagonists increase mTORc1 sensitivity, thereby increasing the downstream effect of agonists.

 

TL;DR: If one were to use ketamine as an antidepressant, it may be beneficial to cycle mTOR inhibitors to increase sensitivity, and maybe to have a bolus dose of BCAAs a few hours before the treatment to maximize effectiveness.



#11 gamesguru

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Posted 01 June 2020 - 12:22 PM

There was an interesting study published a week ago on glutamate and ego-dissocation with psychedelics.

But I think what underlies the antidepressant effects is more likely dopamine related.

 

Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites.

 

Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects.

 

Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism

We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine’s antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery–Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

 

Dopamine D2/D3 but Not Dopamine D1 Receptors Are Involved in the Rapid Antidepressant-Like Effects of Ketamine in the Forced Swim Test

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine.

 

Same thing with Magnesium.

Evidence for the Involvement of the Monoaminergic System in the Antidepressant-Like Effect of Magnesium

Literature data has shown that acute administration of magnesium reduces immobility time in the mouse forced swimming test (FST), which suggests potential antidepressant activity in humans. However, its mechanism of action is not completely understood. Thus, this study is aimed at investigating the antidepressant-like action of magnesium and the possible involvement of the monoaminergic system in its effect in the FST. The immobility time in the FST was significantly reduced by magnesium chloride administration (30-100 mg/kg, i.p.) without accompanying changes in ambulation when assessed in an open-field test. The pre-treatment of mice with NAN-190 (0.5 mg/kg, i.p. a 5-HT(1A) receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), ketanserin (5 mg/kg, a preferential 5-HT(2A) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2 mg/kg, i.p., a non selective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist) 30 min before the administration of magnesium chloride (30 mg/kg, i.p.) significantly prevented its anti-immobility effect in the FST. Moreover, the administration of sub-effective doses of fluoxetine (10 mg/kg, i.p., serotonin reuptake inhibitor), imipramine (5 mg/kg, i.p., a mixed serotonergic noradrenergic reuptake inhibitor), bupropion (1 mg/kg, i.p., dopamine reuptake inhibitor) was able to potentiate the action of sub-effective doses of magnesium chloride. In conclusion, the present study provides evidence indicating that the antidepressant-like effect of magnesium in the FST is dependent on its interaction with the serotonergic (5-HT(1A) and 5-HT(2A/2C) receptors), noradrenergic (alpha(1)- and alpha(2)- receptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

 

Regulation of Anterior Pituitary D2 Dopamine Receptors by Magnesium and Sodium Ions

At D2 3,4-dihydroxyphenylethylamine (dopamine) receptors in anterior pituitary tissue, magnesium ions shifted receptors to agonist high-affinity states, but decreased the affinity of the antagonist [3H]spiperone. Conversely, sodium ions shifted the receptors to agonist low-affinity states, but increased the affinity of [3H]spiperone. Magnesium is proposed to stabilize the hormone-receptor-guanine nucleotide regulatory protein complex, whereas sodium appears to destabilize this ternary complex. Thus, magnesium and sodium appear to mediate their regulatory effects via a common component at the D2 dopamine-receptor ternary complex.

 

We see this dopamine activity in many substances.

 

In terms of classic psychedelics sharing this powerful effect, salvia is probably the closest to ketamine.  It is a short-acting dissociative-deliriant with fast-acting analgesic, antidepressant, and anti-addiction properties.  It can produce "afterglows" lasting days to weeks, and is generally well-tolerated and safe even above the therapeutic window.

 

Using 10 microM dopamine to define 100% stimulation, phencyclidine elicited a maximum incorporation of 46% in rat striata, with a half-maximum concentration of 70 nM for phencyclidine, when compared with 80 nM for dopamine, 89 nM for salvinorin A (48 nM for D2Long), 105 nM for lysergic acid diethylamide (LSD), 120 nM for R-modafinil, 710 nM for dizocilpine, 1030 nM for ketamine, and >10,000 nM for S-modafinil.

 

Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors

 

The in vitro testing which showed the binding affinity of salvinorin A (EC50 values of 89 nM) against the D2 High receptor and blockade by 10 μM S-sulpiride (an antagonist of DRD2) has resulted into the discussion of partial agonism of salvinorin A at D2 receptor (52). Moreso, computational studies have predicted CB1, CB2, or DRD2 as a potential targets of salvinorin A (53). In an in vivo test, the attenuation of neuropathic pain by Salvinorin A was blocked by CB1 and KOP antagonists (41). The inhibition of the effects of salvinorin A on colonic motility by antagonists of OPRK, CB1 and CB2 in vitro and largely by antagonists of OPRK in vivo (54) suggests mechanistic complexity in the activity of salvinorin A as against widely acclaimed KOP selectivity.

 

There are biphasic effects: the amount (threshold) of stimulation required to sustain ICSS behavior is increased (reflects decreased reward) immediately after an injection of salvA, but decreased (reflects increased reward) 24 hr later. The neurobiological mechanisms underlying the effects of salvA may be triggered by the inhibitory actions of KORs on DA release (Di Chiara and Imperato, 1988) and involve subsequent neuroadaptations in DA transmission. This proposal is designed to test how salvA modulates brain reward function and sensitivity to the highly addictive drug of abuse, cocaine. Also, the proposal tests how salvA modulates DA signaling at three independent but complementary levels: presynaptic DA release;postsynaptic DA receptor sensitivity;and postsynaptic cAMP-mediated signaling. In preliminary studies, we found that an immediate effect of salvA in the NAc is a decrease, followed 24 hr later by an increase, in the phosphorylation of extracellular signal-related kinase (P-ERK), a substrate for DA receptor-mediated cAMP signaling. In the NAc, ERK can activate CREB, a transcription factor associated with aversive states (Carlezon et al., 1998;Pliakas et al., 2001). Thus, salvA-mediated P-ERK might represent a novel upstream modulator of CREB function in the NAc and mediate the biphasic effects of salvA on reward function.

 

I would tread cautiously and seldomly on any of these substances.  They were called psychotomimetic for a reason.  Especially ketamine, anyone who takes to daily use turns into some poorly-spoken, unrefined monster reminiscent of a coke head.

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Edited by gamesguru, 01 June 2020 - 12:33 PM.

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#12 StevesPetMacaque

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Posted 05 June 2020 - 08:35 PM

There was an interesting study published a week ago on glutamate and ego-dissocation with psychedelics.

But I think what underlies the antidepressant effects is more likely dopamine related.

 

 

However, dopamine agonists don't generally produce long-lasting antidepressant effects, though this may certainly explain ketamine's popularity as a "party" drug (what kind of party it is when everyone is in a k-hole, I don't know...). mTOR-mediated neuroplasticity does. The recent research in this area is quite compelling.

 

Here is an article showing that dopaminergic effects are downstream of mTOR, specifically that rapamycin and mTOR deletion attenuate dopamine release.


Edited by StevesPetMacaque, 05 June 2020 - 08:39 PM.


#13 gamesguru

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Posted 06 June 2020 - 12:07 AM

However, dopamine agonists don't generally produce long-lasting antidepressant effects, though this may certainly explain ketamine's popularity as a "party" drug (what kind of party it is when everyone is in a k-hole, I don't know...). mTOR-mediated neuroplasticity does. The recent research in this area is quite compelling.

 

Here is an article showing that dopaminergic effects are downstream of mTOR, specifically that rapamycin and mTOR deletion attenuate dopamine release.

 

The article showing effects downstream of mTOR involves cocaine which acts rather as a DRA (reuptake inhibitor like an SSRI for serotonin).

 

The psychedelics in question (LSD, Salvia, Psilocybin) are partial agonists at D2/D3[1].  Mescaline and DMT have at least D1 effects, and I wouldn't be surprised if they can also treat anhedonic depression.  And Ketamine, we've already been discussing about.

 

The fact that they are partial agonists is important.  It means they hit saturation a lot sooner and lower, and sometimes they even produce the beneficial effects without the same adverse ones as full agonists.

partial%20agonists.JPG

ligands.jpg

 

Here's a glimpse into some new research being done on anhedonia and negative schizophrenia revolving around a promising D2/D3 partial agonist compound,

Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial

Background
Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms.

Methods
In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18–65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36.

Findings
Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (−8·90 points for cariprazine vs −7·44 points for risperidone; least squares mean difference −1·46, 95% CI −2·39 to −0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment.

Interpretation
Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia.

 

Cariprazine, a New, Orally Active Dopamine D2/3 Receptor Partial Agonist for the Treatment of Schizophrenia, Bipolar Mania and Depression

Abstract

Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

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#14 Laika

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Posted 28 June 2020 - 12:56 AM

I think there's something to be said for NMDA antagonists.

 

I've always felt like DXM was really helpful for depression at least for a little while.

 

Same  thing with agmatine







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