The Role of Lamotrigine in Reducing Psychologic Side-Effect of Perioperative Ketamine Use
Phase: PHASE3
Conditions: Reducing Psychological Side Effects of Ketamine
Sponsor: The Cleveland Clinic

1 
 
The role of Lamotrigine in Reducing Psychologic Side-Effect of 
Perioperative Ketamine Use 
 
 
 
Department of Outcomes Research 
Cleveland Clinic 
9500 Euclid Avenue / P77 
Cleveland, Ohio 44195  
 
Protocol version 1.2  
Dated: January 7th 2019 
NCT03831854 
 
 
 
 
 
Summary of changes in red 
- 
Page 5 – added “Planned surgery duration 3-6 hours” in inclusion criteria 
- 
Page 5 -  added “history of lamotrigine use” in the exclusion criteria 
- 
Page 6 – added BPRS assessment “within 90 minutes of PACU arrival and the following  
morning” 
- 
Summary of changes in blue 
- 
Pages 2, 3, 4, 5,and 6 There are some language and word flow changes throughout the paper 
 

2 
 
 
1. Introduction 
 
Opioid medications are the mainstay in the multimodal perioperative pain management and 
widely used in the United States.1,2 Ketamine can play a role in perioperative pain management 
by lowering opioid utilizations  and minimizing the opioid related side-effects.3  
1.1 Ketamine 
Ketamine is a well-known general anesthetic functioning by N-methyl-D-aspartate (NMDA)-
receptor antagonism. Additionally, ketamine has diverse molecular targets and neurophysiological 
properties which can help in the management of acute and chronic pain, depression, posttraumatic 
stress disorders, and schizophrenia.4   
1.1.1 Role of ketamine for anesthesia and analgesia 
Ketamine can be used for induction of anesthesia, analgesia and for prevention of inflammation 
and persistent pain. The drug’s analgesic and anti-inflammatory effects are particularly useful in 
perioperative pain management because it reduces opioid requirements.5 The analgesic effect is 
mediated through NMDA receptors6, voltage-gated sodium channels7,8, BK channels9, opioid 
receptors (mu , delta)10,11 and  gamma-aminobutyric acid (GABA) receptors12 (Table 1). 
Unsurprisingly, analgesia requires lower concentrations than general anesthesia.13,14 A range of 
systemic inflammatory response is set in motion by surgical trauma, eliciting complex interaction 
with numerous inflammatory biomarkers.15 Ketamine anti-inflammatory potential is elucidated by 
the reduction of biomarker interleukin-6 (IL-6) in early postoperative period.16 Ketamine also play 
an important role in depression management.17 
Ostensibly ketamine should be used widely for improving postoperative pain and outcomes. 
However this is not the case. The psychologic side-effects are one of the main reasons for its 
limited use. Emergence reactions are in reported in 10-20% of the patients. Consequentially opioid 
medications are the commonly used medications in perioperative pain management. 
Ketamine may play role in reducing perioperative hypotension which has been associated with 
increased perioperative morbidity and mortality.18,19 Usually hypotension is noted as an 
unavoidable side-effect of general anesthetics induction drugs like propofol.20,21  Inhaled 
anesthetics and opioids also contribute to hypotension. Etomidate is an alternative induction agent 
which does not cause hypotension but its use is limited due to assumed adrenal suppression. 22,23   
Ketamine preserves hemodynamics better than commonly used anesthetic induction drug propofol 
and does not cause adrenal suppression like etomidate.  Thus Ketamine seems to be a good 
induction agent, but again the psychologic side-effects again prevents its common use.   
In summary, ketamine is a useful drug for anesthesia and analgesia in surgical patients. Common 
reasons for use in induction and maintenance of anesthesia is the opioid sparing effects and 
hemodynamic stability. And the most important reason not to use is the psychologic effects. 

3 
 
1.1.2 Psychologic side-effects of ketamine 
The use ketamine in perioperative period may lead to psychologic side-effects. But the extent of 
side-effects from low dose ketamine is not fully characterized. Most information of side-effects 
comes from chronic pain and psychiatry literature where the dosage and duration of ketamine 
treatment is much higher. In chronic pain management the use of ketamine is associated with dose-
dependent side effects including psychedelic symptoms (hallucinations, memory defects, panic 
attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, 
hepatoxicity. 24 Usually the dose used is 30 mg/hour for 4-14 days. Blagrove et al reported  an 
increase in dream unpleasantness over the three nights after ketamine use.25  Browdle et al reported 
dose-related psychedelic effects in healthy volunteers with the use of ketamine.26 However no 
amnestic medications were given which are routine in perioperative of setting. 
1.2 The role of Lamotrigine 
The mechanism of psychologic effects of subanesthetic ketamine remains unclear. Increased 
dopamine release, effect on the γ-aminobutyric acid (GABA) system, and modulation of the 
serotonergic system have been suggested as possible mechanisms.27 Lamotrigine, an 
anticonvulsant which decreases presynaptic glutamate release and widely used for 
neuropsychiatric illness.28 Lamotrigine augmentation of serotonin reuptake inhibitors is well 
tolerated in treatment-resistant obsessive–compulsive disorder. 29 Lamotrigine may play a role in 
treating ketamine use disorder.30 
A key study was reported at the Society of Neuroscience meeting in 1997 and later published in 
the Archives of General Psychiatry.  It reported that in healthy subjects, 300 mg oral lamotrigine 
significantly decreased ketamine-induced perceptual abnormalities as assessed by the Clinician-
Administered Dissociative States Scale (P<.001).31 Furthermore lamotrigine increased the 
immediate mood-elevating effects of ketamine (P<.05). The authors concluded that glutamate 
release-inhibiting drugs may reduce the hyperglutamatergic consequences of NMDA receptor 
dysfunction which may be implicated in the pathophysiologic processes of neuropsychiatric 
illnesses.  
In an another experiment designed to identify the sites of action of ketamine in inducing symptoms 
and to determine the role of increased glutamate release using the glutamate release inhibitor 
lamotrigine, the authors concluded that lamotrigine pretreatment prevented many of the signal 
changes and the symptoms associated with ketamine use..  The results of this clinical study were 
confirmed in a laboratory study published in Science 1998 –“Reversal of Phencyclidine Effects by 
a Group II Metabotropic Glutamate Receptor Agonist in Rats”.32  The authors noted that “Group II 
metabotropic glutamate receptors were targeted to normalize glutamatergic disruptions 
associated with an animal model of schizophrenia, the phencyclidine model. An agonist of this 
group of receptors, at a dose that was without effects on spontaneous activity and corticolimbic 
dopamine neurotransmission, attenuated the disruptive effects of phencyclidine on working 
memory, stereotypy, locomotion, and cortical glutamate efflux. This behavioral reversal occurred 
in spite of sustained dopamine hyperactivity.”  
Available evidence therefore supports use of lamotrigine for reducing undesirable psychologic 
effects of low dose ketamine in perioperative period. If it in fact does, lamotrigine might broaden 
use of ketamine for anesthesia and pain management.  

4 
 
2. Specific Aim and Hypothesis  
Aim – The aim of this pilot trial is to determine whether lamotrigine reduces psychologic side-
effects consequent to low-dose ketamine in surgical patients. This pilot study will confirm the 
feasibility of a subsequent hypothesis testing study, and provide data to strengthen a sample-size 
estimate. 
Hypothesis - Preoperative treatment with 300 mg lamotrigine reduces psychologic side-effects 
(measured by four key items of Brief Psychiatric Rating Scale: conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual thought content) in adults given ketamine for 
non-cardiac surgery.  
 
3. Significance 
Ketamine has multiple properties of an ideal anesthetic induction and maintenance agent. The 
analgesic effects has desirable opioid sparing effects, and the anti-inflammatory properties may 
help improve outcomes. But its use in perioperative setting is limited, primarily, due to concerns 
of the psychologic side effect. Lamotrigine can help reduce the undesirable psychologic side-
effects of ketamine. 
4. Plan of investigation 
4.1 Outcomes 
1.1.1 Primary outcome 
1. Psychologic side-effects measured in PACU (up to 90 minutes after ketamine infusion) 
by four key items of Brief Psychiatric Rating Scale (BPRS) corresponding to positive 
symptoms of schizophrenia: conceptual disorganization, hallucinatory behavior, 
suspiciousness, and unusual thought content. Each symptom is rated 1-7 (1 = not 
present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe, 6 = severe, 7 = 
extremely severe), and, therefore, the total score based on four key items of BPRS will 
be between 4 (best score) and 28 (worst score). 
4.1.2 Secondary outcomes 
1. Opioid use in PACU – total IV morphine equivalents 
2. Pain score in PACU – numeric rating scale ( 0-10)  
3. Binary outcome postoperative nausea vomiting (PONV) in PACU 
4. Postoperative Nursing Progress Record (NPR) records nausea vomiting severity as: 
0=none, 1= mild, 2=moderate, 3= severe; analysis will compare two study groups on 
moderate and severe nausea / vomiting (0 or 1 vs. 2 or 3) in the PACU.  
4.1.3 Exploratory outcomes 
1. Sedation agitation scale33 (RASS score) at the time of admission in PACU. 
2. Average daily opioid utilization during hospitalization (morphine equivalents). 

5 
 
3. Opioid related side-effects, using the opioid related symptom distress scale (ORSDS) 
on the first and second postoperative days.34,35  
 
4.2 Trial design 
Double blind, randomized (1:1), pilot study. 
4.3 Sample size 
This pilot study will enroll 50 patients, with 25 randomized to lamotrigine or placebo.   
With 50 total patients we will be able to estimate a treatment effect with 95% confidence interval.     
Variability and treatment effect estimates observed in this pilot study will be used for planning 
larger trials powered for binary outcomes.    
Although not the focus, assuming standard deviation of 2 units (Anand and others, Attention of 
the Neuropsychiatric effects of Ketamine with Lamotrigine reported the mean ± SD of 1.5± 2 for 
BPRS outcome), the sample size of N=25 patients per group (N=50 patients total) will provide 
about 90% power at the 0.05 significance level to detect the difference of 1.9 or larger in units 
drop between two study groups. 
 
 5. Eligibility criteria 
Patient undergoing elective abdominal surgery. Specifically, we will enroll surgical inpatients 
18-65 yr having noncardiac surgery who require a general anesthesia. We will exclude patients 
in whom ICU admission is planned preoperatively.   
5.1 Inclusion criteria  
- 
18-65 years of age 
- 
Planned  overnight hospital stay 
- 
Planned surgery duration 3-6 hours 
5.2 Exclusion criteria 
- 
Pediatric and pregnant patients 
- 
History of seizure 
- 
History of Schizophrenia 
- 
History of unstable angina  
- 
Antiepileptic medications 
- 
History of lamotrigine use 
6. Training for rating scales:  
 
a. BPRS ratings:  will be conducted by anesthesia fellows.  All fellows will be trained on how to do the 
ratings by co-investigator, Dr. Amit Anand (Vice-chair of Research, Center for Behavioral Health). Raters 

6 
 
will also have to pass a quiz used in a large ketamine study being conducted at the Cleveland Clinic to 
assess understanding regarding the ratings.  
6. Protocol  
6.1 Patient recruitment 
From anesthesia preoperative clinic. 
6.2 Randomization and blinding 
1:1 randomization without stratification use web-based software (Redcap) before surgery. 
Allocation will be concealed from the patient, the nurse, the operating room team. Both patient 
and the operating room team will be blinded to the treatment allocation (double blind). 
6.3 Preoperative care 
Standard preoperative care as per anesthesia care team. Patient will receive lamotrigine vs. 
placebo with small sips of water. Lamotrigine reaches peak level 1-4 hours after oral 
administration. Single dose lamotrigine is safe and is not associated with rash.36 
6.4 Intraoperative care 
Standard intraoperative care as per the anesthesia care team. All patients will receive Ketamine 1 
mg/kg at induction. Ketamine 5mcg/kg/min will be started at induction and stopped at the end of 
surgery.   
6.5 Postoperative care 
Standard postoperative care as per PACU team. The psychologic side-effects will be measured 
using 
Brief 
Psychiatric 
Rating 
Scale 
(BPRS)37,38 
using 
an 
online 
tool(http://farmacologiaclinica.info/scales/BPRS/), within 90 minutes of PACU arrival and 
following morning.  
 
Research fellow will receive standardized training in administering BPRS from Dr Amit Anand 
using structured material. Dr Anand has used this training for other current research projects.  
7. Data analysis 
The analysis and reporting of the results will follow the CONSORT guidelines (www.consort-
statement.org ). The process of patient selection and flow throughout the study will be summarized 
using a flow-diagram. 
We will analyze patients in the treatment group to which they are allocated, according to the 
intention-to-treat principle. Any patients lost to follow-up will be censored at the time they are lost 
to follow-up.  
7.1 Statistical plan 
First, we compared two randomized groups (lamotrigine vs. placebo) for balance on potentially 
confounding patients’  demographic, baseline and surgical characteristics using univariable 
summary statistics (mean and standard deviation, median and quartiles, or proportions, as 

7 
 
appropriate) and using absolute standardized difference scores (ASDs).  ASDs are defined as the 
absolute value of the difference between means, mean rankings, or proportions divided by a 
combined estimate of standard deviation; thus the ASD roughly represents the number of standard 
deviations the two study groups are apart from one another.   
The exploratory outcomes will be summarized by two randomized groups using descriptive 
summary measures: expressed as mean (standard deviation) or median (interquartile range) for 
continuous variables and number (percent) for categorical variables. No formal statistical test 
will be conducted for the exploratory outcomes. 
Primary analysis 
As for primary analysis, two randomized groups will be compared on the continuous total score 
based on BPRS four items ranging between 4 (best score) and 28 (worst score). We will estimate 
the effect of Lamotrigine on reduction psychological side-effects of ketamine infusion using the 
two-sample Wilcoxon rank sum test and Hodges Lehmann estimation of location shift (along with 
95% confidence interval). This method is appropriate since we expect that the outcome will exhibit 
a skewed distribution. If the incidence of any psychologic effects is very low, meaning that vast 
majority of the patients will have a score of four (corresponding to no symptoms), we will treat 
the outcome as binary (no symptoms vs. any symptoms). I this case the chi-square test will be used 
to compare two randomized groups; the odds ratio along with 95% confidence interval will be 
reported. 
The Type I error for the primary analysis will be kept at 5% level with significance criterion of 
P<0.05. 
Secondary analysis 
Assuming log-normal distribution of PACU opioid consumption (in IV morphine equivalent), we 
will evaluate the percent difference in geometric mean IV morphine equivalent dose between the 
two randomized groups using t-test on the log-transformed data. To evaluate the difference in 
mean PACU pain scores (in VRS scale) we will first summarize the pain scores (in VRS scale) by 
computing PACU time weighted average (TWA) pain score for each patient. Then we will use a 
t-test to assess the exposure effect on the TWA pain scores. Binary PONV outcome will be 
compared between two study groups using chi-square test. 
We used the Bonferroni adjustment for multiple analyses to preserve Type I error at 5% level for 
the secondary analysis with the significance criterion of 0.017 for each of the secondary outcome 
(i.e., 0.05 / 3). 
7.2 Data management 
Redcap software will be used for storing patient level information for this study. Or paper case 
report form will be used and stored in secure location at Outcomes Research department. 
 
 

8 
 
References:  
1. 
American Society of Anesthesiologists Task Force on Acute Pain M: Practice guidelines for acute 
pain management in the perioperative setting: an updated report by the American Society of 
Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012; 116: 248-73 
2. 
Chou R, Gordon DB, De Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy 
CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, McCarberg B, Montgomery R, Murphy J, 
Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL: 
Management of postoperative pain: A clinical practice guideline from the American pain society, the 
American society of regional anesthesia and pain medicine, and the American society of 
anesthesiologists' committee on regional anesthesia, executive committee, and administrative council. 
Journal of Pain 2016; 17: 131-157 
3. 
Canet J, Castillo J: Ketamine: A familiar drug we trust. Anesthesiology 2012; 116: 6-8 
4. 
Li L, Vlisides PE: Ketamine: 50 years of modulating the mind. Frontiers in Human Neuroscience 
2016; 10 
5. 
Laskowski K, Stirling A, McKay WP, Lim HJ: A systematic review of intravenous ketamine for 
postoperative analgesia. Can J Anaesth 2011; 58: 911-23 
6. 
Oye I, Paulsen O, Maurset A: Effects of ketamine on sensory perception: evidence for a role of 
N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1992; 260: 1209-13 
7. 
Frenkel C, Urban BW: Molecular actions of racemic ketamine on human CNS sodium channels. 
Br J Anaesth 1992; 69: 292-7 
8. 
Haeseler G, Tetzlaff D, Bufler J, Dengler R, Munte S, Hecker H, Leuwer M: Blockade of voltage-
operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine. Anesth Analg 2003; 
96: 1019-26, table of contents 
9. 
Hayashi Y, Kawaji K, Sun L, Zhang X, Koyano K, Yokoyama T, Kohsaka S, Inoue K, Nakanishi H: 
Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-
ketamine on neuropathic pain. J Neurosci 2011; 31: 17370-82 
10. 
Finck AD, Ngai SH: Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982; 56: 
291-7 
11. 
Pacheco Dda F, Romero TR, Duarte ID: Central antinociception induced by ketamine is mediated 
by endogenous opioids and mu- and delta-opioid receptors. Brain Res 2014; 1562: 69-75 
12. 
Irifune M, Sato T, Kamata Y, Nishikawa T, Dohi T, Kawahara M: Evidence for GABA(A) receptor 
agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice. Anesth Analg 
2000; 91: 230-6 
13. 
Sigtermans M, Dahan A, Mooren R, Bauer M, Kest B, Sarton E, Olofsen E: S(+)-ketamine effect on 
experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study 
in healthy volunteers. Anesthesiology 2009; 111: 892-903 
14. 
Sigtermans MJ, van Hilten JJ, Bauer MC, Arbous MS, Marinus J, Sarton EY, Dahan A: Ketamine 
produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. 
Pain 2009; 145: 304-11 
15. 
Davies MG, Hagen PO: Systemic inflammatory response syndrome. British Journal of Surgery 
1997; 84: 920-935 
16. 
Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y: Does intraoperative ketamine attenuate 
inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesthesia and 
Analgesia 2012; 115: 934-943 
17. 
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 Jr CA: A randomized add-
on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of 
General Psychiatry 2010; 67: 793-802 

9 
 
18. 
Salmasi V, Maheshwari K, Yang D, Mascha EJ, Singh A, Sessler DI, Kurz A: Relationship between 
Intraoperative Hypotension, Defined by Either Reduction from Baseline or Absolute Thresholds, and 
Acute Kidney and Myocardial Injury after Noncardiac Surgery: A Retrospective Cohort Analysis. 
Anesthesiology 2016 
19. 
Sun LY, Wijeysundera DN, Tait GA, Beattie WS: Association of intraoperative hypotension with 
acute kidney injury after elective noncardiac surgery. Anesthesiology 2015; 123: 515-23 
20. 
Green RS, Butler MB: Postintubation Hypotension in General Anesthesia: A Retrospective 
Analysis. J Intensive Care Med 2015 
21. 
Südfeld S, Brechnitz S, Wagner JY, Reese PC, Pinnschmidt HO, Reuter DA, Saugel B: Post-
induction hypotension and early intraoperative hypotension associated with general anaesthesia. BJA: 
British Journal of Anaesthesia 2017; 119: 57-64 
22. 
Hildreth AN, Mejia VA, Maxwell RA, Smith PW, Dart BW, Barker DE: Adrenal suppression 
following a single dose of etomidate for rapid sequence induction: a prospective randomized study. J 
Trauma 2008; 65: 573-9 
23. 
Zuckerbraun NS, Pitetti RD, Herr SM, Roth KR, Gaines BA, King C: Use of etomidate as an 
induction agent for rapid sequence intubation in a pediatric emergency department. Acad Emerg Med 
2006; 13: 602-9 
24. 
Niesters M, Martini C, Dahan A: Ketamine for chronic pain: risks and benefits. Br J Clin 
Pharmacol 2014; 77: 357-67 
25. 
Blagrove M, Morgan CJA, Curran HV, Bromley L, Brandner B: The incidence of unpleasant 
dreams after sub-anaesthetic ketamine. Psychopharmacology 2009; 203: 109-120 
26. 
Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP: Psychedelic effects 
of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. Anesthesiology 
1998; 88: 82-88 
27. 
Olney JW, Farber NB: NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, 
and research tools for studying schizophrenia. Neuropsychopharmacology 1995; 13: 335-45 
28. 
Cunningham MO, Jones RS: The anticonvulsant, lamotrigine decreases spontaneous glutamate 
release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. 
Neuropharmacology 2000; 39: 2139-46 
29. 
Bruno A, Micò U, Pandolfo G, Mallamace D, Abenavoli E, Di Nardo F, D'Arrigo C, Spina E, Zoccali 
RA, Muscatello MRA: Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant 
obsessive-compulsive disorder: A double-blind, placebo-controlled study. Journal of 
Psychopharmacology 2012; 26: 1456-1462 
30. 
Huang MC, Chen LY, Chen CK, Lin SK: Potential benefit of lamotrigine in managing ketamine use 
disorder. Medical Hypotheses 2016; 87: 97-100 
31. 
Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH: Attenuation of the 
neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-
methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000; 57: 270-6 
32. 
Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II metabotropic 
glutamate receptor agonist in rats. Science 1998; 281: 1349-52 
33. 
Riker RR, Picard JT, Fraser GL: Prospective evaluation of the Sedation-Agitation Scale for adult 
critically ill patients. Crit Care Med 1999; 27: 1325-9 
34. 
Chan KS, Chen WH, Gan TJ, Hsieh R, Chen C, Lakshminarayanan M, Revicki DA: Development and 
validation of a composite score based on clinically meaningful events for the opioid-related symptom 
distress scale. Qual Life Res 2009; 18: 1331-40 
35. 
Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C: Reliability and validity of the perioperative 
opioid-related symptom distress scale. Anesth Analg 2004; 99: 699-709, table of contents 

10 
 
36. 
Hamilton MJ, Cohen AF, Yuen AW, Harkin N, Land G, Weatherley BC, Peck AW: Carbamazepine 
and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia 
1993; 34: 166-73 
37. 
Hedlund JL, Vieweg BW: The Brief Psychiatric Rating Scale (BPRS): A comprehensive review. 
Journal of Operational Psychiatry 1980; 11: 48-64 
38. 
Overall JE, Gorham DR: The brief psychiatric rating scale. Psychol Rep 1962; 10: 799-812 
  
Table -1 Ketamine receptors