Central Serotonergic Neurotransmission Research Articles

Microbiome composition and central serotonergic activity in patients with depression and type 1 diabetes

The role of gut–brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes–Firmicutes ratio in both patients’ groups. Together, this data suggests that the guts’ microbiota composition might play an important role in regulating the central serotonergic activity in the brain.

The Loudness Dependence of Auditory Evoked Potentials is associated with the Symptom Severity and Treatment in Boys with Attention Deficit Hyperactivity Disorder.

ObjectiveThe loudness dependence of the auditory evoked potential (LDAEP) is associated with central serotonergic neurotransmission. Recent studies have proposed that LDAEP is also influenced by dopaminergic activity. Evidence shows attention deficit hyperactivity disorder (ADHD) symptoms are associated with dopamine dysfunction. This study aimed to evaluate the relation between ADHD symptoms and LDAEP, as well as medication-mediated changes of LDAEP.MethodsA total of 38 male children (6−12 years old) with ADHD were analyzed in this study. Symptom severity was assessed using the ADHD rating scale (ARS) and the continuous performance test. To determine LDAEP, the auditory event-related potential was evaluated before medication. Changes in LDAEP were measured after 12 weeks of treatment with methylphenidate.ResultsThe subjects had a mean age of 9.24 ± 1.74 years with an average IQ of 109.4 ± 13.8. Before pharmacological treatment with methylphenidate, LDAEP was positively associated with the ARS score after adjusting for age and IQ (r = 0.592, p = 0.005). LDAEP was correlated with inattention (r = 0.522, p = 0.015) and hyperactivity-impulsivity (r = 0.6, p = 0.004). However, the LDAEP of 15 subjects decreased following methylphenidate treatment (Z = −1.988, p = 0.047).ConclusionIn boys with ADHD, LDAEP appears to be associated with symptom severity. LDAEP showed a significant association with impulsivity and inattention. Importantly, LDAEP was shown to decrease after drug treatment. Our findings support the utility of LDAEP as a noninvasive and clinically useful method to assess symptom severity in children with ADHD.

The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference.

Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT7 receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT2A, 5-HT3 and 5-HT7) as well as those providing an antidepressant effect (5-HT1A, 5-HT1B, 5-HT2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT7 receptors. Activation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C receptors attenuate aggressiveness, whereas agonists of 5-HT3 intensify aggressive behavior.

Narcissism and central serotonergic neurotransmission in depression

Objectives Based on previous research, it has been proposed that the development of depressive disorders is related to altered functioning of the serotonergic systems as well as the personality style, including narcissism. However, it is unclear to date how personality style, especially narcissism, depressive disorders and serotonergic activity are related. Methods We included 74 patients with a depressive disorder (DP) and 74 healthy controls (HC) in the study. All participants completed the Personality Style and Disorder Inventory (PSDI) and the Beck Depression Inventory (BDI II). Moreover, we conducted EEG recordings for analysis of serotonergic neurotransmission by using the so-called intensity or loudness dependence of the auditory evoked potentials (LDAEP). Results Significantly higher LDAEP results emerged for the DP group compared to the HC group, which indicated lower serotonergic activity in the patient's group. In addition, the positive correlation between ambitious-narcissistic personality and LDAEP reached significance in depressive patients. Limitations There was only a monocentric cross-sectional study with only one scale having differences between the two groups due to age and education. Conclusions Our data supports the theory of lower serotonergic activity in patients with depressive disorders and further suggests that high narcissistic personality traits are related to lower serotonergic neurotransmission in patients.

The 5α-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia

Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5α-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved.

Mirtazapine induced steatosis

Introduction Mirtazapine is a commonly used drug indicated for the treatment of severe depression. It works as a presynaptic alpha2-adrenoreceptor antagonist which increases central noradrenergic and serotonergic neurotransmission. Although steatosis is not a noted side effect or risk in the British National Formulary, we present a case of mirtazapine induced steatosis in a 48-year-old office worker in the absence of any other risk factors, discuss management options and review the literature associated with drug induced steatosis. Case description A 48-year-old woman with a past medical history of pernicious anaemia, hypertension and depression was admitted with a two day history of painless jaundice and a three week history of peripheral oedema and lethargy. No other stigmata of liver disease were present. Medications included once daily Ramipril 2.5mg and Mirtazapine 15mg (recently started). She denied any alcohol use/unprotected sex/recent travel. On admission, her bilirubin level was 199umol/L (normal Results and conclusions Liver ultrasound and CT imaging of the abdomen/pelvis did not yield a cause for her acute jaundice. An ERCP with sphincterotomy and balloon trawl was also negative. Subsequent liver biopsy indicated marked steatosis with active steatohepatitis and early fibrosis which were not consistent with large bile duct obstruction. Experimentally, and with no other identifiable cause for her worsening jaundice, her mirtazapine was stopped. Her liver function results improved immediately with notable improvements in her bilirubin and ALP levels. She subsequently made a full recovery. Take-home message We demonstrate a case where no autoimmune/anatomical infectious or alcohol pathology accounted for the significant steato-hepatitis. Furthermore, with withdrawal of Mirtazipine, the patients' liver function rapidly improved, giving a Naranjo score of 7, thus suggesting a highly probable adverse drug reaction induced by Mirtazipine. Mirtazipine induced hepato-toxicity is rare, probably owing to toxic intermediates following cytochrome p450 metabolism. Acute steatosis is even rarer, and may reflect weight gain caused by the offending drug. We conclude that drug causes should always be sought following exclusion of all other causes.

Pioglitazone attenuates lipopolysaccharide-induced depression-like behaviors, modulates NF-κB/IL-6/STAT3, CREB/BDNF pathways and central serotonergic neurotransmission in mice

Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has exhibited antidepressant-like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression-like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression-like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF-κB/IL-6/STAT3) pathway, improving down-regulation of the cAMP response-element-binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR-γ specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF-κB/IL-6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR-γ-dependent effects of PIO on depression-like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression-like behaviors in patients with inflammatory status.

Harmful Effects of Recreational Ecstasy Use on Memory Functioning

MDMA (3,4-methylenedioxymethamphetamine), often referred to as ‘ecstasy’, has been shown to selectively and persistently impair central serotonergic neurotransmission in laboratory animals. As of recent, evidence in human studies has suggested a link between recreational ecstasy use and a disruption of the brain’s serotonergic system. However, human neurocognitive and neuroimaging studies have yielded inconsistent findings regarding the functional impact of these neuro-adaptations, possibly due to methodological difficulties. Although the literature on the effects of recreational ecstasy use on neurocognitive function remains inconclusive, studies have most consistently shown negative effects on memory. Here, we provide a review of accumulating evidence supporting a link between recreational ecstasy use and impaired memory.

The loudness dependence of auditory evoked potentials (LDAEP) as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms.

Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT) system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP). The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.

Acute manic and psychotic symptoms following subcutaneous leuprolide acetate in a male patient without prior psychiatric history: A case report and literature review

Leuprolide acetate is usually used in the treatment of advanced prostate cancer. The adverse events associated with administration of leuprolide acetate include fatigue, hot flashes, loss of libido, impotence, and depression. These side effects can be treated conservatively. Acute manic and psychiatric symptoms following leuprolide acetate injection are very rare. Few case reports have been published documenting these symptoms. Here, we describe the case of a 62-year-old male with metastatic prostate cancer, who developed acute manic and psychiatric symptoms 2 months after subcutaneous leuprolide acetate injection. These symptoms were relieved after administration of neuroleptic drugs, such as risperidone. Administration of leuprolide acetate was eventually stopped. The exact mechanism causing the manic and psychiatric adverse events is unclear. Some experts have theorized that estrogen withdrawal following leuprolide acetate therapy may induce psychiatric symptoms. Manic episodes may arise from a deficit in central serotonergic neurotransmission. Based on these hypotheses, risperidone, lithium, and some anticonvulsants, such as divalproex sodium and carbamazepine, have been used effectively in the treatment and prophylaxis of manic episodes. Although psychiatric adverse events are rare following administration of leuprolide acetate, clinicians should be aware of the possibility.

Childhood Maltreatment Affects the Serotonergic System in Male Alcohol‐Dependent Individuals

Reduced central serotonergic neurotransmission has been demonstrated in individuals with excessive alcohol consumption and/or alcohol dependence. Childhood maltreatment has also been found to have a negative impact on central serotonergic neurotransmission. The aim of this study was to evaluate the impact of childhood maltreatment on central serotonergic dysfunction in alcohol-dependent individuals. Adult men with a diagnosis of alcohol dependence (n = 18) were recruited from outpatient treatment units for alcoholism. Central serotonergic neurotransmission was assessed by a neuroendocrine method, that is, the prolactin (PRL) response to the selective 5-HT reuptake inhibitor citalopram. Childhood maltreatment was assessed retrospectively by the Childhood Trauma Questionnaire. Alcohol-dependent individuals with childhood experience of emotional abuse had significantly lower PRL response compared with those without such abuse (3 ± 5 and 64 ± 24 mU/l, respectively; t = 6.51, p < 0.001). Among those who reported childhood emotional abuse, 4 of 7 individuals had flat PRL responses in comparison with none in those with no report of such abuse (p < 0.01). This is the first study to show that self-reported childhood maltreatment, in particular emotional abuse, in male alcohol-dependent individuals is associated with a quite dramatic (more than 90%) reduction in central serotonergic neurotransmission. It should, however, be noted that the number of individuals is relatively small, and the results should therefore be considered as preliminary.

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

Usefulness of LDAEP to Predict Tolerability to SSRIs in Major Depressive Disorder: A Case Report

We report here a patient with major depressive disorder who experienced severe adverse effects after the administration of SSRIs (serotonin selective reuptake inhibitors) without improvement of his depressive symptoms. These adverse effects disappeared and his depressive symptoms improved after discontinuation of the SSRIs and the administration of tianeptine. The patient exhibited a low value for the loudness dependent of auditory evoked potentials (LDAEP) -0.14 at baseline, which means that his central serotonergic neurotransmission was already highly active. We assumed that it was this high serotonergic activity that rendered him unresponsive to SSRIs, and brought on him the adverse effects, and that the tianeptine was effective due to the lack of serotonin reuptake inhibitory action. Thus, we suggest that LDAEP can be used to predict an individual patient's tolerability and clinical response to SSRIs in major depression.

Neuroendocrine Assessment of Serotonergic, Dopaminergic, and Noradrenergic Functions in Alcohol‐Dependent Individuals

Alcohol dependence has been associated with reduced function of serotonin, dopamine as well as noradrenaline activities in several neuroendocrine studies. To our knowledge, there is, however, no study investigating all these 3 systems with the use of neuroendocrine methods in one and the same alcohol-dependent individual. Alcohol-dependent individuals (n = 42) and controls (n = 28) participated in the neuroendocrine test series. Central serotonergic neurotransmission was assessed by the prolactin (PRL) response to citalopram (CIT). The postsynaptic DRD2 function was measured by the growth hormone (GH) response to apomorphine (APO) and the postsynaptic α2-adrenoceptor function by GH response to clonidine (CLON). In the alcohol-dependent individuals, the PRL concentrations were significantly lower at the time points 240 minutes and 300 minutes after CIT administration and mean delta PRL value was significantly reduced by 45% in comparison with controls. There were no significant differences in APO-GH and CLON-GH concentrations at any time points or in mean delta GH values between the groups. An impaired monoaminergic profile, including all 3 systems, was significantly more frequent in alcohol-dependent individuals than controls (43% vs. 6% respectively). The monoaminergic dysfunction was restricted to an impairment of the serotonergic system, suggesting that this system is especially vulnerable to long-term and excessive alcohol consumption. Moreover, impaired monoaminergic profiles, including low responses in 2 or 3 systems, were more frequently observed in alcohol-dependent individuals than in controls. Such impaired profiles may be of clinical importance, but further studies are needed.

Nonsuicidal Self-Injury as a Predictor of Suicidal Behavior in Depressed Adolescents

Nonsuicidal Self-Injury as a Predictor of Suicidal Behavior in Depressed Adolescents

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

The loudness dependence of the auditory evoked potential (LDAEP) has been reported to be an effective non-invasive measure of central serotonergic neurotransmission. However, acute manipulations of the serotonergic system in humans and animals have yielded inconsistent findings. In this study, we examined the chronic effect of serotonergic manipulation using the selective serotonin reuptake inhibitor, sertraline, on the LDAEP. In addition, we examined the influence of 5-HTTLPR genotype and individual differences in plasma drug concentrations on the LDAEP. The study utilised a double-blind, placebo-controlled, between-group design in which 40 (24 female) healthy adults (M age = 22.0 years, SE = 0.7) were tested following placebo or sertraline for an average of 24 days. The LDAEP was assessed 6 h post-final dose, and changes in the slope of amplitude of the N1/P2 across intensities (60, 70, 80, 90, 100 dB) were examined at Cz. The sertraline group had a significantly smaller LDAEP than the placebo group [F(1,38) = 5.97, p = 0.02]. Drug plasma levels did not correlate with the LDAEP in the sertraline group, and there was no influence of 5-HTTLPR genotype. We show for the first time that chronically modulating serotonin neurotransmission alters the LDAEP in healthy adults, consistent with extant literature indicating a moderating role of serotonin on this neurophysiological biomarker. The findings from this study together with previous studies suggest that the LDAEP may be a more sensitive marker of long-term or chronic rather than acute changes in the serotonin system.

Early life exposure of rats to citalopram, a selective reuptake inhibitor (SSRI) antidepressant, results in structural abnormalities in the adrenal gland

Thirty percent of infants exposed in utero to SSRIs display behavioral and physiological abnormalities in the first few weeks after birth including increased incidence of pulmonary hypertension. Rats exposed from postnatal day (PN) 1–21 to SSRIs display persistent neurobehavioral abnormalities which include severe deficits in social interactions and expression of serotonergic neurons. The adrenal glands function as a reserve in response to stress. Chronically elevated cortisol may induce clinical depression by interfering with central serotonergic neurotransmission. SSRIs were developed to restore serotonin homeostasis. However, exposure to SSRIs can increase glucocorticoids in females and decreases in LH, FSH, and testosterone (T) in males. Therefore, adrenal gland morphology in male and female rats exposed to an SSRI as neonates was evaluated. Long Evans rats (30 male, 30 female) were treated from PN 1–21 with 0.1 mL s.c. of either saline or citalopram (5, 10 or 20mg/Kg). Animals were sacrificed at PN‐180. No changes in glomerulosa zone areas were seen. However, decreases in fasiculata areas were evident in female rats, and the reticularis area was increased in the male rats. In conclusion, data collected from this study indicate than early life exposure to citalopram results in morphological abnormalities in adrenal structure which may result in disturbances in corticosteroid levels in female rats and alterations in LH, FSH, and T in male rats. Supported by RR 017710 to IAP, KLS, and MH 084194 to RCSL.

Hypothalamic glutamate levels following serotonergic stimulation: A pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers

Introduction and purpose Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7 T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers. Methods A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7 day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4 h and MRS scans at 7 T were performed every 30 min over 3 h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios. Results In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180 min but induced a significant decrease of Glx at 60 min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E max of 60.2 ng/L at 80 min followed by cortisol with an E max of 246.4 ng/mL at 110 min. Conclusions The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.

An auditory fMRI correlate of impulsivity

Impulsivity and serotonergic neurotransmission have previously been shown to be linked to the intensity dependence of auditory evoked potentials. The present study investigates whether impulsivity in normal healthy subjects has a similar influence on the neuronal correlates of the coding of sound intensity using functional magnetic resonance imaging (fMRI). Forty-four participants completed Cloninger's Tridimensional Personality Questionnaire (TPQ). The dependence of fMRI activation on sound intensity was examined using continuous pink noise with varying intensity as acoustic stimuli. Imaging data were analyzed for the volume of activation sensitive to sound intensity. Impulsivity has a significant effect on the volume of activation sensitive to sound intensity. Persons with high impulsivity scores on the TPQ scale show approximately twice the volume of activation when compared with persons with low impulsivity scores. The neuronal correlate of impulsivity as revealed by fMRI gives strong evidence of a link between impulsive behavior and neural activity evoked by auditory stimulation. This link may prove useful for measuring central serotonergic neurotransmission in a clinical setting.

No association between chronic cannabis use and loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission

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 24h 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.