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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 18, 2013

A Short Rise Out of Depression

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Posted by Derek

Here's another one to file under "What we don't know about brain chemistry". That's a roomy category for sure, which (to be optimistic about it) leaves a lot of room for discovery. In that category are the observations that ketamine seems to dramatically help some people with major depression. It's an old drug, of course, still used in some situations as an anesthetic, and also used (or abused) by people who wish to deliberately derange themselves in dance clubs. Chemists will note the chemical resemblance to phencyclidine (PCP), a compound whose reputation for causing derangement is thouroughly deserved. (Ketamine was, in fact, a "second-generation" version of PCP, many years on).

Both of these compounds are, among other things, NMDA receptor antagonists. That had not been considered a high-priority target for treating depression, but you certainly can't argue with results (not, at least, when you know as little about the mechanisms of depression as we do). There are better compounds around, fortunately:

AZD6765, an inhibitor of the N-methyl-D-aspartate (NMDA) receptor, a glutamate signaling protein involved in cellular mechanisms for learning and memory, was originally developed as a treatment for stroke. It was shelved in 2000 by the drug's manufacturer, AstraZeneca, after phase 2 trials failed to show signs of efficacy. In the decade that followed, however, small clinical reports started to emerge showing that ketamine, an analgesic that also blocks the NMDA receptor, produced rapid responses in people who didn't benefit from any other antidepressants. And unlike most therapies for major depression, which usually take weeks to kick in, ketamine's mood-lifting effects could be seen within two hours, with a therapeutic boost that often lasted for weeks following a single infusion. Ketamine treatment also came with a number of debilitating side effects, though, including psychosis and detachment from reality. Fortunately for AstraZeneca, the company had a cleaner drug on its shelves that could harness ketamine's benefits with fewer problems.

Note that AZD6765 (lanicemine) has a rather simple structure, further confirmation (if anyone needed any) that things this size can be very effective drugs. Here's the clinical study that Nature Medicine news item refers to, and it makes clear that this was a pretty tough patient cohort:

This double-blind, placebo-controlled, proof-of-concept study found that a single intravenous infusion of a low-trapping nonselective NMDA channel blocker in patients with treatment-resistant MDD rapidly (within minutes) improved depressive symptoms without inducing psychotomimetic effects. However, this improvement was transitory. To our knowledge, this is the first report showing rapid antidepressant effects associated with a single infusion of a low-trapping nonselective NMDA channel blocker that did not induce psychotomimetic side effects in patients with treatment-resistant MDD.

More specifically, patient depression scores improved significantly more in patients receiving AZD6765 than in those receiving placebo, and this improvement occurred as early as 80 min. This difference was statistically significant for the MADRS, HDRS, BDI, and HAM-A. These findings are particularly noteworthy, because a large proportion of study participants had a substantial history of past treatment that was not efficacious. The mean number of past antidepressant trials was seven, and 45% of participants had failed to respond to electroconvulsive therapy.

The problem is the short duration. By one evaluation scale, the effects only lasted about two hours (by another less stringent test, some small effect could still be seen out to one or two days). Ketamine lasts longer, albeit at a cost of some severe side effects. This doesn't seem to be a problem with high clearance of AZD6765 (its PK had been well worked out when it was a candidate for stroke). Other factors might be operating:

These differences could be due to subunit selectivity and trapping blockade. It is also possible that the metabolites of ketamine might be involved in its relatively sustained antidepressant effects, perhaps acting on off-site targets; a recent report described active ketamine metabolites that last for up to 3 days. It is also important to note that, although trapping blockade or broadness of antagonist effects on the NMDA subunit receptors might be key to the robustness of antidepressant effects, these same properties might be involved in the dissociative and perceptual side effects of ketamine. Notably, these side effects were not apparent at the dose of AZD6765 tested.

If that last part is accurate, this is going to be a tricky target to work with. I doubt if AZD6765 itself has a future as an antidepressant, but if it can help to understand that mode of action, what the downstream effects might be, and which ones are important, it could lead to something very valuable indeed. The time and effort that will be needed for that is food for thought, particularly when you consider the patients in this study. What must it be like to feel the poison cloud of major depression lift briefly, only to descend again? The Nature Medicine piece has this testimony:

(David) Prietz, 48, a scheduling supervisor at a sheet-metal manufacturer in Rochester, New York, who has been on disability leave for several years, started to feel his head clear from the fog of depression within days of receiving AZD6765. After his second infusion, he vividly began noticing the fall foliage of the trees outside his doctor's office—something he hadn't previously appreciated in his depressed state. “The greens seemed a lot greener and the blue sky seemed a lot bluer,” he says. Although the lift lasted only a couple months after the three-week trial finished and the drug was taken away, the experience gave Prietz hope that he might one day get better. “I can't recall feeling as well I did at the time,” he says.

Fall foliage for Algernon? I hope we can do something for these people, because as it is, a short-duration effect is scientifically fascinating but emotionally cruel.

Comments (44) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System


COMMENTS

1. Vanzetti on January 18, 2013 9:24 AM writes...

Maybe you can use it as a daily drug anyway. The anticipation of the shot may itself make people feel better.

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2. Christian Bonanno on January 18, 2013 11:26 AM writes...

I am six years off medications that were treating my strongly genetic very terrible Bipolar Type I symptoms. I have accomplished by following a low glutamate diet and taking supplements that enhance the action of glutamate decarboxylase (GAD). GAD turns glutamate into GABA.

Blocking these neurotransmitters will always lead to side effects (lithium worked for my brain but gave me horrible psoriasis). Instead I feel they should be looking at limiting dietary sources and find ways of assisting the body clearing glutamate from the extracellular space.

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3. karl on January 18, 2013 11:58 AM writes...


The compound is probably chewed up by MAO.
Perhaps slowing down this degradation would extend its usefulness. Two methods that come to mind are.... N-methylation and/or placing a deuterium atom on the same carbon atom as the amine function. Both methods extend/increase the activity of amphetamine.

KL

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4. Anonymous on January 18, 2013 12:45 PM writes...

Memantine is partial trapping and has a better side effect profile, so it is not an impossible target. Does memantine improve depression scores?

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5. NJBiologist on January 18, 2013 12:55 PM writes...

It sounds like AZ set a really high bar for efficacy by choosing such a challenging patient population (seriously, 45% unresponsive to ECT? I didn't know that was possible). I'm glad to see they didn't take the easy road in trial design.

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6. pete on January 18, 2013 1:48 PM writes...

"low-trapping nonselective NMDA channel blocker"

Can someone explain this type of antagonism. What is it ? Thanks.

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7. luysii on January 18, 2013 2:00 PM writes...

Here's the problem with the study -- from the abstract

"Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects."

The results only achieve significance because of the low placebo effect in the group. In most studies of antidepressants, the placebo effect is around 33% (which is what they found for a therapeutic effect).

Nonetheless, it is a fascinating piece of work. NMDA blockers have prominent psychoactive effects. What would a similar study with other psychoactive drugs (cocaine or amphetamine) have shown.

It's always been fascinating to me that the antidepressants (tricyclics, SSRIs) are not drugs of abuse. No one breaks into drugstores to get them.

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8. pete on January 18, 2013 2:25 PM writes...

@6 I think these guys (below) answered my question. Apparently, "low-trapping" = deep within the NMDA channel.

Sobolevsky, A.I. & Yelshansky M.V. (2000) Journal of Physiology 526.3, 493.
The trapping block of NMDA receptor channels in acutely isolated rat hippocampal neurones.

"The effects of many drugs used in clinical practice for the treatment of a broad range of neurological disorders are based on NMDA channel blockade (Parsons et al. 1998). The most effective and tolerant drugs, such as memantine and amantadine, can be ‘trapped’ within the channel following dissociation of the agonist from the receptor (Blanpied et al. 1997; Chen & Lipton, 1997). When applied externally, these drugs can enter the open NMDA channel and bind to the ‘blocking site’ located deep within the pore. Occupancy of this site, however, does not prevent channel closure and the blocking molecule can remain within the pore for a relatively long time, being trapped by the closed activation gate. The subsequent opening of the gate allows the trapped blocker to leave the channel.

NMDA channels are blocked via the trapping mechanism by MK-801, ketamine and phencyclidine and its structural analogue N-ethyl-1,4,9,9á-tetrahydro-4áR-cis-4áH-fluoren- 4á-amine (NEFA) (Huetter & Bean, 1988; MacDonald et al. 1991; Dilmore & Johnson, 1998). All these compounds have slow binding/unbinding kinetics and their trapping manifests itself in use dependence of both blockade and recovery from it (Neely & Lingle, 1986). However, trapping is not apparent for blockers which bind to and escape from the channel with kinetics which are faster than the channel opening and closure, respectively."

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9. pete on January 18, 2013 3:05 PM writes...

@8 -- or not. More likely, lower time-occupancy of the "trap site".

(and pardon the monologue)

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10. Todd on January 18, 2013 3:58 PM writes...

@5: I think with MDD drugs, you need to really throw it at the worst of the worst. Since you have such high placebo response rates with most drugs, and since depression on the low-end is so nebulous, you need to throw the drugs through the ringer to get workable numbers. That's the only way you can tell if you have something real or not.

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11. Anonymous on January 18, 2013 5:05 PM writes...

Nmda receptor has glutamate and glycine as agonist, and you can competitively antagonise both. Or in this case, as it is an ion channel you can block the pore stopping anything getting through.

The channel cycles through states which include open and closed, and if the affinity of your blocker is high enough in the pore then it can close and open again but now the channel is blocked.

Magnesium is the endogenous blocker here and its removal lets the calcium permeable nmda receptor open. Memantine also binds here but in a more special way. Together with the obvious effects of pcp and ketamine it shows that small changes in binding here can lead to big differences in man.

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12. Chemist For Life on January 18, 2013 5:08 PM writes...

Some recent research suggests that ketamine-mediated blockade of NMDAR at rest deactivates a protein-kinase known as eEF2K (CaMKIII), resulting in reduced phosphorylation of eEF2K and de-suppression of translation of brain-derived neurotrophic factor (BDNF). These findings were reported in Nature 2011, vol 475, p91-95, and reported on in "GEN News Highlights" at the time.

The authors administered either "rottlerin" (which incidentally hits numerous targets including potassium channels, and several protein-kinases) and a compound by the name of NH125 (claimed to be somewhat selective for eEF2K...) to wt mice.

They observed that administration of either of these eEF2 inhibitors, proved sufficient to trigger antidepressant-like responses within 30 minutes in wild-type mice undertaking the forced swim test (FST) activity, and seemed to generate long-lasting antidepressant-related behavioral effects.

The authors went on to administer rottlerin to BDNF-knockout mice and tested FST behavior. Rottlerin was ineffective in BDNF-knockouts, suggesting that increased BDNF expression upon eEF2K inhibition is required to produce antidepressant-like behavioral responses.

This suggests that selective and brain-penetrant eEF2K inhibitors might be useful as rapid-onset antidepressants... However one thing that does concern me is seemingly eEF2K is also highly expressed in heart and skeletal muscle, suggesting that EEF2 phosphorylation may be particularly important in muscle physiology...something one might not want to mess with.

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13. NYCguy on January 18, 2013 5:50 PM writes...

Hello, I could not help but weigh in on this commentary. I was on a six-week trial of ketamine for depression. Two infusions per week. The trial ended just before Thanksgiving. I've had ups and downs since then, and feel "leveled off" at better-than-average. I rank myself on the depression scale at 7. I'm still getting used to "normal" having struggled with major depression since my late 20s. I'm now in my 50s. Don't dismiss this drug, please.

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14. NYCguy on January 18, 2013 5:50 PM writes...

Hello, I could not help but weigh in on this commentary. I was on a six-week trial of ketamine for depression. Two infusions per week. The trial ended just before Thanksgiving. I've had ups and downs since then, and feel "leveled off" at better-than-average. I rank myself on the depression scale at 7. I'm still getting used to "normal" having struggled with major depression since my late 20s. I'm now in my 50s. Don't dismiss this drug, please.

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15. Christian Bonanno on January 18, 2013 7:07 PM writes...

NYCguy, I don't think these guys will hear you. I mean I told them I no longer need psychiatric meds and they continue talking about things that matter little to the people who are suffering with these symptoms.

I am just curious to those who posted comments, why do you think that about my comment #2?

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16. Ibim on January 18, 2013 9:23 PM writes...

I am writing this comment from my hospital bed within the National Institutes of Health (Clinical Center) where I am an inpatient, having just participated in a ketamine study for MDD. My MADRS score was 38 prior to receiving ketamine. Within one hour of infusion I achieved near total remission of symptoms lasting about two weeks. I am enthused to see such vigorous discussion in the comments above, but as a sufferer for 30+ years, I want the medical community to embrace ketamine as a viable MDD treatment immediately, even while the research continues. Perhaps one day it will yield an effective and safe treatment with no side effects. But that will take years, and in the meantime people like me are suffering immensely, and dying in appalling numbers. I can't wait for the perfect NMDA antagonist to be synthesized and tested and approved. Ketmine's efficacy for severe MDD is already very well established and the side effects are tolerable. When something even better is available, I will happily switch meds. But for now, ketamine is quite literally a life saver, and it must be made available to those who desperately need it. Ease our suffering -- please.

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17. Dan on January 19, 2013 6:43 AM writes...

I'm one of those people who's taken ketamine in a dance party setting. Causes psychosis? That's simply untrue. It has some visual and auditory effects, but they're extremely short lived. To the extent you've heard otherwise, it probably benefits AZ, who will no doubt be looking for a molecule with the same effects that, unlike ketamine, is patentable.

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18. Dan on January 19, 2013 6:44 AM writes...

I'm one of those people who's taken ketamine in a dance party setting. Causes psychosis? That's simply untrue. It has some visual and auditory effects, but they're extremely short lived. To the extent you've heard otherwise, it probably benefits AZ, who will no doubt be looking for a molecule with the same effects that, unlike ketamine, is patentable.

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19. Vince on January 19, 2013 8:01 AM writes...

#7, luysii said, The results only achieve significance because of the low placebo effect in the group. In most studies of antidepressants, the placebo effect is around 33% (which is what they found for a therapeutic effect).

Absolutely. This is exactly the problem with all the ketamine trials thus far, they've lacked an active placebo. It's impossible to genuinely know what's what. NIMD's Carlos Zarate has previously said the same.

Because as of right now, we have ketamine (hallucinogenic) which has a large effect size in humans, AZD6765 (less hallucinogenic) which has a significantly smaller effect size in humans and MK801 which is (hallucinogenic) and I seem to recall at least one study from Poland showing no AD effect in an animal model. So, the question seems to be: is there an effect and some NMDAR idiosyncrasy to be teased out or do rats just not care they are in a drug trial?!

In an ideal world, we'll see a trial with a ketamine arm verse an active hallucinogenic one, verse a passive placebo one.

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20. James on January 19, 2013 8:22 AM writes...

What dose did you get NYCguy + Ibim? How strong would you say the acute effects are? I agree with Dan, it's probably already a more viable treatment than AZ would like. I expect most people would actually enjoy the 'side-effects' - people don't use it recreationally for nothing - while some would not. Of the people who don't, many would probably still find it worthwhile and should probably have the chance to find out if it's beneficial for them.

Christian (#15), this is a med-chem blog, most people here are interested in mechanisms and such and like talking about it. It's great you found something that works for you, and I agree we should put a lot more effort into studying non-drug treatments. I think the way we use drugs could also use a lot of refinement.

luysii - "It's always been fascinating to me that the antidepressants (tricyclics, SSRIs) are not drugs of abuse. No one breaks into drugstores to get them."

Have you tried them? They're not much fun, or even nice really.

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21. TX Raven on January 19, 2013 9:35 AM writes...

@ 15 and others

CNS diseases are very complex. Finding treatments is not easy. It is highly likely that a multi-prong approach is needed, which might include diet control, psychotherapy, and (last but not least), medicine(s).

Creating a medicine is a labor of love, and lots of decent, caring, smart, and extermely dedicated human beings spend their entire careers looking for such drug.

For sure, our industry has made mistakes and not everyone is a saint. But most of us are not villains, and actually are on your side. Your support and encouragement is part of what drives us back to the lab everyday.

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22. Will on January 19, 2013 10:21 AM writes...

TX Raven, A quote from a brilliant doctor who I knew in medical school; "The only diseases that are complex are the ones we do not yet understand, the ones that do not yet reveal a common denominator to the varied expression of symptoms."

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23. sgcox on January 19, 2013 12:25 PM writes...

@22 Will. Please name "not complex" diseases. Ok, infections - locate the agent then: find vaccine, antibiotic, protease inhibitor, etc. Ok, monogenic diseases like cystic fibrosis or Down syndrome. What else ? Cancer, Alzheimer (and the rest of CNS), Metabolic syndrome, autoimmune ? Are these the "only" diseases ?

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24. paperclip on January 19, 2013 12:27 PM writes...

@7: The low placebo rate may be explained by the fact that the patients are people who have not responded to multiple antidepressants, and even in many cases to ECT. It is not likely among them that depression will lift on its own, nor that they will respond just from the hope of trying something new.

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25. Ibim on January 19, 2013 2:08 PM writes...

James: My dose was .5mg/kg (35mg total) delivered over 40 minutes. This appears to be the standard dose in ketamine trials for MDD, and it is considerably lower than other uses such as anesthesia or pain management. I experienced a mild dissociative effect but remained lucid and able to converse with medical staff. It was a calm and relaxing experience, entirely tolerable. Other patients received the same weight-based dosage and had effects of similar or lesser intensity, with some reporting only a mild dizziness with no dissociative effect. Although it was pleasant, it was completely ancillary to the relief of MDD, and I am ambivalent as to whether I ever experience that effect again.

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26. Beaucoup on January 19, 2013 3:07 PM writes...

Derek wrote that "a short-duration effect is scientifically fascinating but emotionally cruel."

That may be true for some patients, but not for all. I've struggled with major depression since my 30s, and I *live* for those rare moments when the fog lifts, even if they are merely moments. For me, a year with twenty minutes of clarity and feeling well beats the hell out of a year without it. If I didn't have the hope of having such moments, well...

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27. Derek Lowe on January 19, 2013 5:47 PM writes...

#26 Beaucoup

I'm glad to hear that. I've never suffered from depression (fortunately), so it seemed to me that it would be rough to go through these brief respites. But I can definitely see your point! Here's hoping that they can be made to last longer.

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28. ya_anon on January 19, 2013 10:08 PM writes...

I've been dosing myself on ketamine 3-4 times/month for about 15 years now, and have also observed hundreds of experiences of other users. As a fan of this blog for many years, perhaps I can help shed some light on effects relevant to the med-chem crowd.

I usually describe ketamine as the weirdest recreational drug, with three distinctly different effects at different doses (the below are nasal insufflated dosage; IM experiences are about 2-3x as strong per mg):

* low dose, 10-20 mg or a "bump": slight wooziness, equivalent to a beer or two. Can walk, talk, dance, and even drive (not recommended for beginners, and nothing I'd ever do, but I've seen it done and it wasn't a scary experience. driver would have easily passed a roadside test).

Reaction time is slightly higher, somewhere on the order of 300ms instead of 150ms, which is still quite a bit faster than most 60-70 yo drivers. As studies have shown, people on ketamine actually have slightly better decision making skills with this increased reaction time, likely due to increased integration time for decision making. This fits with my experience: my writings while under the influence generally stand up remarkably well to review the next day, unlike drunken ramblings.

First timers of a low dose will be disoriented a bit and may not trust their motor skills, but after a half dozen or dozen experiences, people universally get comfortable with slightly distorted perceptions, and can appear perfectly normal. A group of a half dozen folks can be standing in a circle at a party, all six dosing, and if you didn't know these people already you might not even realize that they're on a drug.

I think the mild acute effects, which get less disorienting with familiarity, will make it viable to use low-dosage ketamine for long-term treatment of depression. Sure, it should get the "do not operate heavy machinery" label from the pharmacy, but the effects are less than a drink or two, and on par with a 5mg hydrocodone (vicodin).

* medium dose, 50-100 mg line(s) (insufflated): dissociative effects stronger, sitting or lying down only with little desire to move, significantly slower speech and comprehension (~500ms). Pronounced visual and auditory effects. Drug usage is very obvious, with light open eye visuals, and very pleasant effects.

* high dose "k-hole" (~500 mg nasal, 100-150 mg IM), anesthetic dose, effective paralysis, catatonic, open eye visuals, terrifying and/or tremendously interesting depending on users mindset. Only psychonauts go here; it's recreational, but not necessarily fun. Going to even higher doses are simply anesthetic with little memory of the experience.

With a 15-20 minute half life for IM/IV usage (it appears longer for nasal because of slower absorption via that route), the 35 mg dose administered over 40 minutes mentioned above would fall into the light effects category.

A few other random notes:

* In order to achieve the same effects on the next day after using ketamine, the dosage has to be roughly doubled. On a third day in a row, 4x-5x as much would have to be taken. It takes about 7 days before the same dose of ketamine will have the same effect. Residual effects of even a 50 mg nasal dose are significantly decreased after 3 days, and are mostly gone after 10 days. For a few years I dosed almost every Sunday, and could feel myself become less level-headed if I missed a week. Nowadays, I'll usually dose every 5-8 days to keep an even keel.

* Ketamine has both R- and S+ enantiomers. The R- enantiomer seems to cause stronger cravings for immediate re-dosing. The S+ is both more active (1.5-2x stronger per mg), but causes more of the dissociative effects. Users are less likely to move after taking S+, shifting them into the "medium dose" effects noted above, and is still the case when comparing S+ to 2x the dose of R-. Pharmaceutical preparations of ketamine from different vendors apparently have different ratios of R- to S+, and the ratios are not published. Some people prefer different ratios for recreational use, but everyone I've spoken to prefers racemic mixes to pure S+ or R- (unless they're completely broke, in which case they opt for S+ because it's more bang for the buck, the same reason malt liquor is popular in low-income neighborhoods). It really feels like a polydrug experience with the two enantiomers combined.

* There is significant cross-tolerance with opiates. If a short acting opiate is taken one day, and ketamine the next, the result is a very different experience from the usual ketamine experience. Ketamine also hits opioid receptors, and with this portion of the experience knocked out it's a lot less interesting. I've only done this a handful of times, but if I had to guess, I'd say that the S+ enantiomer effects are blocked more strongly than R-.

* Drug trivia: the name "k-hole" comes from the fact that the inner ear and/or gravity forces felt on the body are no longer being processed by the brain at close to anesthetic doses, which can make you feel like you're falling down a very deep hole. Experienced users can intentionally manipulate what direction feels "up" at k-hole doses and can imagine a roller coaster complete with g-forces experienced in banking and loops, something not possible on other psychedelics. The fact that it can be terrifying, with immersive visualizations only semi-controllable, is why ketamine is co-administered with a benzodiazepine when used anesthetically.

I'm happy to answer any questions.

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29. Anonymous on January 20, 2013 12:30 PM writes...

So what about ketamine in AD?

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30. luysii on January 20, 2013 1:34 PM writes...

@24 Paperclip -- "The low placebo rate may be explained by the fact that the patients are people who have not responded to multiple antidepressants, and even in many cases to ECT."

That certainly is a plausible explanation, and one that I considered, as these were very treatment resistant cases. But it will remain only a plausible explanation until the drug is compared to an active placebo. The study was effectively not a blinded one.

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31. Devil in the Drain on January 20, 2013 10:51 PM writes...

@7 luysii, @24 Paperclip, @30 luysii -- Low placebo effect seems perfectly plausible. For one thing, as Paperclip points out, patients in this population have already experienced many treatments that didn't work; that's going to militate against placebo effect.

For another, placebo effect is increased if the subject expects the treatment to work. We're primed to think that pills can reduce depression -- pills for depression are heavily advertised and are all over popular culture. And most of us have at least heard of ECT. But an injection for depression? If that seems odd or unlikely to the general population, there will be less placebo effect.

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32. Gaspode on January 21, 2013 4:04 AM writes...

A while ago i worked on schizophrenia, where we targeteted the GlyT1 receptor to increase NMDA activity. Interestingly the compounds were used to counter the effects of Ketamine and PCP (lab dogs).
So schiziphrenia has a too low NMDA activity and dpression a too high activity?
Its probably not that easy but appearantly you need a very specific NMDA activity, which could be one reason for the varying effectiveness of CNS drugs.

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33. CP_Future on January 21, 2013 5:38 AM writes...

GLYX-13 will be the first next generation anti-depressant.

"These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of ‘metaplasticity’ by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression."

http://www.nature.com/npp/journal/vaop/naam/abs/npp2012246a.html

- Onset within 24 hours
- Effect duration of at least 7 days per single dose
- Effect size of one dose was nearly double the effect size of standard anti-depressants treatment for 4 to 6 weeks
- Implications for the treatment of Alzheimer's Disease and other neurologic disorders

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34. Ibim on January 21, 2013 9:35 PM writes...

ya_anon, thank you very much for your post. I found a physician willing to employ intranasal ketamine as an ongoing anti-depression treatment, pending a diagnostic exam, which will happen as soon as I am discharged from NIH. There are very few places to learn about the practical aspects of repeated ketamine usage, such as tolerance and effect intensity, from an informed source. So your post is extremely helpful. Do you mind sharing your reasons for taking ketamine? Is it strictly recreational, or is there a therapeutic benefit (i.e., keeping an "even keel"), or both? Thanks.

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35. Anonymous on January 22, 2013 2:54 PM writes...

@34 Ibim Did you have a similar experience to that described by ya_anon?

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36. Xplodyncow on January 22, 2013 3:03 PM writes...

I hope we can do something for these people, because as it is, a short-duration effect is scientifically fascinating but emotionally cruel.


It sucks to feel better -- to have hope again -- only to have it rapidly, mysteriously dissolve and then be utterly unable to reclaim any semblance of "feeling good."


Although Beaucoup is right --

a year with twenty minutes of clarity and feeling well beats the hell out of a year without it. If I didn't have the hope of having such moments, well...

-- it is, however, a little difficult to cram a year's to-do list into a mere twenty minutes. :-)

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37. adsa on May 30, 2013 10:39 AM writes...

Thanks to ya_anon for the details concerning Ketamine.
Can anyone advise me on the particulars of Ketamine treatment such as dosing and scheduling of treatments for severe treatment resistant depression? Another question I've been unable to find a answer to is whether individuals become tolerant to lower doses over time requiring higher doses? What are the merits of dosing Ketamine intranasally vs IV or IM administration? Lastly, ya_anon indicated that he doses regularly? Does anyone know about longer term consequences?

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38. nitram on June 2, 2013 11:50 AM writes...

Yeah, Pigpharma are really nice. Pfizer destroyed Nardil at 2003. This is what I call evolution by the way. It took until now before some probably worthless STAR*D trial showed that Mirtazapine + Venlafaxine would yield the same benefit as low dose parnate..
Yes, they are so sweet and intelligent people doing their outmost to make themselves superflous, selective results handed to FDA, knowing of sideeffects (zyprexa) but not saying anything because their sale will cover the courttrials. Registering 20 daughtercompanies, releasing some speculative drug and then just scratching the 0x and sell some other junk by some other. Oh and don't forget the evergreening.. what a charmful bunch of people there must be in the bigpharma corps.. I would say sociopaths? or is it perhaps something worse?

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39. nitram on June 2, 2013 11:52 AM writes...

Did they say something about Iatrogenic SSRI anhedonia btw? or PSSD, or something other fun they just brush of because it's just people that experienced those things and not something that they calculated and put unto a paper themselves.

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40. Dee Debeaumont on June 21, 2013 3:48 AM writes...

I am not sure if my subscription info came through to you nor am I clear how to pay the $5.00.
Thanks this is really a wonderful idea if I'm able to connect! Judy

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41. nnuubzbnlofi on June 23, 2013 4:39 PM writes...

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42. ugtpkzwqblik on June 26, 2013 12:55 AM writes...

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43. Karl on October 19, 2013 10:14 PM writes...

A short term duration effect is not emotionally cruel. Absolutely no relief is cruel.It is a known fact in most medical circles that opiates can give a person suffering from severe depression almost instant relief even though temporary because of tolerance and addiction issues.Can you imagine the number of suicides that could have been prevented if many of those people had temporay relief just that last day or night on earth? They might otherwise still be here.

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44. Starsky on December 21, 2013 3:39 AM writes...

In my case, dozens of SSRIs, TCAs, MAOIs, CBTherapy, & electro convulsive therapy all failed to treat my debilitating, near suicidal depression. At last a doctor was found who was actually willing to try it(previous doctors just flatly refused to consider it). The depression completely lifted within 30 minutes. It was temporary, but that was because of the half life, not lack of efficacy. Just because you can't see what is causing the pain doesn't mean the patient isn't in intense pain. Having been through a lot of physical pain & brutal stress to the body, they still are not as bad as losing the ability to experience any good emotion. Ketamine s keeping me alive, although, it is becoming less effective because of tolerance.

It truly is sad to watch all the needless suffering, because much of the medical community won't embrace cutting edge medicine. I hope these new drugs come out as quickly as possible. Let the suffering patient decide if they have a shot at relief, not the FDA, DEA & big government. All they do is slow down the development of these drugs by making them so expensive to get through trials & approval.

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