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No association between chronic cannabis use and loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission
Neuroscience Letters 465 (2009) 113–117
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
No association between chronic cannabis use and loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission Patrik Roser ∗ , Beate Della, Christine Norra, Georg Juckel, Idun Uhl Department of Psychiatry, Ruhr-University, Alexandrinenstr. 1, 44791 Bochum, Germany
a r t i c l e
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Article history: Received 2 June 2009 Received in revised form 1 September 2009 Accepted 14 September 2009 Keywords: Cannabis Serotonin Loudness dependence Auditory evoked potentials
a b s t r a c t Chronic cannabis use has been found to be associated with major depression. It is suggested that cannabis use induces changes in neurotransmitter systems involved in the pathogenesis of depressive disorders, particularly in the serotonergic system. The analysis of the loudness dependence of auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity in animals and humans. In the present study, we investigated the effects of chronic cannabis use on LDAEP in 30 psychiatrically unaffected users compared to 30 non-user controls. Users were required to abstain from cannabis for at least 24 h before testing. Putative depressive symptoms were assessed by using the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-21). LDAEP as well as BDI and HAMD-21 scores did not differ between cannabis users and controls. Moreover, LDAEP neither correlate with duration and quantity of cannabis use nor with psychometric assessments. These results indicate that chronic cannabis use had no influence on the LDAEP in this study sample. It can be suggested that significant alterations in serotonergic systems may rather be related to acute activation of the endogenous cannabinoid system or to cannabis dependence accompanied by manifest depressive symptoms. © 2009 Elsevier Ireland Ltd. All rights reserved.
Cannabis sativa is the most widely used illicit drug in the Western world. 9 -Tetrahydrocannabinol (9 -THC) has been identified as the primary psychoactive constituent of the Cannabis sativa plant acting at central cannabinoid (CB1 ) receptors [11]. There is increasing evidence that cannabis modulates affective and emotional regulation. Acute effects of cannabis include feelings of ‘high’, euphoria and contentment [18], whereas chronic cannabis use has been found to increase the rates of depressive symptoms [8]. The association between cannabis use and depression has been subject to considerable controversy. Chen et al. found that a greater number of occasions of cannabis use were associated with a higher risk of having experienced a major depressive episode, and that life-time cannabis dependence was associated with a 3.4 times increased risk of major depression [4]. Another epidemiological survey demonstrated that cannabis abuse or dependence within the past year was associated with a 6.4 times increased risk of meeting criteria for major depression [12]. In particular, early onset of regular cannabis use as well as heavy cannabis use were related to the strongest increase in risk of later major depression, whereas little evidence was found for an association between infrequent cannabis use and depression [3,7,10,33]. However, a recent review
∗ Corresponding author. Tel.: +49 234 5077 370; fax: +49 234 5077 234. E-mail address: [email protected] (P. Roser). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.09.027
showed that the findings for an increased risk of affective disorders due to cannabis use were less consistent than for psychosis [24]. In this context, animal studies demonstrated acute as well as chronic effects of cannabinoids on the serotonergic system that is strongly associated with the pathogenesis of depressive disorders [28]. Acute cannabinoid treatment has been found to modulate serotonergic neuronal activity in the rat dorsal raphe nucleus [1]. On the other hand, Hill et al. found that chronic cannabinoid treatment may alter the activity of different serotonin receptor subtypes in rats [17]. Nevertheless, an association between cannabis use and serotonergic dysfunctions in humans have not been explored so far. Loudness dependence of auditory evoked potentials (LDAEP), a specific aspect of information processing, has been proposed to be a valid indicator of central serotonergic function [39]. The LDAEP can be measured by the increase of N1/P2 amplitude values with increasing tone loudness during auditory stimulation. Based on animal findings demonstrating that sensory processing in the primary auditory cortex is modulated by serotonergic neurotransmission, the intensity of the LDAEP has been found to be inversely correlated with central serotonergic activity [21,39]. In humans, the sensitivity of the LDAEP to acute and chronic changes in serotonergic activity is less consistent. A strong LDAEP has been found in patients with psychiatric disorders with an assumed deficiency of serotonin, such as borderline personality disorder [27] or schizophrenia [19]. In depressed patients, a significant relationship between
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Table 1 Demographic characteristics of the study sample (in medians and ranges). All users n = 30
Long-term users n = 15
Short-term users n = 15
Heavy users n = 16
Light users n = 14
Controls n = 30
Age (years) Sex (male/female)b Education (years)a
22.0 (19–27) 17/13 16.0 (12–17)**
24.0 (21–27)** 9/6 16.0 (12–17)
21.0 (19–26) 8/7 14.0 (13–17)
23.0 (21–27) 8/8 15.5 (12–17)
22.0 (19–26) 9/5 16.0 (13–17)
24.0 (18–27) 15/15 17.0 (12–21)
Cannabis use Quantity (joints/week)a Duration (years)a Abstinence (days)a
15.5 (3–32) 7.5 (2–13) 2.0 (1–10)
18.0 (6–32) 9.0 (8–13)*** 2.0 (1–3)
12.0 (3–28) 5.0 (2–7) 2.0 (1–10)
20.5 (15–32)*** 8.0 (3–13)* 1.5 (1–3)*
8.0 (3–14) 5.5 (2–10) 2.0 (1–10)
0 0 0
Nicotine use Smokers (yes/no)c Quantity (cig./day)a Duration (years)a
30/0* 6.5 (2–30) 6.0 (1–13)
15/0 10.0 (2–30) 10.0 (7–13)**
15/0 4.0 (2–20) 3.0 (1–12)
16/0 9.0 (2–30) 7.5 (1–13)
14/0 4.0 (1–20) 3.5 (1–12)
9/21 0.0 (0–15) 0.0 (0–12)
Alcohol use Quantity (drinks/week)a BDI scoresa HAMD scoresa
3.0 (0–9)* 1.0 (0–4) 0.0 (0–1)
3.0 (0–9) 0.0 (0–2)* 0.0 (0–1)
3.0 (0–6) 2.0 (0–4) 0.0 (0–1)
2.5 (0–9) 1.0 (0–3) 0.0 (0–1)
3.5 (0–6) 1.0 (0–4) 0.0 (0–1)
2.0 (0–7) 0.0 (0–8) 0.0 (0–5)
a
Long-term users: ≥8 years; short-term users: <8 years; heavy users: ≥15 joints/week; light users: <15 joints/week. a Mann–Whitney test: *p < 0.05, **p < 0.01, ***p < 0.001 (users vs. controls; long-term vs. short-term; heavy vs. light). b 2 test: p > 0.1. c 2 test: p < 0.05.
strong LDAEP indicating low serotonergic function, and a favorable response to selective serotonin reuptake inhibitors (SSRI) has been found [16]. Moreover, depressive patients who had attempted suicide showed a stronger LDAEP than non-suicidal patients [5]. In healthy human subjects, 5-HT1B receptor polymorphisms were significantly related to LDAEP responses [20]. However, as pharmacological challenge studies with SSRIs in healthy subjects revealed conflicting results [13,26,38], the sensitivity and specificity of the LDAEP to acute and chronic changes in serotonergic neurotransmission have to be questioned. The aim of this study was to investigate the effects of chronic cannabis use on LDAEP in users compared to non-user controls. We hypothesized stronger LDAEP values in the user group as an indicator of dysfunctional serotonergic neurotransmission resulting from chronic cannabis use. In addition, we particularly focused on the influence of quantity and duration of cannabis use on the LDAEP. Thirty chronic cannabis users and 30 non-user controls were included in this study. The minimum requirement for participation as a cannabis user was regular use of at least three times per week for a period of at least 2 years. Detailed drug histories were assessed, and for all users cannabis abuse could be diagnosed according to DSM-IV criteria. The cannabis user group was split at the median on both quantity (light: <15 joints/week vs. heavy: ≥15 joints/week) and duration (short-term: <8 years vs. long-term: ≥8 years) of cannabis use. No meaningful division of groups could be achieved on the basis of age at onset of cannabis use. The demographic characteristics of the entire sample and the mean levels of cannabis use for each group are provided in Table 1. The group of non-user controls was matched for age and gender (p > 0.1). The control subjects had never used cannabis in the past according to their statement in the questionnaire. Both cannabis users and controls were normal hearing, right-handed and had no history of any psychiatric or neurological disorders, or use of any other drugs, as confirmed by a structured psychiatric interview (M.I.N.I.) [36]. Depressive symptoms were assessed by using the Beck Depression Inventory (BDI) [2] and the Hamilton Rating Scale for Depression (HAMD-21) [14]. Cannabis users were instructed to abstain from cannabis for at least 24 h prior to testing in order to exclude acute cannabis effects. For both cannabis users and controls, alcohol consumption was not allowed either for at least 24 h prior to testing. The urine of all subjects was checked for illegal drugs including cannabinoids. The cannabis users were tested
negative for amphetamines and ecstasy, benzodiazepines, cocaine, methadone and opioids, and positive for cannabinoids thus ensuring current use of cannabis and excluding the use of any other drug. The controls were tested negative for all substances. All subjects did not take any medication before the onset of the study. The study was approved by the local ethics committee. All subjects gave their written informed consent. Recording of auditory evoked potentials (AEP) took place in a sound-attenuated and electrically shielded room adjacent to the recording apparatus and was performed with the subject’s eyes open using BrainVision BrainAmp® MR (Brain Products GmbH, Munich, Germany). Subjects were seated in a slightly reclined chair with a head rest. The AEPs were recorded by 32 Ag–AgCl electrodes referred to FCz, using an electrode cap. We used FCz as reference site as it allowed us to keep the distance between recording reference and active electrodes small, thereby minimizing the chance of amplifier saturation. The electrodes were placed according to the international 10/20 system. Auditory stimuli (1000 Hz, 40 ms duration, 10 ms rise/fall time, ISI 1800–2200 ms) of five intensities (60, 70, 80, 90, 100 dB SPL) were presented binaurally in a pseudo-randomized form via headphones (Presentation 11.3® , Neurobehavioral Systems Inc., Albany, CA, USA). Eye movements were monitored using an electrode located 1 cm below the left outer canthus. Impedances were kept below 5 k. Data were collected with a sampling rate of 256 Hz and an analogous bandpass filter (0.16–70 Hz). At least 40 artifact-free (±50 V) sweeps per intensity were averaged (BrainVision Analyzer® , Brain Products GmbH, Munich, Germany). N1 peaks (60–125 ms) and P2 peaks (110–210 ms) were determined semi-automatically at the Cz electrode. The N1/P2 amplitude was defined as the difference in peak amplitude between N1 and P2. The LDAEP was calculated as the least-squares linear regression slope with stimulus intensity as independent and N1/P2 amplitude as dependent variables [20]. Statistical calculations were based on non-parametric tests. Group differences of the LDAEP values as well as the demographic parameters were assessed by the Mann–Whitney test and the 2 test. Values were expressed by medians and ranges. Spearman’s correlation coefficients were calculated to determine relationships between variables such as duration and quantity of cannabis use, and the LDAEP. Statistical significance was taken as p ≤ 0.05. All statistical analyses were carried out by using the statistical analysis software package SPSS 15.0® (Munich, Germany).
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Fig. 1. Grand average ERPs for the cannabis users (a) and the control (b) group for each of the five intensities (60, 70, 80, 90, 100 dB).
Demographic characteristics are presented in Table 1. There were no significant differences in age and gender between the user group and the control group. Cannabis users consumed more alcohol per week (p < 0.05) and had less years of education than non-user controls (p < 0.01). Moreover, all cannabis users were cigarette smokers compared to the control group that consisted of nine smokers and 21 non-smokers (p < 0.05). Long-term users were older than short-term users (p < 0.01). The time since last use of cannabis was shorter in heavy users compared to light users (p < 0.05). However, alcohol consumption and years of education did not differ between groups based on duration and quantity of use (p > 0.1). BDI and HAMD-21 scores did not differ between cannabis users and non-user controls (BDI: Z = −1.573, p = 0.116; HAMD: Z = −1.306, p = 0.192). Considering the cannabis user group, longterm users had lower BDI scores compared to short-term users (Z = −2.374, p = 0.018), whereas no significant differences in HAMD21 scores have been detected (Z = −0.482, p = 0.630). Moreover, there were no differences in BDI (Z = −0.346, p = 0.729) as well as in HAMD-21 (Z = −0.322, p = 0.748) scores for heavy users compared to light users. BDI and HAMD-21 scores of all groups did not fulfill criteria for a depressive syndrome and were not clinically relevant. AEP waveforms for each of the two groups and each of the five intensities are given in Fig. 1. Group comparison revealed no significant change in LDAEP values with increasing stimulus intensity for the cannabis users compared to the non-user controls (Z = −0.370, p = 0.712, Table 2). With regard to the cannabis user subgroups, there were no significant differences for long-term users compared to short-term users (Z = −1.265, p = 0.206) as well as for heavy users compared to light users (Z = −0.166, p = 0.868). Accordingly, quantity (r = 0.033, p = 0.864) and duration (r = −0.242, p = 0.198) of use as well as duration of abstinence (r = −0.103, p = 0.586) did not correlate with the LDAEP. Moreover, no significant correlation between Table 2 N1/P2 slopes (in medians and ranges) and amplitude ranges for the cannabis users, the non-user controls and the cannabis user subgroups.
Cannabis users Non-user controls Long-term users Short-term users Heavy users Light users
N1/P2 slope (V/10 dB)
N1/P2 amplitude range (V)
0.19 (0.01–0.46) 0.20 (0.06–0.46) 0.18 (0.08–0.46) 0.20 (0.01–0.34) 0.20 (0.01–0.46) 0.19 (0.08–0.34)
0.08–0.46 0.06–0.46 0.08–0.46 0.08–0.34 0.08–0.46 0.08–0.34
duration and quantity of nicotine consumption, quantity of alcohol consumption as well as BDI and HAMD-21 scores, and the LDAEP has been detected for both cannabis users and non-user controls. In addition, there was no influence of covariates such as age, gender or education on LDAEP values in both groups. This study investigated the effects of chronic cannabis use on the LDAEP as a potential marker of central serotonergic activity. AEPs were recorded in a group of 30 chronic cannabis users and in 30 non-user controls. Interestingly, we found no significant differences in LDAEP values in cannabis users compared to controls. In addition, duration and quantity of cannabis use within the user group had no influence on the LDAEP. Several explanations may account for these negative findings. Recently, a close relationship between cannabinoids, the endogenous cannabinoid system and serotonergic neurotransmission has been described. Animal experimental studies demonstrated that activation of the endogenous cannabinoid system by CB1 receptor agonists, such as WIN55,212-2, may enhance serotonergic and, to a minor degree, noradrenergic neurotransmission in the rat brain [1]. As the effects of WIN55,212-2 on serotonergic firing rate could be prevented by SR141716, a selective CB1 receptor antagonist, this effect may be based on a CB1 receptor-mediated mechanism. It is of note that these effects upon central serotonergic systems have been observed under acute and repeated drug influence [32]. In contrast, subjects who participated in this study were required to abstain from cannabis for at least 24 h before testing and, subsequently, were not acutely intoxicated. As the half-life of 9 -THC is about 1 h [25], it can be suggested that the endogenous cannabinoid system was virtually not affected by acute 9 -THC effects at the testing period. Chronic cannabis use has often been found to be dose dependently associated with depressed mood, dysthymia and major depression [18]. Based on the crucial role of serotonergic neurotransmission in the pathophysiology of depressive disorders, a strong LDAEP indicating low serotonergic function has been detected in depressed patients [16]. However, our study was carried out in young and psychiatrically unaffected subjects meeting the DSM-IV criteria for cannabis abuse that, in particular, demonstrated no depressive symptoms as confirmed by their low BDI and HAMD21 scores. It remains speculative whether cannabis users fulfilling the DSM-IV criteria for cannabis dependence and, thus, presumably showing more pronounced depressive symptoms would reveal a stronger intensity dependence compared to our study sample reflecting lower central serotonergic neurotransmission.
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Similar results were obtained by Tuchtenhagen et al. [37] who found no differences in serotonergic activity as assessed by using LDAEP in cannabis users instructed to abstain from use of cannabis at the study day. Another study using the same methods failed to demonstrate any serotonergic dysfunctions in cannabis users as well, although no information on the period of abstinence from cannabis prior to testing was given [6]. However, both research groups showed significantly increased LDAEP scores with higher stimulus intensities in both abstinent and long-term ecstasy (MDMA) users compared to drug-naïve controls within the same studies indicating that MDMA consumption may cause serotonergic impairments in humans [6,37]. It therefore appears that cannabis use, if at all, does not reach the magnitude of change in serotonergic function seen in MDMA users. In addition to its purported sensitivity to serotonin, several reports have discussed possible effects of other neuromodulatory systems on the LDAEP. For example, an animal study demonstrated a significant effect of dopaminergic modulation on the LDAEP [23], but this finding could not be replicated in healthy humans [29]. Moreover, acute tyrosine/phenylalanine depletion (ATPD) which has been used as a method to reduce dopamine function had no effect on the LDAEP [31]. On the other hand, a single-photon emission computed tomography (SPECT) study found a correlation between the LDAEP and striatal dopamine transporter (DAT) binding in patients with obsessive-compulsive disorder (OCD) [34]. More recently, a significant association of catechol-O-methyltransferase (COMT) genetic variants involved in the inactivation of synaptic dopamine with the LDAEP in healthy subjects has been detected [22]. Taken together, the evidence for an association between the dopaminergic system and the LDAEP is not consistent and, given the impact of cannabinoids on dopaminergic neurotransmission [35], cannot be supported by this study. Several limitations of this study have to be considered. First, information on duration, quantity and period of abstinence of cannabis use were obtained by self-report without external validation. However, previous studies have demonstrated that selfreports of use of cannabis and other drugs seem to be fairly reliable [15]. Second, a possible selection bias caused by the study requirements might have affected the results. It can be speculated whether chronic cannabis users with manifest depressive symptoms might have been less likely to participate in the study. Therefore, an underrepresentation of subjects suffering from depression within the study sample may be assumed. Third, the majority of evidence for an association between the LDAEP and serotonergic function has come from animal studies. However, several clinical and pharmacological studies in humans suggest that the LDAEP may lack sensitivity and specificity to acute and chronic changes in serotonergic transmission [30]. Considering this background, it is possible that cannabis use may have produced an effect on serotonergic function but that this effect was not strong enough to be detected by using the LDAEP. And finally, interindividual differences in the response to cannabinoids within the study sample have to be taken into account. In this context, a recent study demonstrated a genetic subpopulation of rats that was unaffected by cannabinoid agonists on an auditory gating task [9]. Consequently taken together, the results of this study have to be interpreted with caution. In summary, the results of this study indicate that chronic cannabis use in young and psychiatrically unaffected subjects was not associated with alterations in the LDAEP as a potential marker of central serotonergic neurotransmission. Moreover, duration and quantity of cannabis use had no influence on LDAEP values. It can be suggested that, on the one hand, acute activation of the endogenous cannabinoid system and, on the other hand, cannabis dependence accompanied by manifest depressive symptoms may rather reveal significant alterations in the LDAEP. Based on the supposed relationship between cannabis, the serotonergic system and
the pathogenesis of depression, our findings underline the need for further studies in this novel field of research. Conflict of interest The authors declare that they have no potential conflicts of interest in the context of the subject of this article. References [1] F.R. Bambico, N. Katz, G. Debonnel, G. Gobbi, Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex, J. Neurosci. 27 (2007) 11700–11711. [2] A.T. Beck, C.H. Ward, M. Mendelson, J. Mock, J. Erbaugh, An inventory for measuring depression, Arch. Gen. Psychiatry 4 (1961) 561–571. [3] D.W. Brook, J.S. Brook, C. Zhang, P. Cohen, M. Whiteman, Drug use and the risk of major depressive disorder, alcohol dependence, and substance use disorders, Arch. Gen. Psychiatry 59 (2002) 1039–1044. [4] C.Y. Chen, F.A. Wagner, J.C. Anthony, Marijuana use and the risk of major depressive episode. Epidemiological evidence from the United States National Comorbidity Survey, Soc. Psychiatry Psychiatr. Epidemiol. 37 (2002) 199–206. [5] T.J. Chen, Y.W. Yu, M.C. Chen, S.Y. Wang, S.J. Tsai, T.W. Lee, Serotonin dysfunction and suicide attempts in major depressives: an auditory event-related potential study, Neuropsychobiology 52 (2005) 28–36. [6] R.J. Croft, A. Klugman, T. Baldeweg, J.H. Gruzelier, Electrophysiological evidence of serotonergic impairment in long-term MDMA (“ecstasy”) users, Am. J. Psychiatry 158 (2001) 1687–1692. [7] L. Degenhardt, W. Hall, M. Lynskey, The relationship between cannabis use, depression and anxiety among Australian adults: findings from the National Survey of Mental Health and Well-Being, Soc. Psychiatry Psychiatr. Epidemiol. 36 (2001) 219–227. [8] L. Degenhardt, W. Hall, M. Lynskey, Exploring the association between cannabis use and depression, Addiction 98 (2003) 1493–1504. [9] D.W. Dissanayake, M. Zachariou, C.A. Marsden, R. Mason, Auditory gating in rat hippocampus and medial prefrontal cortex: effect of the cannabinoid agonist WIN55,212-2, Neuropharmacology 55 (2008) 1397–1404. [10] D.M. Fergusson, L.J. Horwood, N. Swain-Campbell, Cannabis use and psychosocial adjustment in adolescence and young adulthood, Addiction 97 (2002) 1123–1135. [11] Y. Gaoni, R. Mechoulam, Isolation, structure and partial synthesis of an active constituent of hashish, J. Am. Chem. Soc. 86 (1964) 1646–1647. [12] B.F. Grant, Comorbidity between DSM-IV drug use disorders and major depression: results of a national survey of adults, J. Subst. Abuse 7 (1995) 481–497. [13] V. Guille, R.J. Croft, B.V. O’Neill, S. Illic, K.L. Phan, P.J. Nathan, An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline, Hum. Psychopharmacol. 23 (2008) 231–241. [14] M. Hamilton, A rating scale for depression, J. Neurol. Neurosurg. Psychiatry 23 (1960) 56–62. [15] E.R. Harrison, J. Haaga, T. Richards, Self reported drug use data: what do they reveal? Am. J. Drug Alcohol Abuse 19 (1993) 423–441. [16] U. Hegerl, J. Gallinat, G. Juckel, Event-related potentials. Do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J. Affect. Disord. 62 (2001) 93–100. [17] M.N. Hill, J.C. Sun, M.T. Tse, B.B. Gorzalka, Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment, Int. J. Neuropsychopharmacol. 9 (2006) 277–286. [18] A. Johns, Psychiatric effects of cannabis, Br. J. Psychiatry 178 (2001) 116–122. [19] G. Juckel, J. Gallinat, M. Riedel, S. Sokullu, C. Schulz, H.J. Möller, N. Müller, U. Hegerl, Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity, Schizophr. Res. 64 (2003) 115–124. [20] G. Juckel, U. Hegerl, I. Giegling, P. Mavrogiorgou, A. Wutzler, C. Schuhmacher, I. Uhl, M. Brüne, C. Mulert, O. Pogarell, D. Rujescu, Association of 5-HT1B receptor polymorphisms with the loudness dependence of auditory evoked potentials in a community-based sample of healthy volunteers, Am. J. Med. Genet. B Neuropsychiatry Genet. 147 (2008) 454–458. [21] G. Juckel, U. Hegerl, M. Molnar, V. Csepe, G. Karmos, Auditory evoked potentials reflect serotonergic neuronal activity—a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus, Neuropsychopharmacology 21 (1999) 710–716. [22] G. Juckel, W. Kawohl, I. Giegling, P. Mavrogiorgou, C. Winter, O. Pogarell, C. Mulert, U. Hegerl, D. Rujescu, Association of catechol-O-methyltransferase variants with loudness dependence of auditory evoked potentials, Hum. Psychopharmacol. 23 (2008) 115–120. [23] G. Juckel, M. Molnár, U. Hegerl, V. Csépe, G. Karmos, Auditory-evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats, Biol. Psychiatry 41 (1997) 1181–1195. [24] T.H. Moore, S. Zammit, A. Lingford-Hughes, T.R. Barnes, P.B. Jones, M. Burke, G. Lewis, Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review, Lancet 370 (2007) 319–328. [25] T. Nadulski, F. Pragst, G. Weinberg, P. Roser, M. Schnelle, E.M. Fronk, A.M. Stadelmann, Randomized, double-blind, placebo-controlled study about the effects
P. Roser et al. / Neuroscience Letters 465 (2009) 113–117
[26]
[27]
[28] [29]
[30]
[31]
[32]
of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract, Ther. Drug Monit. 27 (2005) 799–810. P.J. Nathan, R. Segrave, K.L. Phan, B. O’Neill, R.J. Croft, Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function, Hum. Psychopharmacol. 21 (2006) 47–52. C. Norra, M. Mrazek, F. Tuchtenhagen, R. Gobbelé, H. Buchner, H. Sass, S.C. Herpertz, Enhanced intensity dependence as a marker of low serotonergic neurotransmission in borderline personality disorder, J. Psychiatr. Res. 37 (2003) 23–33. D.J. Nutt, The neuropharmacology of serotonin and noradrenaline in depression, Int. Clin. Psychopharmacol. 17 (2002) S1–12. B.V. O’Neill, R.J. Croft, S. Leung, V. Guille, M. Galloway, K.L. Phan, P.J. Nathan, Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans, Psychopharmacology 188 (2006) 92–99. B.V. O’Neill, R.J. Croft, P.J. Nathan, The loudness dependence of the auditory evoked potential (LDAEP) as an in vivo biomarker of central serotonergic function in humans: rationale, evaluation and review of findings, Hum. Psychopharmacol. 23 (2008) 355–370. B.V. O’Neill, V. Guille, R.J. Croft, S. Leung, K.E. Scholes, K.L. Phan, P.J. Nathan, Effects of selective and combined serotonin and dopamine depletion on the loudness dependence of the auditory evoked potential (LDAEP) in humans, Hum. Psychopharmacol. 23 (2008) 301–312. E. Palazzo, V. de Novellis, S. Petrosino, I. Marabese, D. Vita, C. Giordano, V. Di Marzo, G.S. Mangoni, F. Rossi, S. Maione, Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system, Eur. J. Neurosci. 24 (2006) 2011–2020.
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[33] G.C. Patton, C. Coffey, J.B. Carlin, L. Degenhardt, M. Lynskey, W. Hall, Cannabis use and mental health in young people: cohort study, BMJ 325 (2002) 1195–1198. [34] O. Pogarell, K. Tatsch, G. Juckel, C. Hamann, C. Mulert, G. Pöpperl, M. Folkerts, M. Choukèr, M. Riedel, M. Zaudig, H.J. Möller, U. Hegerl, Serotonin and dopamine transporter availabilities correlate with the loudness dependence of auditory evoked potentials in patients with obsessive-compulsive disorder, Neuropsychopharmacology 29 (2004) 1910–1917. [35] F. Rodríguez De Fonseca, M.A. Gorriti, A. Bilbao, L. Escuredo, L.M. García-Segura, D. Piomelli, M. Navarro, Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implications for Parkinson’s disease and schizophrenia, Neurotox. Res. 3 (2001) 23–35. [36] D.V. Sheehan, Y. Lecrubier, K.H. Sheehan, P. Amorim, J. Janavs, E. Weiller, T. Hergueta, R. Baker, G.C. Dunbar, The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, J. Clin. Psychiatry 59 (1998) 22–33. [37] F. Tuchtenhagen, J. Daumann, C. Norra, R. Gobbelé, S. Becker, S. Pelz, H. Sass, H. Buchner, E. Gouzoulis-Mayfrank, High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users, Neuropsychopharmacology 22 (2000) 608–617. [38] I. Uhl, I. Gorynia, J. Gallinat, C. Mulert, A. Wutzler, A. Heinz, G. Juckel, Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects? Hum. Psychopharmacol. 21 (2006) 463–471. [39] A. Wutzler, C. Winter, W. Kitzrow, I. Uhl, R.J. Wolf, A. Heinz, G. Juckel, Loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission: simultaneous electrophysiological recordings and in vivo microdialysis in the rat primary auditory cortex, Neuropsychopharmacology 33 (2008) 3176–3181.
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No association between chronic cannabis use and loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission Patrik Roser ∗ , Beate Della, Christine Norra, Georg Juckel, Idun Uhl Department of Psychiatry, Ruhr-University, Alexandrinenstr. 1, 44791 Bochum, Germany
a r t i c l e
i n f o
Article history: Received 2 June 2009 Received in revised form 1 September 2009 Accepted 14 September 2009 Keywords: Cannabis Serotonin Loudness dependence Auditory evoked potentials
a b s t r a c t Chronic cannabis use has been found to be associated with major depression. It is suggested that cannabis use induces changes in neurotransmitter systems involved in the pathogenesis of depressive disorders, particularly in the serotonergic system. The analysis of the loudness dependence of auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity in animals and humans. In the present study, we investigated the effects of chronic cannabis use on LDAEP in 30 psychiatrically unaffected users compared to 30 non-user controls. Users were required to abstain from cannabis for at least 24 h before testing. Putative depressive symptoms were assessed by using the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-21). LDAEP as well as BDI and HAMD-21 scores did not differ between cannabis users and controls. Moreover, LDAEP neither correlate with duration and quantity of cannabis use nor with psychometric assessments. These results indicate that chronic cannabis use had no influence on the LDAEP in this study sample. It can be suggested that significant alterations in serotonergic systems may rather be related to acute activation of the endogenous cannabinoid system or to cannabis dependence accompanied by manifest depressive symptoms. © 2009 Elsevier Ireland Ltd. All rights reserved.
Cannabis sativa is the most widely used illicit drug in the Western world. 9 -Tetrahydrocannabinol (9 -THC) has been identified as the primary psychoactive constituent of the Cannabis sativa plant acting at central cannabinoid (CB1 ) receptors [11]. There is increasing evidence that cannabis modulates affective and emotional regulation. Acute effects of cannabis include feelings of ‘high’, euphoria and contentment [18], whereas chronic cannabis use has been found to increase the rates of depressive symptoms [8]. The association between cannabis use and depression has been subject to considerable controversy. Chen et al. found that a greater number of occasions of cannabis use were associated with a higher risk of having experienced a major depressive episode, and that life-time cannabis dependence was associated with a 3.4 times increased risk of major depression [4]. Another epidemiological survey demonstrated that cannabis abuse or dependence within the past year was associated with a 6.4 times increased risk of meeting criteria for major depression [12]. In particular, early onset of regular cannabis use as well as heavy cannabis use were related to the strongest increase in risk of later major depression, whereas little evidence was found for an association between infrequent cannabis use and depression [3,7,10,33]. However, a recent review
∗ Corresponding author. Tel.: +49 234 5077 370; fax: +49 234 5077 234. E-mail address: [email protected] (P. Roser). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.09.027
showed that the findings for an increased risk of affective disorders due to cannabis use were less consistent than for psychosis [24]. In this context, animal studies demonstrated acute as well as chronic effects of cannabinoids on the serotonergic system that is strongly associated with the pathogenesis of depressive disorders [28]. Acute cannabinoid treatment has been found to modulate serotonergic neuronal activity in the rat dorsal raphe nucleus [1]. On the other hand, Hill et al. found that chronic cannabinoid treatment may alter the activity of different serotonin receptor subtypes in rats [17]. Nevertheless, an association between cannabis use and serotonergic dysfunctions in humans have not been explored so far. Loudness dependence of auditory evoked potentials (LDAEP), a specific aspect of information processing, has been proposed to be a valid indicator of central serotonergic function [39]. The LDAEP can be measured by the increase of N1/P2 amplitude values with increasing tone loudness during auditory stimulation. Based on animal findings demonstrating that sensory processing in the primary auditory cortex is modulated by serotonergic neurotransmission, the intensity of the LDAEP has been found to be inversely correlated with central serotonergic activity [21,39]. In humans, the sensitivity of the LDAEP to acute and chronic changes in serotonergic activity is less consistent. A strong LDAEP has been found in patients with psychiatric disorders with an assumed deficiency of serotonin, such as borderline personality disorder [27] or schizophrenia [19]. In depressed patients, a significant relationship between
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Table 1 Demographic characteristics of the study sample (in medians and ranges). All users n = 30
Long-term users n = 15
Short-term users n = 15
Heavy users n = 16
Light users n = 14
Controls n = 30
Age (years) Sex (male/female)b Education (years)a
22.0 (19–27) 17/13 16.0 (12–17)**
24.0 (21–27)** 9/6 16.0 (12–17)
21.0 (19–26) 8/7 14.0 (13–17)
23.0 (21–27) 8/8 15.5 (12–17)
22.0 (19–26) 9/5 16.0 (13–17)
24.0 (18–27) 15/15 17.0 (12–21)
Cannabis use Quantity (joints/week)a Duration (years)a Abstinence (days)a
15.5 (3–32) 7.5 (2–13) 2.0 (1–10)
18.0 (6–32) 9.0 (8–13)*** 2.0 (1–3)
12.0 (3–28) 5.0 (2–7) 2.0 (1–10)
20.5 (15–32)*** 8.0 (3–13)* 1.5 (1–3)*
8.0 (3–14) 5.5 (2–10) 2.0 (1–10)
0 0 0
Nicotine use Smokers (yes/no)c Quantity (cig./day)a Duration (years)a
30/0* 6.5 (2–30) 6.0 (1–13)
15/0 10.0 (2–30) 10.0 (7–13)**
15/0 4.0 (2–20) 3.0 (1–12)
16/0 9.0 (2–30) 7.5 (1–13)
14/0 4.0 (1–20) 3.5 (1–12)
9/21 0.0 (0–15) 0.0 (0–12)
Alcohol use Quantity (drinks/week)a BDI scoresa HAMD scoresa
3.0 (0–9)* 1.0 (0–4) 0.0 (0–1)
3.0 (0–9) 0.0 (0–2)* 0.0 (0–1)
3.0 (0–6) 2.0 (0–4) 0.0 (0–1)
2.5 (0–9) 1.0 (0–3) 0.0 (0–1)
3.5 (0–6) 1.0 (0–4) 0.0 (0–1)
2.0 (0–7) 0.0 (0–8) 0.0 (0–5)
a
Long-term users: ≥8 years; short-term users: <8 years; heavy users: ≥15 joints/week; light users: <15 joints/week. a Mann–Whitney test: *p < 0.05, **p < 0.01, ***p < 0.001 (users vs. controls; long-term vs. short-term; heavy vs. light). b 2 test: p > 0.1. c 2 test: p < 0.05.
strong LDAEP indicating low serotonergic function, and a favorable response to selective serotonin reuptake inhibitors (SSRI) has been found [16]. Moreover, depressive patients who had attempted suicide showed a stronger LDAEP than non-suicidal patients [5]. In healthy human subjects, 5-HT1B receptor polymorphisms were significantly related to LDAEP responses [20]. However, as pharmacological challenge studies with SSRIs in healthy subjects revealed conflicting results [13,26,38], the sensitivity and specificity of the LDAEP to acute and chronic changes in serotonergic neurotransmission have to be questioned. The aim of this study was to investigate the effects of chronic cannabis use on LDAEP in users compared to non-user controls. We hypothesized stronger LDAEP values in the user group as an indicator of dysfunctional serotonergic neurotransmission resulting from chronic cannabis use. In addition, we particularly focused on the influence of quantity and duration of cannabis use on the LDAEP. Thirty chronic cannabis users and 30 non-user controls were included in this study. The minimum requirement for participation as a cannabis user was regular use of at least three times per week for a period of at least 2 years. Detailed drug histories were assessed, and for all users cannabis abuse could be diagnosed according to DSM-IV criteria. The cannabis user group was split at the median on both quantity (light: <15 joints/week vs. heavy: ≥15 joints/week) and duration (short-term: <8 years vs. long-term: ≥8 years) of cannabis use. No meaningful division of groups could be achieved on the basis of age at onset of cannabis use. The demographic characteristics of the entire sample and the mean levels of cannabis use for each group are provided in Table 1. The group of non-user controls was matched for age and gender (p > 0.1). The control subjects had never used cannabis in the past according to their statement in the questionnaire. Both cannabis users and controls were normal hearing, right-handed and had no history of any psychiatric or neurological disorders, or use of any other drugs, as confirmed by a structured psychiatric interview (M.I.N.I.) [36]. Depressive symptoms were assessed by using the Beck Depression Inventory (BDI) [2] and the Hamilton Rating Scale for Depression (HAMD-21) [14]. Cannabis users were instructed to abstain from cannabis for at least 24 h prior to testing in order to exclude acute cannabis effects. For both cannabis users and controls, alcohol consumption was not allowed either for at least 24 h prior to testing. The urine of all subjects was checked for illegal drugs including cannabinoids. The cannabis users were tested
negative for amphetamines and ecstasy, benzodiazepines, cocaine, methadone and opioids, and positive for cannabinoids thus ensuring current use of cannabis and excluding the use of any other drug. The controls were tested negative for all substances. All subjects did not take any medication before the onset of the study. The study was approved by the local ethics committee. All subjects gave their written informed consent. Recording of auditory evoked potentials (AEP) took place in a sound-attenuated and electrically shielded room adjacent to the recording apparatus and was performed with the subject’s eyes open using BrainVision BrainAmp® MR (Brain Products GmbH, Munich, Germany). Subjects were seated in a slightly reclined chair with a head rest. The AEPs were recorded by 32 Ag–AgCl electrodes referred to FCz, using an electrode cap. We used FCz as reference site as it allowed us to keep the distance between recording reference and active electrodes small, thereby minimizing the chance of amplifier saturation. The electrodes were placed according to the international 10/20 system. Auditory stimuli (1000 Hz, 40 ms duration, 10 ms rise/fall time, ISI 1800–2200 ms) of five intensities (60, 70, 80, 90, 100 dB SPL) were presented binaurally in a pseudo-randomized form via headphones (Presentation 11.3® , Neurobehavioral Systems Inc., Albany, CA, USA). Eye movements were monitored using an electrode located 1 cm below the left outer canthus. Impedances were kept below 5 k. Data were collected with a sampling rate of 256 Hz and an analogous bandpass filter (0.16–70 Hz). At least 40 artifact-free (±50 V) sweeps per intensity were averaged (BrainVision Analyzer® , Brain Products GmbH, Munich, Germany). N1 peaks (60–125 ms) and P2 peaks (110–210 ms) were determined semi-automatically at the Cz electrode. The N1/P2 amplitude was defined as the difference in peak amplitude between N1 and P2. The LDAEP was calculated as the least-squares linear regression slope with stimulus intensity as independent and N1/P2 amplitude as dependent variables [20]. Statistical calculations were based on non-parametric tests. Group differences of the LDAEP values as well as the demographic parameters were assessed by the Mann–Whitney test and the 2 test. Values were expressed by medians and ranges. Spearman’s correlation coefficients were calculated to determine relationships between variables such as duration and quantity of cannabis use, and the LDAEP. Statistical significance was taken as p ≤ 0.05. All statistical analyses were carried out by using the statistical analysis software package SPSS 15.0® (Munich, Germany).
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Fig. 1. Grand average ERPs for the cannabis users (a) and the control (b) group for each of the five intensities (60, 70, 80, 90, 100 dB).
Demographic characteristics are presented in Table 1. There were no significant differences in age and gender between the user group and the control group. Cannabis users consumed more alcohol per week (p < 0.05) and had less years of education than non-user controls (p < 0.01). Moreover, all cannabis users were cigarette smokers compared to the control group that consisted of nine smokers and 21 non-smokers (p < 0.05). Long-term users were older than short-term users (p < 0.01). The time since last use of cannabis was shorter in heavy users compared to light users (p < 0.05). However, alcohol consumption and years of education did not differ between groups based on duration and quantity of use (p > 0.1). BDI and HAMD-21 scores did not differ between cannabis users and non-user controls (BDI: Z = −1.573, p = 0.116; HAMD: Z = −1.306, p = 0.192). Considering the cannabis user group, longterm users had lower BDI scores compared to short-term users (Z = −2.374, p = 0.018), whereas no significant differences in HAMD21 scores have been detected (Z = −0.482, p = 0.630). Moreover, there were no differences in BDI (Z = −0.346, p = 0.729) as well as in HAMD-21 (Z = −0.322, p = 0.748) scores for heavy users compared to light users. BDI and HAMD-21 scores of all groups did not fulfill criteria for a depressive syndrome and were not clinically relevant. AEP waveforms for each of the two groups and each of the five intensities are given in Fig. 1. Group comparison revealed no significant change in LDAEP values with increasing stimulus intensity for the cannabis users compared to the non-user controls (Z = −0.370, p = 0.712, Table 2). With regard to the cannabis user subgroups, there were no significant differences for long-term users compared to short-term users (Z = −1.265, p = 0.206) as well as for heavy users compared to light users (Z = −0.166, p = 0.868). Accordingly, quantity (r = 0.033, p = 0.864) and duration (r = −0.242, p = 0.198) of use as well as duration of abstinence (r = −0.103, p = 0.586) did not correlate with the LDAEP. Moreover, no significant correlation between Table 2 N1/P2 slopes (in medians and ranges) and amplitude ranges for the cannabis users, the non-user controls and the cannabis user subgroups.
Cannabis users Non-user controls Long-term users Short-term users Heavy users Light users
N1/P2 slope (V/10 dB)
N1/P2 amplitude range (V)
0.19 (0.01–0.46) 0.20 (0.06–0.46) 0.18 (0.08–0.46) 0.20 (0.01–0.34) 0.20 (0.01–0.46) 0.19 (0.08–0.34)
0.08–0.46 0.06–0.46 0.08–0.46 0.08–0.34 0.08–0.46 0.08–0.34
duration and quantity of nicotine consumption, quantity of alcohol consumption as well as BDI and HAMD-21 scores, and the LDAEP has been detected for both cannabis users and non-user controls. In addition, there was no influence of covariates such as age, gender or education on LDAEP values in both groups. This study investigated the effects of chronic cannabis use on the LDAEP as a potential marker of central serotonergic activity. AEPs were recorded in a group of 30 chronic cannabis users and in 30 non-user controls. Interestingly, we found no significant differences in LDAEP values in cannabis users compared to controls. In addition, duration and quantity of cannabis use within the user group had no influence on the LDAEP. Several explanations may account for these negative findings. Recently, a close relationship between cannabinoids, the endogenous cannabinoid system and serotonergic neurotransmission has been described. Animal experimental studies demonstrated that activation of the endogenous cannabinoid system by CB1 receptor agonists, such as WIN55,212-2, may enhance serotonergic and, to a minor degree, noradrenergic neurotransmission in the rat brain [1]. As the effects of WIN55,212-2 on serotonergic firing rate could be prevented by SR141716, a selective CB1 receptor antagonist, this effect may be based on a CB1 receptor-mediated mechanism. It is of note that these effects upon central serotonergic systems have been observed under acute and repeated drug influence [32]. In contrast, subjects who participated in this study were required to abstain from cannabis for at least 24 h before testing and, subsequently, were not acutely intoxicated. As the half-life of 9 -THC is about 1 h [25], it can be suggested that the endogenous cannabinoid system was virtually not affected by acute 9 -THC effects at the testing period. Chronic cannabis use has often been found to be dose dependently associated with depressed mood, dysthymia and major depression [18]. Based on the crucial role of serotonergic neurotransmission in the pathophysiology of depressive disorders, a strong LDAEP indicating low serotonergic function has been detected in depressed patients [16]. However, our study was carried out in young and psychiatrically unaffected subjects meeting the DSM-IV criteria for cannabis abuse that, in particular, demonstrated no depressive symptoms as confirmed by their low BDI and HAMD21 scores. It remains speculative whether cannabis users fulfilling the DSM-IV criteria for cannabis dependence and, thus, presumably showing more pronounced depressive symptoms would reveal a stronger intensity dependence compared to our study sample reflecting lower central serotonergic neurotransmission.
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Similar results were obtained by Tuchtenhagen et al. [37] who found no differences in serotonergic activity as assessed by using LDAEP in cannabis users instructed to abstain from use of cannabis at the study day. Another study using the same methods failed to demonstrate any serotonergic dysfunctions in cannabis users as well, although no information on the period of abstinence from cannabis prior to testing was given [6]. However, both research groups showed significantly increased LDAEP scores with higher stimulus intensities in both abstinent and long-term ecstasy (MDMA) users compared to drug-naïve controls within the same studies indicating that MDMA consumption may cause serotonergic impairments in humans [6,37]. It therefore appears that cannabis use, if at all, does not reach the magnitude of change in serotonergic function seen in MDMA users. In addition to its purported sensitivity to serotonin, several reports have discussed possible effects of other neuromodulatory systems on the LDAEP. For example, an animal study demonstrated a significant effect of dopaminergic modulation on the LDAEP [23], but this finding could not be replicated in healthy humans [29]. Moreover, acute tyrosine/phenylalanine depletion (ATPD) which has been used as a method to reduce dopamine function had no effect on the LDAEP [31]. On the other hand, a single-photon emission computed tomography (SPECT) study found a correlation between the LDAEP and striatal dopamine transporter (DAT) binding in patients with obsessive-compulsive disorder (OCD) [34]. More recently, a significant association of catechol-O-methyltransferase (COMT) genetic variants involved in the inactivation of synaptic dopamine with the LDAEP in healthy subjects has been detected [22]. Taken together, the evidence for an association between the dopaminergic system and the LDAEP is not consistent and, given the impact of cannabinoids on dopaminergic neurotransmission [35], cannot be supported by this study. Several limitations of this study have to be considered. First, information on duration, quantity and period of abstinence of cannabis use were obtained by self-report without external validation. However, previous studies have demonstrated that selfreports of use of cannabis and other drugs seem to be fairly reliable [15]. Second, a possible selection bias caused by the study requirements might have affected the results. It can be speculated whether chronic cannabis users with manifest depressive symptoms might have been less likely to participate in the study. Therefore, an underrepresentation of subjects suffering from depression within the study sample may be assumed. Third, the majority of evidence for an association between the LDAEP and serotonergic function has come from animal studies. However, several clinical and pharmacological studies in humans suggest that the LDAEP may lack sensitivity and specificity to acute and chronic changes in serotonergic transmission [30]. Considering this background, it is possible that cannabis use may have produced an effect on serotonergic function but that this effect was not strong enough to be detected by using the LDAEP. And finally, interindividual differences in the response to cannabinoids within the study sample have to be taken into account. In this context, a recent study demonstrated a genetic subpopulation of rats that was unaffected by cannabinoid agonists on an auditory gating task [9]. Consequently taken together, the results of this study have to be interpreted with caution. In summary, the results of this study indicate that chronic cannabis use in young and psychiatrically unaffected subjects was not associated with alterations in the LDAEP as a potential marker of central serotonergic neurotransmission. Moreover, duration and quantity of cannabis use had no influence on LDAEP values. It can be suggested that, on the one hand, acute activation of the endogenous cannabinoid system and, on the other hand, cannabis dependence accompanied by manifest depressive symptoms may rather reveal significant alterations in the LDAEP. Based on the supposed relationship between cannabis, the serotonergic system and
the pathogenesis of depression, our findings underline the need for further studies in this novel field of research. Conflict of interest The authors declare that they have no potential conflicts of interest in the context of the subject of this article. References [1] F.R. Bambico, N. Katz, G. Debonnel, G. Gobbi, Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex, J. Neurosci. 27 (2007) 11700–11711. [2] A.T. Beck, C.H. Ward, M. Mendelson, J. Mock, J. Erbaugh, An inventory for measuring depression, Arch. Gen. Psychiatry 4 (1961) 561–571. [3] D.W. Brook, J.S. Brook, C. Zhang, P. Cohen, M. Whiteman, Drug use and the risk of major depressive disorder, alcohol dependence, and substance use disorders, Arch. Gen. Psychiatry 59 (2002) 1039–1044. [4] C.Y. Chen, F.A. Wagner, J.C. Anthony, Marijuana use and the risk of major depressive episode. Epidemiological evidence from the United States National Comorbidity Survey, Soc. Psychiatry Psychiatr. Epidemiol. 37 (2002) 199–206. [5] T.J. Chen, Y.W. Yu, M.C. Chen, S.Y. Wang, S.J. Tsai, T.W. Lee, Serotonin dysfunction and suicide attempts in major depressives: an auditory event-related potential study, Neuropsychobiology 52 (2005) 28–36. [6] R.J. Croft, A. Klugman, T. Baldeweg, J.H. Gruzelier, Electrophysiological evidence of serotonergic impairment in long-term MDMA (“ecstasy”) users, Am. J. Psychiatry 158 (2001) 1687–1692. [7] L. Degenhardt, W. Hall, M. Lynskey, The relationship between cannabis use, depression and anxiety among Australian adults: findings from the National Survey of Mental Health and Well-Being, Soc. Psychiatry Psychiatr. Epidemiol. 36 (2001) 219–227. [8] L. Degenhardt, W. Hall, M. Lynskey, Exploring the association between cannabis use and depression, Addiction 98 (2003) 1493–1504. [9] D.W. Dissanayake, M. Zachariou, C.A. Marsden, R. Mason, Auditory gating in rat hippocampus and medial prefrontal cortex: effect of the cannabinoid agonist WIN55,212-2, Neuropharmacology 55 (2008) 1397–1404. [10] D.M. Fergusson, L.J. Horwood, N. Swain-Campbell, Cannabis use and psychosocial adjustment in adolescence and young adulthood, Addiction 97 (2002) 1123–1135. [11] Y. Gaoni, R. Mechoulam, Isolation, structure and partial synthesis of an active constituent of hashish, J. Am. Chem. Soc. 86 (1964) 1646–1647. [12] B.F. Grant, Comorbidity between DSM-IV drug use disorders and major depression: results of a national survey of adults, J. Subst. Abuse 7 (1995) 481–497. [13] V. Guille, R.J. Croft, B.V. O’Neill, S. Illic, K.L. Phan, P.J. Nathan, An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline, Hum. Psychopharmacol. 23 (2008) 231–241. [14] M. Hamilton, A rating scale for depression, J. Neurol. Neurosurg. Psychiatry 23 (1960) 56–62. [15] E.R. Harrison, J. Haaga, T. Richards, Self reported drug use data: what do they reveal? Am. J. Drug Alcohol Abuse 19 (1993) 423–441. [16] U. Hegerl, J. Gallinat, G. Juckel, Event-related potentials. Do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J. Affect. Disord. 62 (2001) 93–100. [17] M.N. Hill, J.C. Sun, M.T. Tse, B.B. Gorzalka, Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment, Int. J. Neuropsychopharmacol. 9 (2006) 277–286. [18] A. Johns, Psychiatric effects of cannabis, Br. J. Psychiatry 178 (2001) 116–122. [19] G. Juckel, J. Gallinat, M. Riedel, S. Sokullu, C. Schulz, H.J. Möller, N. Müller, U. Hegerl, Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity, Schizophr. Res. 64 (2003) 115–124. [20] G. Juckel, U. Hegerl, I. Giegling, P. Mavrogiorgou, A. Wutzler, C. Schuhmacher, I. Uhl, M. Brüne, C. Mulert, O. Pogarell, D. Rujescu, Association of 5-HT1B receptor polymorphisms with the loudness dependence of auditory evoked potentials in a community-based sample of healthy volunteers, Am. J. Med. Genet. B Neuropsychiatry Genet. 147 (2008) 454–458. [21] G. Juckel, U. Hegerl, M. Molnar, V. Csepe, G. Karmos, Auditory evoked potentials reflect serotonergic neuronal activity—a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus, Neuropsychopharmacology 21 (1999) 710–716. [22] G. Juckel, W. Kawohl, I. Giegling, P. Mavrogiorgou, C. Winter, O. Pogarell, C. Mulert, U. Hegerl, D. Rujescu, Association of catechol-O-methyltransferase variants with loudness dependence of auditory evoked potentials, Hum. Psychopharmacol. 23 (2008) 115–120. [23] G. Juckel, M. Molnár, U. Hegerl, V. Csépe, G. Karmos, Auditory-evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats, Biol. Psychiatry 41 (1997) 1181–1195. [24] T.H. Moore, S. Zammit, A. Lingford-Hughes, T.R. Barnes, P.B. Jones, M. Burke, G. Lewis, Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review, Lancet 370 (2007) 319–328. [25] T. Nadulski, F. Pragst, G. Weinberg, P. Roser, M. Schnelle, E.M. Fronk, A.M. Stadelmann, Randomized, double-blind, placebo-controlled study about the effects
P. Roser et al. / Neuroscience Letters 465 (2009) 113–117
[26]
[27]
[28] [29]
[30]
[31]
[32]
of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract, Ther. Drug Monit. 27 (2005) 799–810. P.J. Nathan, R. Segrave, K.L. Phan, B. O’Neill, R.J. Croft, Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function, Hum. Psychopharmacol. 21 (2006) 47–52. C. Norra, M. Mrazek, F. Tuchtenhagen, R. Gobbelé, H. Buchner, H. Sass, S.C. Herpertz, Enhanced intensity dependence as a marker of low serotonergic neurotransmission in borderline personality disorder, J. Psychiatr. Res. 37 (2003) 23–33. D.J. Nutt, The neuropharmacology of serotonin and noradrenaline in depression, Int. Clin. Psychopharmacol. 17 (2002) S1–12. B.V. O’Neill, R.J. Croft, S. Leung, V. Guille, M. Galloway, K.L. Phan, P.J. Nathan, Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans, Psychopharmacology 188 (2006) 92–99. B.V. O’Neill, R.J. Croft, P.J. Nathan, The loudness dependence of the auditory evoked potential (LDAEP) as an in vivo biomarker of central serotonergic function in humans: rationale, evaluation and review of findings, Hum. Psychopharmacol. 23 (2008) 355–370. B.V. O’Neill, V. Guille, R.J. Croft, S. Leung, K.E. Scholes, K.L. Phan, P.J. Nathan, Effects of selective and combined serotonin and dopamine depletion on the loudness dependence of the auditory evoked potential (LDAEP) in humans, Hum. Psychopharmacol. 23 (2008) 301–312. E. Palazzo, V. de Novellis, S. Petrosino, I. Marabese, D. Vita, C. Giordano, V. Di Marzo, G.S. Mangoni, F. Rossi, S. Maione, Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system, Eur. J. Neurosci. 24 (2006) 2011–2020.
117
[33] G.C. Patton, C. Coffey, J.B. Carlin, L. Degenhardt, M. Lynskey, W. Hall, Cannabis use and mental health in young people: cohort study, BMJ 325 (2002) 1195–1198. [34] O. Pogarell, K. Tatsch, G. Juckel, C. Hamann, C. Mulert, G. Pöpperl, M. Folkerts, M. Choukèr, M. Riedel, M. Zaudig, H.J. Möller, U. Hegerl, Serotonin and dopamine transporter availabilities correlate with the loudness dependence of auditory evoked potentials in patients with obsessive-compulsive disorder, Neuropsychopharmacology 29 (2004) 1910–1917. [35] F. Rodríguez De Fonseca, M.A. Gorriti, A. Bilbao, L. Escuredo, L.M. García-Segura, D. Piomelli, M. Navarro, Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implications for Parkinson’s disease and schizophrenia, Neurotox. Res. 3 (2001) 23–35. [36] D.V. Sheehan, Y. Lecrubier, K.H. Sheehan, P. Amorim, J. Janavs, E. Weiller, T. Hergueta, R. Baker, G.C. Dunbar, The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, J. Clin. Psychiatry 59 (1998) 22–33. [37] F. Tuchtenhagen, J. Daumann, C. Norra, R. Gobbelé, S. Becker, S. Pelz, H. Sass, H. Buchner, E. Gouzoulis-Mayfrank, High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users, Neuropsychopharmacology 22 (2000) 608–617. [38] I. Uhl, I. Gorynia, J. Gallinat, C. Mulert, A. Wutzler, A. Heinz, G. Juckel, Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects? Hum. Psychopharmacol. 21 (2006) 463–471. [39] A. Wutzler, C. Winter, W. Kitzrow, I. Uhl, R.J. Wolf, A. Heinz, G. Juckel, Loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission: simultaneous electrophysiological recordings and in vivo microdialysis in the rat primary auditory cortex, Neuropsychopharmacology 33 (2008) 3176–3181.