Depression is a Form of Pain and Ketamine May be a Cure if One Can Make It Last

Recent studies has demonstrated short infusions of ketamine can quickly and perhaps completely remove depression for up to 1 week (who says there is no happy pill?). Infusions for neuropathic pain can give significant improvements for time periods as well. Ketamine could be a Miracle Drug For Pain and Depression.   How To Make It Last and Make it Easy is discussed.

WARNING at end.

Question is, why does it give rapid relief of depression?

  • Most obvious conclusion is that NMDA inhibition of glutamate pain circuits directly modifies depression:
    Current Psychiatry Reports
    Volume 9, Number 6, 467-474, DOI: 10.1007/s11920-007-0063-1
    The role of glutamate in mood disorders: Results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects
    Sungho Maeng and Carlos A. Zarate  abstract here
  • Blocking AMPA  (NMDA competing) receptors “attenuated”(lessened) its antidepressant effects suggesting it is the increased activity of competing AMPA receptors that might do the job:
    Biological Psychiatry Volume 63, Issue 4, 15 February 2008, Pages 349-352
    Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors
    Sungho Maenga, Carlos A. Zarate Jra, Jing Dua, Robert J. Schloessera, Joseph McCammona, Guang Chena and Husseini K. Manji,  abstract here
    “NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.”
  • Recently it has been found to quickly grow new brain connections: 
     – by rapidly activate the “mTOR pathway”,
    –  leading to increased dendritic synaptic signaling proteins
    –  which increases number and function of new dendritic spine synapses
    –  in the prefrontal cortex of   rat mTOR-dependent synapse formation
    Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, and Ronald S. Duman
    Science. 2010 August 20; 329(5994): 959–964.  free article here
  • A novel explanation suggested that its rapid effects could be the inhibition of brain cytokinins:
    Does ketamine exert a fast-acting antidepressant effect via inhibition of pro-inflammatory cytokines?
    Yang JJ, Zhou ZQ, Yang C. (And reply by J I R I HORACEK et al)
    Psychol Med. 2011 Aug;41(8):1787 no abstract
    “ketamine has been recommended for patients with sepsis because it may inhibit the endotoxin induced pro-inflammatory cytokines including IL-1 and TNF-a both in vitro and in vivo (Taniguchi & Yamamoto, 2005).”
    There also appears facilitation of 5-HTP in the hippocampus that inhibits TNF
  • A newly released review of Ketamine in NATURE describes “rapid synthesis of brain-derived neurotrophic factor” involved in the fast acting effects
    Nature. 2011 Jun 15;475(7354):91-5. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
    Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM.  abstract here

Ketamine is a general anesthetic. It has been known for years that people post-operatively are less depressed after surgery. Here is a recent example:

Small-Dose Ketamine Improves the Postoperative State of Depressed Patients
Akira Kudoh, MD*, Yoko Takahira†, Hiroshi Katagai, MD†, and Tomoko Takazawa, MD
ANESTH ANALG 2002;95:114–8       Free article here

Treating Depression:

Successful trial in depression was first noted in 2000:

Biol Psychiatry. 2000 Feb 15;47(4):351-4.
Antidepressant effects of ketamine in depressed patients.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH.
Abraham Ribicoff Center Clinical Neuroscience Research Unit of the Connecticut
Mental Health Center, New Haven 06519, USA.  free article here

  • 0.5 mg/kg in 50 mls saline run in over 40 minutes
  • relief depression within 72 hours

Good trial on major depression was in 2006:

  • Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
    A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant
    major depression.
    Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA,
    Charney DS, Manji HK.     free article here
  • 0.5 mg kg over 40 minutes  – initially and in 1 week
  • “Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.” – 35% got it last 1 week.

This was confirmed in a case the following year:

Intravenous ketamine therapy in a patient with a treatment-resistant major depression
Michael Liebrenza, Alain Borgeatb, Ria Leisingera, Rudolf Stohlera
SWISS MED WKLY 2007 ; 137 : 234 – 236  free article here

  • treatment resistant case
  • intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes
  • “Ketamine not only seems to have strong antidepressant effects but also to act very swiftly. These actions were unaffected by an alcohol or benzodiazpine dependence”
  • Only gave 7 day results.

This was confirmed in a trial with Bipolar cases:
Arch Gen Psychiatry. 2010 Aug;67(8):793-802.
A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK,  Zarate CA Jr.
free article here

  • ketamine hydrochloride (0.5 mg/kg) on 2 test days 2 weeks apart. .
  • Seventy-one percent of subjects responded to ketamine and 6%  responded to placebo at some point during the trial.
  • One subject receiving ketamine and 1 receiving placebo developed manic symptoms.
  • well tolerated with dissociative “unreal feelings” during 40 minutes.
  • “CONCLUSION: In patients with treatment-resistant bipolar depression, robust and  rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.”

Subjects with a family history of alcohol dependence seem to benefit well:
Family History of Alcohol Dependence and Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist
Laura E. Phelps, Nancy Brutsche, Jazmin R. Moral, David A. Luckenbaugh, Husseini K. Manji, and Carlos A. Zarate Jr.
BIOL PSYCHIATRY 2009;65:181–184  free article here

Suicidal subjects can be relieved of suicidality easily:
G.L. Larkin1, A.L. Beautrais1, R.R. Turelli1, G. Sanacora2, S. Powsner3, M. Lippmann1, J. Krystal
European Psychiatry, Volume 26, Supplement 1, 2011, Page 1607

  • IV bolus of ketamine (0.2 mg/kg) over 1-2 minutes
  • Cut suicidality scores from 3.9 to 0.6 and was still good at day 10

    Unfortunately, for many ,the relief did not last more than 3-7 days. This is very reminiscent of the relief of pain one can get with IV lidocaine:

    IV lidocaine my experience:

    1)      Short infusion not wingy – good for 1-3 days
    2)      1 hour or less infusion some wingy – good for up to 1 week (like above ketamine protocols)
    3)      Prolonged infusion – 30 hours –not so wingy – residual effects for up to a month
    4)      5 day infusions – progressively more wingy – relief for month

    Attempts with ketamine to obtain persistent relief for depression include:

    6 infusions on day 1, 3, 5, 8, 10, 12 over 2 weeks

    Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression
    Marije aan het Rot, Katherine A. Collins, James W. Murrough, Andrew M. Perez, David L. Reich,
    Dennis S. Charney, and Sanjay J. Mathew
    BIOL PSYCHIATRY 2010;67:139–145  free article here

    • IV – 0.5 mg/kg unless “distressing agitations or hallucinations” whereupon 0.4 mg/kg could be used – never had any problems though
    • Had to get a response to first infusion >50% reduction depression after infusion to be in study
    • days 1,3,5,8,10,12 over 2 weeks
    • mean duration after cessation of therapy was approximately 3 weeks

     IV ketamine 5 days as inpatient

    PAIN MEDICINE Volume 7 Number 1 2006 92–95
    Two Case Studies of Patients with Major Depressive Disorder Given Low-Dose (Subanesthetic) Ketamine Infusions
    Graeme E. Correll, BE, MBBS, Dip, Obst, FANZCA,* and Graham E. Futter, MB, ChB, MMed (Psych), FRANZCP    abstract here

    First case:  IV – “commenced at 15 mg/h  (0.15 mg/kg/h) and titrated to 27.5 mg/h (0.27 mg/kg/h).” (Heady sensation). Stayed good, discharged at 5 days and controlled with citalopram 40 mg.

    2nd case: ketamine –

    • started at 20 mg/h (0.2 mg/ kg/h) and titrated to 30 mg/h (0.3 mg/kg/h) (just heady).
    • 5 day treatment and discharged
    • 2.5 month returned – 0.3 mg/kg/h for 5 days – change took further 10 days to be apparent
    • still fine on lithium carbonate 500 mg/day

    IV ketamine 3 times weekly – Monday, Wednesday and Friday – similar to an ECT timing given with antidepressants

    A Case of Sustained Remission Following an Acute Course of Ketamine in Treatment-Resistant Depression
    James W. Murrough, MD; Andrew M. Perez, MD, Sanjay J. Mathew, MD, Dennis S. Charney, MD

    • 45 year old treatment resistant case – female
    • 3-times-weekly (Monday, Wednesday, Friday) intravenous infusions (0.5 mg/kg over 40 minutes) for 2 weeks
    • 3 months remission
    • desvenlafaxine 50 mg daily, aripiprazole 10 mg daily, and modafinil 200 mg daily used but patient had some livable depression

    What protocols can one find re: ketamine use in chronic pain?

    Short infusions seems to do nothing:
    For example, in a study by Schwartzman  was administered IV at .35 mg/kg over 4 hours with good analgesic effect in patients with complex regional pain syndrome (whereas shorter durations or bolus infusions were generally not effective in this population (personal communication between JWM and Dr. Schwartzman).”  [In Reply to: Dose- and Exposure-Response to Ketamine in Depression. James W. Murrough, et al  BIOL PSYCHIATRY 2011;70:e11–e12]

    One protocol day ketamine over 1.5-3 hours:
    Efficacy of IV ketamine to treat pain disrorders in the pain clinic
    J Krusz, J Cagle, S HalL
    The Journal of Pain, Volume 9, Issue 4, Supplement 2, April 2008, Page 30 no abstract

    • 0.4mg ketamine/kg was administered by IV infusion  over 90 minutes. If there were no side effects, another 0.4mg/kg  was administered over the same time.

    In companinon article a 3rd set would be used in resistent migraine:
    Efficacy of IV ketamine in treating refractory migraines in the clinic
    J Krusz, J Cagle, S Hall
    One article using continuous infusion over a day
    same protocol except would de a 3rd set if no undesirable effects

    Ketamine in the management of chronic pancreatic pain 
    Journal of Pain and Symptom Management, Volume 26, Issue 6, December 2003, Pages 1071-1072
    Stephen Mannion, Tony O’Brien

    • got some benefit from 0.8 mg/kg/hour (100 mg over 24 hours – must have weighed only 51 kg)
    • better pain relief (referenced too) from 0.2 – 1.5/mg/kg hour though they went up to only 0.3 mg/kg/hour
    • initially looks like you could get relief some from 0.1 mg/kg/hour and then gauge requirements after.
    • Irritation at subcut site will mean pulling and placing butterfly in new spot as needed.


    Repeated exposures are necessary:

    5 day IV infusion:

    Pain. 2009 Oct;145(3):304-11.
    Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.
    Sigtermans MJ, van Hilten JJ, Bauer MC, Arbous MS, Marinus J, Sarton EY, Dahan A.
    free article here

    • procedure – “drug infusion rate started at 1.2 lg kg1 min1 (or 5 mg/h for a 70-kg patient) at 8 AM on day 1 and was titrated at regular intervals (max. thrice daily) to a maximum of 7.2 lg kg1 min1 (or 30 mg/h for a 70-kg patient). The infusion rate was increased when pain relief was insufficient (based on reported visual analogue pain scores reported at 2 h (day)–8 h (night) intervals) and side effects were acceptable to the patients.  If side effects were unacceptable but pain relief insufficient, the infusion rate was decreased one step for one interval and subsequently increased again. In case of full pain relief, the infusion rate was not increased further and was kept constant until the end of the treatment period. The treatment ended on day 5…”
    •  had a control group
    • Initially cut pain in 1/2 : “The lowest pain score was at the end of week 1: ketamine 2.68+/-0.51, placebo 5.45+/-0.48.”
    • Lasted 12 weeks – “In week 12, significance in pain relief between groups was lost (P = 0.07).”
    • side effects were mostly mild”mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P<0.001)”;  2/40 cases had to stop the 5 day infusion.
    • took a hit for saying this was long term relief when only 12 weeks and wrote subsequent article:
      Pain. 2010 May;149(2):409-10; author reply 410-1.
      What is considered long-term pain relief in chronic pain management? Re:
      Sigtermans et al., Pain 2009;145:304-311.
      Kapural L, Stanton-Hicks M.
      Comment on Pain. 2009 Oct;145(3):304-11.

     Repeated IV’s:

    An Unusual Case of Chronic Neuropathic Pain Responds to an Optimum Frequency of Intravenous Ketamine Infusions
    Alison C. Mitchell, MB ChB
    J Pain Symptom Manage 2001;21:443–446.  abstract here

    • Severe post amputation case
    • Initially,  2 infusions ketamine, 30 mg in 500 ml saline over 4 hours – certainly for chronic depression, this would be too little over 4 hours to do anything and indeed it did little – 3 day relief
    • 3rd infusion – infusion of 50 mg of intravenous ketamine in 500 ml saline was given four weeks after the initial dose
    • Further infusions –  dose  60 mg in 500 ml saline over 3 hours – three infusions per week. – patient’s analgesia improved markedly with the increase in frequency of the ketamine
    • After two weeks of 3 weekly infusions, the frequency of infusions was reduced to twice a week.
    • The dose of ketamine was also reduced to 40 mg as the patient had become transiently hypertensive towards the end of infusion no. 11
    • Then had a flare requiring 3 x a week ketamine
    • Following weekly infusions of intravenous ketamine, with recurrence of pain approximately 24–48 hours  prior to the next infusion managed by opioids

    This is a visual of treatment plan:

    • It certainly looked like 3 X week was needed to capture control and relapses have to be expected

    IV is difficult but a clever technique of three 10-15 minute IM injections was devised by one author for pain

    John Claude Krusz, PhD, MD, Stephanie Hall, BS, MPH, Jane Cagle, LVN
    Anodyne Headache and PainCare, Dallas    free poster here

    • 10 chronic headache and 7 chronic radiculopathy cases
    • Pulse oximetry (very reassuring should subject become drowsy)
    • 0.3-0.4 mg per kilogram of ketamine was used. The average dose of ketamine was 68.3 mg.
    • “The dose was injected in three to four portions intramuscularly, with 10 to 15 minutes between injections”. Injections are nearly painless as drug causes no irritation.
    • Shots repeated in 24 hours if return symptoms;  One patient received 11 sets of injections for frequent refractory migraines.
    • Neuropathic pain relief was good


    However, Blood levels Curves of IV and IM are different: (IV 0.5 mg/kg over 40 min)

    Addendum – wrote Paul Glue who confirmed this was modelled after IM Gluteal injection only…

    Deltoid/Shoulder muscles have quicker absorption. EG.:



     Antiarrhythmic Effectiveness of Intramuscular Lidocaine: Influence of Different Injection Sites
    The Journal of Clinical Pharmacology February-March, 1974; 77-83

     BIOL PSYCHIATRY 2011;70:e9–e10.
    Dose- and Exposure-Response to Ketamine in Depression.
    Paul Glue, Abhishek Gulati, Martin Le Nedelec, Stephen Duffull

    Addendum – this was a modelled estimate and there can be some problems with that:
    Reply to: Dose- and Exposure-Response to Ketamine in Depression
    James W. Murrough, James M. Gallo, Katherine A. Collins, Marije aan het Rot, Dennis S. Charney
    BIOL PSYCHIATRY 2011;70:e11–e12

    They found that there could be considerable variability in absorption. I found in one case considerable more effect  from IM deltoid than over 20 minutes IV.

    Dose- Response
    the dose IM for antidepressant effect:(but this is with one dose) from slow acting buttock IM injection – I suspect with deltoid injection not need as big a dose…


    Hazards of shots include:

    • brief hypertensive and tachycardia
    • occasional headache
    • Spaciness, unreality, depersonalization – almost all
    • Agitation, hallucinations – uncommon but could be relieved by Midazolam 0.5 mg iv and should be available for use (may need 1 mg+)
    • Nausea – one subject got nauseated and took and antinauseant orally
    • Hypotensive – one case was given less dose the next time
    • It has been pointed out that mTOR upregulation can accelerate cancer growth
      Be Prudent of Ketamine in Treating Resistant Depression in Patients with Cancer
      Chun Yang, Zhi-qiang Zhou and Jian-jun Yang. Journal of Palliative Medicine. May 2011, 14(5): 537-537  free article here
    • When given to bipolar cases one became hypomanic(though one on placebo did too) – maybe make sure  bipolar subjects on a mood stabilizer before trying meds – at least some risperidone

    addendum – one case of hypomania high-lighted:
    BIOL PSYCHIATRY 2011;70:e13–e14
    Induction of Prolonged Mania During Ketamine Therapy for Reflex Sympathetic Dystrophy
    Amy K. Ricke, Riley J. Snook, Amit Ananda

    • Ketamine given IV continuous for at least 5 days in intensive care unit (vague if longer) [ can one get any sleep in intensive care?]
    • concomitant  duloxetine 20 mg and mirtazapine 45 mg were restarted on 3rd IV
    • duloxetine was continued even in hypomania
    • Comment – Not convinced ketamine did this – stress and lack of sleep in intensive care, and two antidepressants could have been enough to tip someone over. One must not also forget the high rates of bipolar in chronic pain ie.- in fibromyalgia repeated studies have found 25-26% rates

    Long term chronic use is associated with kidney and bladder issues:

    • Many of the bladder cases were with street drug  use on a constant basis. – could have been contaminants.
    • Any non- street drug cases were in severe chronic pain cases with long term continual use
    • The above one case of early IC was actually a bladder irritation from constant use:

    Urology. 2008 Jun;71(6):1232-3. A pediatric case of ketamine-associated cystitis.  Grégoire MC, MacLellan DL, Finley GA.

    [16 year old girl]”After unsuccessful trials of multiple medications, oral ketamine was added to her regimen, and she reported a significant decrease in her neuropathic pain. The dose was quickly titrated to 8 mg/kg per day. After 9 days on ketamine, she started to develop dysuria, frequency, urgency, and incontinence. The urinalysis was normal and the urine culture was negative. The symptoms decreased after decreasing the ketamine dose to 6 mg/kg per day and completely disappeared at 2 mg/kg per day. The ketamine was eventually stopped following improvement of the CRPS symptoms. A few months later, as her pain was flaring up again, we restarted ketamine and the urinary symptoms reappeared at a dose of 5 mg/kg per day. Similar to the first episode, the cystitis symptoms stopped after lowering the ketamine dose to 3 mg/kg per day. A cystoscopy was not performed, as the patient opted not to have invasive investigations.”

    • This early version appeared with continual use, was dose- related, and was reversible by stopping the drug

    There are some concerns of cognitive dysfunction with long term use but these occur with constant use.  In  repeated infusion study:

    Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression
    Marije aan het Rot, Katherine A. Collins, James W. Murrough, Andrew M. Perez, David L. Reich,
    Dennis S. Charney, and Sanjay J. Mathew
    BIOL PSYCHIATRY 2010;67:139–145   free article here

    found “NO increases in “poor memory”, “trouble concentrating” or “word-finding difficulties”, suggesting that ketamine did not have any persistent cognitive impact as per self report.”

    Another article re Congitive dysfunction, followed “reactiaonal users”  and found “Cognitive deficits were mainly observed only in frequent users”

    Addiction. 2010 Jan;105(1):121-33. Epub 2009 Nov 17.
    Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study.
    Morgan CJ, Muetzelfeldt L, Curran HV.  abstract here

    What about “Ketamine Psychosis” – reported in one case given it for geneneral anesthesia at 300 mg – ten times the doses used by me. The above longitudinal article did find “greater dissociative symptoms in frequent users”.  None of the repeat administration articles for depression found any such complications but I imagine they didn’t include frequent drug users in their study. My understanding so far, is to avoid schizophrenic cases, drug users, avoid very high doses and avoid usage over several months.

    Comment –

    It looks like

    • I prefer Deltoid IM – faster and more predictable responses – no problem of inadvertantly giving into fat rather than muscle – there is no irritation with ketamine.
    • Start low IM <0.4 mg/kg – maybe 10 mg each  in divided doses (every 10  – 15 minutes) and work up
    • for full therapeutic effect 0.4- 0.7 /kg IM divided in 3 doses given 10 minutes apart  – dose cut if agitation etc. – I, however,  have been sticking to max 30 mg as an outpatient
    • every other day Monday, Wednesday, and Friday given for 2-3 weeks.
    • ?followed by a repeat course at 3 weeks or taper to twice weekly.
    • It is possible after the second go, once weekly injections could hold the case.
    • Relapses should be expected and given a repeat course of treatment.
    • Midazolam 0.5-1mg IV if agitation

    I am excited about the possibility of treating subjects previously untreatable. It might be wise to start a subject with a 10 – 15 mg (depending on size subject)  subcutaeous injection – watch for 30 + minutes and see.

    You should have a female staff member or a family member present when these shots are given and patient should not drive home unless watched until stable. Use pulse oximetry.


    Recent studies have suggested urinary symptoms may be a problem (they asked users online if they EVER had a problem (what EVER that means))

    BJU Int. 2012 Mar 14. doi: 10.1111/j.1464-410X.2012.11028.x. [Epub ahead ofprint]
    The prevalence and natural history of urinary symptoms among recreational ketamine users.
    Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM.  abstract here

    It has also been suggeested that there are cognitive concerns but I think the cognitive concerns of unremitting depression and pain are probably worse.
    There are also concerns of liver damage so blood tests would have to be done:
    Curr Opin Support Palliat Care. 2012 Mar 20. [Epub ahead of print]
    Ketamine for chronic noncancer pain: concerns regarding toxicity.
    Bell RF.   abstract here

    To this end I have devised a simple urinary questionnaire that should be filled every 2 weeks – if there are any yeses (that weren’t there before) then maybe stop the drug

    Name______________________________________      Date_____________

    Do you have any discomfort in the lower abdomen?         N    Y   
    Does it burn or sting to pass urine?                     N    Y   
    Do you find you need to pass urine more frequently?      N    Y 

    Do you go:      
    < every 2 hours                               N    Y                                        
    < every hour                                  N    Y
    Do you have to get up at night to urinate?    N    Y    _______ Times
    Have you had any leakage of urine?            N    Y 
    Have you had any blood in urine               N    Y

    I have gotten 4 of these on one word page and will get them to fill consequetively so can see the difference. Each sheet should have one liver function result on.

    can get 4 on a page in word  here

    Anyone tried this? nike air max bw nike air max bw

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