1. Changes in the serum metabolites of tryptophan in abstinent cocaine and alcohol users and their relationship with co-morbid disorders
October 24, 2017
Rebeca Vidal

2. Last year prevalence of cocaine use among young adults (15-34)
Spain is the country reporting the largest seizures of cocaine among the EU member States
Statistical bulletin 2017, EMCDDA

3. Projected estimates consumption (litres/year)
Total alcohol per capita (>15 years of age) consumption, projected estimates, 2015
Projected estimates consumption (litres/year)
<2.5
2.5 – 5.4
>12

4. The kynurenine pathway in the periphery and CNS
Liver
Spleen
5-HT QA KA
TRP
KYN
3-HK
Tryptophan (TRP)
Kynurenine (KYN)
3-Hydroxykynurenine (3-HK)
Quinolinic acid (QA)
Kynurenic acid (KA)
TDO
IDO
KMO
Neuroprotective arm
Tryptophan
Kynurenic acid
Gut
Neuron
Astrocyte
HPA axis
activation
CNS
Periphery
Glucocorticoids
Immune cells
Microglia
Neurotoxic arm
Quinolinic acid
Blood brain
barrier
KAT
TPH2
TPH1
IFN-γ
IL-1β
IL-6
NAD+

5. Is the Kynurenine Pathway altered in abstinent cocaine and alcohol-addicted patients?

6. Is the Kynurenine Pathway disbalanced in abstinent cocaine and alcohol-addicted patients?
Plasma levels of TRP, 5-HT, KYN, KA were measured by HPLC (QA using a ELISA kit) and evaluated according to relevant substance use disorder variables and psychiatric comorbidity.

7. ABSTINENT PATIENTS DIAGNOSED WITH COCAINE USE DISORDERS
VARIABLE
COCAINE GROUP
N=100
CONTROL GROUP
N=60
P-value
Age
[mean (SD)]
Years
35.4 (7.5)
36.4 (10.4)
ns a
Body mass index
Kg/m2
25.4 (4.4)
24.6 (4.3)
Sex
[N (%)]
Female
Male
18 (18.0)
82 (82.0)
30 (50.0)
<0.001 b
Cocaine users exclusively by intranasal use and abstinent for at least 2 weeks before testing (average abstienence 7.3 months).

8. Plasma levels in abstinent cocaine-addicted patients and control subjects
Tryptophan 10 20 30
Control
Cocaine
nmol/mL
Serotonin
Control
Cocaine
pmol/mL 50
100
150
200 **
Kynurenine
0.0
0.5
1.0
1.5
2.0
Control
Cocaine
nmol/mL

9. Plasma levels in abstinent cocaine-addicted patients and control subjects
Tryptophan 10 20 30
Control
Cocaine
nmol/mL
Serotonin
Control
Cocaine
pmol/mL 50
100
150
200 **
Kynurenic acid 10 20 30 40
Control
Cocaine
pmol/mL *
Kynurenine
0.0
0.5
1.0
1.5
2.0
Control
Cocaine
nmol/mL
Quinolinic acid 5 10 15 20 25
Control
Cocaine
pmol/mL

10. Plasma levels in abstinent cocaine-addicted patients and control subjects
Tryptophan 10 20 30
Control
Cocaine
nmol/mL
Serotonin
Control
Cocaine
pmol/mL 50
100
150
200 **
5HT/TRYP 1 2
Control
Cocaine * 4 3
Ratio
(x 103)
Kynurenic acid 10 20 30 40
Control
Cocaine
pmol/mL *
Kynurenine
0.0
0.5
1.0
1.5
2.0
Control
Cocaine
nmol/mL
KA/KYN
0.5
1.0
1.5
2.0
2.5
Control
Cocaine *
Ratio
(x 103)
KYN/TRP 20 40 60 80
100
Control
Cocaine
Ratio
(x 103)
Quinolinic acid 5 10 15 20 25
Control
Cocaine
pmol/mL

11. Characteristics related to cocaine use in cocaine-addicted patients
VARIABLE
COCAINE GROUP
(N=100)
Current cocaine abstinence (duration)
[mean (SD)]
days
221.8 (429.4)
Problematic cocaine use (duration)
years
7.34 (6.47)
DSM-IV criteria for cocaine abuse and dependence
(0-11)
8.4 (2.2)
Comorbid substance use disorders
[N (%)] No
Yes
32 (32.0)
68 (68.0)

12. COMORBID MENTAL DISORDERS
Psychiatric characteristics of cocaine-addicted patients grouped according to diagnosis of comorbid mental disorders
VARIABLE
COMORBID MENTAL DISORDERS NO
N=41
YES
N=59
P-value
Prescribed psychotropic medication use
[N (%)] No
Yes
24 (58.5)
17 (41.5)
14 (23.7)
45 (76.3)
<0.001
Treatment for substance use disorders
10 (24.4)
31 (75.6)
4 (6.8)
55 (93.2)
<0.05
Outpatient
Income
29 (70.7)
2 (4.9)
47 (79.7)
8 (13.6) --
Lifetime substance use disorders (excluding cocaine)
18 (43.9)
23 (56.1)
Alcohol
21 (51.2)
38 (64.4)
Cannabis
4 (9.8)
13 (22.0)
Heroin
0 (0.0)
9 (15.3)
Sedatives
3 (7.3)
Others
7 (11.9)
Common lifetime mental disorders
41 (100.0)
59 (100.0)
Mood -
28 (47.5)
Anxiety
22 (37.3)
Psychosis
16 (27.1)
Personality

13. Abstinent cocaine-addicted patients and comorbid mental disorders
Tryptophan
Non-comorbid
Comorbid
nmol/mL 10 20 30 40
Serotonin
pmol/mL 50
100
150
200
250 **
Non-comorbid
Comorbid
Kynurenine
nmol/mL
0.0
0.5
1.0
1.5
2.0
Non-comorbid
Comorbid
Kynurenic acid
pmol/mL 10 20 30
Non-comorbid
Comorbid 5 10 15 20 25
Quinolinic acid
pmol/mL
Non-comorbid
Comorbid
* vs non-comorbid

14. Plasma serotonin levels and comorbid mental disorders in abstinent CUD patients*
Personality disorders
5-HT (pmol/mL) 75
150
225
300
Non-comorbid
Non-personality disorders
Mood disorders 75
150
225
300 *
5-HT (pmol/mL)
Non-comorbid
Non-mood disorders
Anxiety disorders **
5-HT (pmol/mL) 75
150
225
300
Non-comorbid
Non-anxiety disorders *
5-HT (pmol/mL)
Psychotic disorders 75
150
225
300
Non-comorbid
Non-psychotic disorders
* vs non-comorbid

15. In summary:
Kynurenic acid is affected by historial of cocaine use disorder
Serotonin is associated to psychiatric comorbidity in abstinent cocaine-adicted patients

16. ABSTINENT PATIENTS DIAGNOSED WITH COCAINE USE DISORDERS
VARIABLE
ALCOHOL GROUP
N=130
CONTROL GROUP
N=80
p-value
Age
[mean (SD)]
Years
48.6 (7.9)
43.0 (10.9)
<0.001 a
Body mass index
Kg/m2
26.0 (4.4)
25.6 (4.4)
ns a
Sex
[N (%)]
Female
Male
35 (26.9)
95 (73.1)
40 (50.0)
0.001 b
Alcohol users were abstinent for at least 4 weeks (mean 11.5 months) before testing

17. Plasma levels in abstinent alcohol-addicted patients and control subjects
nmol/mL 10 20 30 40
Control
Alcohol
Tryptophan
Serotonin
pmol/mL 20 40 60 80
100
Control
Alcohol
Kynurenine
nmol/mL
0.0
0.5
1.0
1.5
2.0
2.5 **
Control
Alcohol
Kynurenic acid
pmol/mL 10 20 30 *
Control
Alcohol

18. Plasma levels in abstinent alcohol-addicted patients and control subjects
nmol/mL 10 20 30 40
Control
Alcohol
Tryptophan
Serotonin
pmol/mL 20 40 60 80
100
Control
Alcohol 2 4 6 8
Ratio
(x 103)
KYN/TRP Ratio **
Control
Alcohol
Kynurenine
nmol/mL
0.0
0.5
1.0
1.5
2.0
2.5 **
Control
Alcohol
Kynurenic acid
pmol/mL 10 20 30 *
Control
Alcohol
0.0
0.5
1.0
1.5
2.0
Ratio
(x 103)
KA/KYN Ratio
***
Control
Alcohol

19. Characteristics related to alcohol use in abstinent AUD patients
VARIABLE
ALCOHOL GROUP
N=130
Current alcohol abstinence (duration)
[mean (SD)]
Months
11.5 (17.4)
Problematic alcohol use (duration)
Years
14.5 (7.7)
DSM-IV criteria for AUD
Criteria (0-11)
7.2 (2.3)
Alcohol-related liver/pancreas diseases
[N (%)] No
Yes
96 (73.8)
34 (26.2)
Psychoactive medication use
[N (%)]
Last year
90 (69.2)
Lifetime psychiatric comorbidity No
SUD
Mental disorders
Both
36 (27.7)
9 (6.9)
40 (30.8)
45 (34.6)
Comorbid substance use disorders (SUD)
Yes
76 (58.5)
54 (41.5)
Comorbid mental disorders
85 (65.4)

20. Plasma concentrations of TRP-derived metabolites in abstinent AUD patients relative to psychiatric comorbidity
VARIABLE
PSYCHIATRIC COMORBIDITY
NO COMORBIDITY
N=36
SUBSTANCE USE DISORDERS (SUD)
N=9
MENTAL DISORDERS
N=40
SUD+MENTAL DISORDERS
N=45
Tryptophan (TRP)
[mean (95%CI)]
nmol/mL
34.77
( )
31.01
( )
33.21
( )
28.16
( ) **
Kynurenine (KYN)
1.92
( )
1.79
( )
2.07
( )
1.78
( )
Kynurenic acid (KA)
pmol/mL
20.23
( )
19.95
( )
17.06
( )
17.66
( )
Serotonin (5-HT)
60.12
( )
68.87
( )
47.75
( )
76.74
( )
KYN/TRP Ratio
0.058
( )
0.056
( )
0.062
( )
0.067
( )
KA/KYN Ratio
0.0018
( )
0.0023
( )
0.0015
( )
0.0028
( )
5-HT/TRP Ratio
0.0016
( )
0.0026
( )
0.0019
( )
( )

21. Plasma concentrations of TRP-derived metabolites in abstinent AUD patients relative to psychiatric comorbidity
VARIABLE
PSYCHIATRIC COMORBIDITY
NO COMORBIDITY
N=36
SUBSTANCE USE DISORDERS (SUD)
N=9
MENTAL DISORDERS
N=40
SUD+MENTAL DISORDERS
N=45
Tryptophan (TRP)
[mean (95%CI)]
nmol/mL
34.77
( )
31.01
( )
33.21
( )
28.16
( ) **
Kynurenine (KYN)
1.92
( )
1.79
( )
2.07
( )
1.78
( )
Kynurenic acid (KA)
pmol/mL
20.23
( )
19.95
( )
17.06
( )
17.66
( )
Serotonin (5-HT)
60.12
( )
68.87
( )
47.75
( )
76.74
( )
KYN/TRP Ratio
0.058
( )
0.056
( )
0.062
( )
0.067
( )
KA/KYN Ratio
0.0018
( )
0.0023
( )
0.0015
( )
0.0028
( )
5-HT/TRP Ratio
0.0016
( )
0.0026
( )
0.0019
( )
( )

22. Plasma TRP concentrations in the alcohol group according to psychiatric comorbidity
Comorbid substance use disorders (SUD)
[N (%)] No
Yes
76 (58.5)
54 (41.5)
Cocaine
Cannabis
Other drugs
41 (31.5)
20 (15.4)
15 (11.5)
Comorbid mental disorders
45 (34.6)
85 (65.4)
Mood disorders
Anxiety disorders
Psychosis disorders
Personality disorders
59 (45.4)
25 (19.2)
12 (9.2)
31 (23.8) 10 20 30 40 50 **
TRP (nmol/mL)
Total SUD
Cocaine
***
Cannabis
Other SUD *
No comorbid disorder
Comorbid SUD + MD
Comorbid SUD
Comorbid MD

23. Conclusions
Kynurenic acid is affected by both history of cocaine and alcohol use disorders
Serotonin is associated to psychiatric comorbidity in abstinent cocaine-adicted patients
AUD patients diagnosed with comorbid SUD and mental disorders showed lower TRP concentrations than AUD patients with no comorbidity

24. I would like to thank to