Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n = 30) or 0.17 mg/kg psilocybin (n = 30). Blood samples were taken to assess acute and persisting (7 day) changes in immune status. Seven days' post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field (7-Tesla) magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1ß, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-α concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF-α were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin did not significantly alter the stress response. Results are discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Cannabis containing equivalent concentrations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) induces less state anxiety than THC-dominant cannabis.

RATIONALE: Delta-9-tetrahydrocannabinol (THC), an active component of cannabis, can cause anxiety in some users during intoxication. Cannabidiol (CBD), another constituent of cannabis, has anxiolytic properties suggesting that cannabis products containing CBD in addition to THC may produce less anxiety than THC-only products. Findings to date around this issue have been inconclusive and could conceivably depend on moderating factors such as baseline anxiety levels in users. OBJECTIVE: The present study examined whether anxiety following single doses of vaporised THC, CBD and THC/CBD might be explained by state and trait anxiety levels at baseline. METHODS: A placebo-controlled, randomised, within-subjects study including 26 healthy recreational cannabis users tested the effects of vaporised THC-dominant cannabis (13.75 mg THC), CBD-dominant cannabis (13.75 mg CBD), THC/CBD-equivalent cannabis (13.75 mg THC/13.75 mg CBD) and placebo cannabis on anxiety. Self-rated trait anxiety was assessed with the State-Trait Anxiety Inventory (STAI). State levels of anxiety were objectively assessed with a computer-based emotional Stroop task (EST) and subjectively rated with the STAI-state questionnaire and a visual analogue scale. RESULTS: Both THC and THC/CBD significantly increased self-rated state anxiety compared to placebo. State anxiety after THC/CBD was significantly lower than after THC alone. THC-induced anxiety was independent of anxiety at baseline. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety; however, when baseline anxiety was high, CBD did not counteract THC-induced anxiety. There were no effects of any treatment condition on the EST. CONCLUSION: Overall, the study demonstrated that the THC/CBD-equivalent cannabis induces less state anxiety than THC-dominant cannabis.

Spontaneous and deliberate creative cognition during and after psilocybin exposure.

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats.

Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain ß-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.

[Microdosing with psychedelics: what do we know?] / Microdoseren met psychedelica: wat weten we ervan?

BACKGROUND: The repeated use of small doses of psychedelics such as psilocybin and lsd over a period of time (microdosing, md) has gained popularity and scientific attention in recent years. Retrospective reports from users suggest clinical potential.
AIM: To answer the question whether md with psychedelics could theoretically provide symptom relief for people with psychiatric disorders.
METHOD: Investigate what the current evidence is about the effects of md with psychedelics on the behavioral level, psychological functioning and mental well-being. A search for relevant articles in PubMed and Medline databases (on January 10, 2020), which resulted in a total of 28 hits. After de-duplication, removal of irrelevant and addition of relevant articles, 23 articles were included.
RESULTS: Most of the knowledge we have so far comes from uncontrolled online questionnaire studies in which users report retrospectively or keep diaries of the effects they experience during md. According to users, it leads to positive effects on mood, concentration, focus and productivity. Negative effects, including physical discomfort and increased fear, also seem to occur. The limited number of experimental studies in healthy people revealed that md has subtle effects on cognitive processes and brain connectivity.
CONCLUSION: The findings of experimental studies in combination with the reports from users give cause for further investigation into the clinical potential of low-dose psychedelics in combating certain symptoms. More placebo-controlled studies are needed to provide clarity for who (age, diagnosis) md can be effective and for which (cognitive, emotional) processes.

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin.

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one's self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms.

BACKGROUND: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited. AIMS: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience. METHODS: Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. RESULTS: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. CONCLUSION: A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.

Psychedelic medicine: The biology underlying the persisting psychedelic effects.

Psychedelic substances have regained interest as therapeutic agents in the treatment of stress-related disorders. The effects seem to be of persisting nature even after a single dose. Also in lower than 'regular' recreational doses, so-called micro-doses, without the typical effects on consciousness, users report beneficial effects on cognitive processes and well-being. The exact neurobiological mechanism underlying these persisting effects is not clear. While previous research has mainly focused on the central nervous system including the immune system and the neuroendocrine system, I propose a central role for sleep and the microbiome in the effects of regular and low doses of psychedelics respectively. It will be explained why this is hypothesized and studies to test this idea proposed. It is concluded that while these studies are needed to understand the biology underlying psychedelic medicine, it is also important to approach it in a holistic way, including all the above mentioned biological processes psychedelics are known to affect, and explore the role of other substance-related factors like route of administration and form, and factors like diet and lifestyle which are part of the psychedelic experience.

A First-in-Man Study with 4-Fluoroamphetamine Demonstrates it Produces a Mild Psychedelic State.

The phenethylamine 4-fluoroamphetamine (4-FA) is a so-called novel psychoactive substance with a chemical structure resembling that of amphetamine and MDMA. Since 4-FA users report their subjective experience ranges between the effects induced by amphetamine and MDMA, and it is known that both substances can produce an altered state of consciousness, this study tests whether 4-FA induces a psychedelic state. A placebo-controlled two-way crossover study in 12 healthy poly-drug users was conducted to test subjective and behavioral effects of 4-FA. 4-FA concentrations were determined in serum up to 12 hours after administration and a series of questionnaires and the picture concept test were administered between one hour and 11 hours post-administration. Findings showed that 4-FA induced a psychedelic state which was highest one hour after 4-FA administration, at peak 4-FA serum concentrations. The 4-FA-induced psychedelic state decreased over time and was in general associated with the decreasing 4-FA serum concentrations. There was no 4-FA-induced change in creative (flexible) thinking. It is concluded that while the 4-FA-induced psychedelic state is mild in intensity and in between that produced by amphetamine and MDMA as hypothesized, more research is needed to indicate whether 4-FA can change creative thinking.

Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution.

RATIONALE: Ayahuasca is a psychotropic plant tea from South America used for religious purposes by indigenous people of the Amazon. Increasing evidence indicates that ayahuasca may have therapeutic potential in the treatment of mental health disorders and can enhance mindfulness-related capacities. Most research so far has focused on acute and sub-acute effects of ayahuasca on mental health-related parameters and less on long-term effects. OBJECTIVES: The present study aimed to assess sub-acute and long-term effects of ayahuasca on well-being and cognitive thinking style. The second objective was to assess whether sub-acute and long-term effects of ayahuasca depend on the degree of ego dissolution that was experienced after consumption of ayahuasca. RESULTS: Ayahuasca ceremony attendants (N = 57) in the Netherlands and Colombia were assessed before, the day after, and 4 weeks following the ritual. Relative to baseline, ratings of depression and stress significantly decreased after the ayahuasca ceremony and these changes persisted for 4 weeks. Likewise, convergent thinking improved post-ayahuasca ceremony up until the 4 weeks follow-up. Satisfaction with life and several aspects of mindfulness increased the day after the ceremony, but these changes failed to reach significance 4 weeks after. Changes in affect, satisfaction with life, and mindfulness were significantly correlated to the level of ego dissolution experienced during the ayahuasca ceremony and were unrelated to previous experience with ayahuasca. CONCLUSION: It is concluded that ayahuasca produces sub-acute and long-term improvements in affect and cognitive thinking style in non-pathological users. These data highlight the therapeutic potential of ayahuasca in the treatment of mental health disorders, such as depression.

Drug liking and wanting, not impulsive action or reflection is increased by 4-fluoroamphetamine.

BACKGROUND: New psychoactive substances (NPS) are chemical analogues designed to mimic the effects of various classic recreational drugs of abuse including MDMA, LSD, and cannabis. NPS use is associated with concern about the acute and longer-term effects particular substances might have, with abuse and addiction as potential consequences. Impulsivity and sensitivity to the rewarding effects of drugs have been considered as risk factors for drug abuse. In light of the popularity of 4-fluoroamphetamine (4-FA), it is important to assess whether 4-FA can lead to subjective drug liking and wanting, and impulsive behavior, all factors contributing to the abuse likelihood of a substance. METHODS: A placebo-controlled 2-way crossover study in 12 healthy poly-drug using participants was conducted to test subjective and behavioral effects of 4-FA (100 mg). 4-FA concentrations were determined in serum up to 12 h after administration and two impulsivity tasks and two drug experience questionnaires assessing drug liking and wanting, and good and bad drug effect, were administered between 1 and 11 h post-administration. RESULTS: Findings showed that 4-FA did not affect impulsive behavior. Self-ratings of drug liking and wanting and good drug effect were increased 1 h after administration; this effect was absent 11 h after drug intake. DISCUSSION AND CONCLUSION: To conclude, 4-FA (single dose) increased self-rated liking and wanting, which is known to contribute to the abuse likelihood of a substance; however, it left another factor impulsive behavior unaffected. It has to be noted that the current picture is limited and might change with increased sample size, and/or different 4-FA doses. CLINICAL TRIAL REGISTRATION: Trial acronym: 4-FA. URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6164 . Registration number: NTR6164 (Dutch clinical trial registry number).

Out of the box: A psychedelic model to study the creative mind.

Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multicomponent construct includes flexible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin can enhance creativity and affect state of mind (mood, empathy, openness). Of note, flexible thinking is disturbed in psychopathological conditions like anxiety disorders and depression and preliminary findings have shown psychedelics to be efficacious in the treatment of those conditions. The question how psychedelics induce this state of enhanced flexible thinking remains to be answered and investigating the neurobiology underlying this phenomenon will not only help in understanding why psychedelics are of use in the therapeutic setting but also in other settings where flexible thinking is challenged. A model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy volunteers.

Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter.

MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant ('s-group') of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele ('l-group'). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (Ns-group = 48; Nl-group = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced -independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect.

MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor.

BACKGROUND: MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor. AIM: The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT2A receptor in these effects. METHODS: Twenty healthy recreational users entered a 2 × 2, placebo-controlled, within-subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests. RESULTS: Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT2 receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal. CONCLUSION: It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process.

Peripheral endocannabinoid concentrations are not associated with verbal memory impairment during MDMA intoxication.

BACKGROUND: Preclinical data have suggested involvement of the endocannabinoid (eCB) system in MDMA-induced memory impairment. Clinical research has shown that blockade of the 5-HT2 receptor nulls memory impairment during MDMA intoxication. Interestingly, studies have demonstrated that the eCB and the 5-HT system interact. It was hypothesized that MDMA would cause an increase in eCB concentrations together with a decrease in memory performance, and that combining MDMA with a 5-HT2 receptor blocker ketanserin would lead to a counteraction of the MDMA effects on eCB concentrations and memory. METHODS: Twenty healthy recreational polydrug users entered a double-blind placebo-controlled within-subject study. Participants received a pre-treatment (ketanserin 40 mg, placebo) followed 30 min later by a treatment (MDMA 75 mg, placebo). Verbal memory was tested by means of a 30-word learning test. Endocannabinoid concentrations (anandamide (2-AG); N-arachidonylethanolamine (AEA)) were assessed in blood at baseline, before (90 min post-treatment) and after cognitive tests (150 min post-treatment). RESULTS: Findings showed that MDMA impaired memory 90 min post-treatment in the word learning task. This effect was a replication of previous studies using the same dose of MDMA (75 mg) and the same learning paradigm. Contrary to our hypothesis, MDMA did not affect eCB concentrations, nor did ketanserin block MDMA-induced memory impairment. Ketanserin caused an increase in AEA concentrations, 180 min after administration. CONCLUSION: Current findings suggest that peripherally measured endocannabinoids are not associated with the verbal memory deficit during MDMA intoxication. TRIAL REGISTRATION NUMBER: NTR3691.

A pooled analysis of on-the-road highway driving studies in actual traffic measuring standard deviation of lateral position (i.e., "weaving") while driving at a blood alcohol concentration of 0.5 g/L.

INTRODUCTION: The on-the-road highway driving test is generally regarded as a gold standard for assessing drug-induced driving impairment. The primary outcome measure is the standard deviation of lateral position (SDLP), a measure of road tracking error or "weaving". The test has been calibrated for incremental doses of alcohol almost 30 years ago in order to define the impact of drug-induced impairment in terms of blood alcohol concentration (BAC) equivalents. Drug-induced changes in SDLP exceeding 2.4 cm have been evaluated as clinically relevant ever since. The present analysis was conducted to assess the robustness of the alcohol effect in a range of on-the-road driving studies which have been conducted since the initial alcohol calibration study. METHODS: The present study pooled data of 182 participants from nine placebo-controlled crossover studies who performed the highway driving test, while their BAC was at or just below the legal limit for drivers (i.e., 0.5 g/L). RESULTS: Overall, mean SDLP increased with 2.5 cm (95% CI 2.0-2.9 cm). Equivalence testing showed that the clinical relevance criterion value of 2.4 cm fell well within the 95% CI in each individual study. Gender did not affect alcohol-induced changes in SDLP. DISCUSSION: These results demonstrate the robustness and validity of the clinical relevance criterion for SDLP as measured during on-the-road driving.

Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking.

INTRODUCTION: Ayahuasca is a South American psychotropic plant tea traditionally used in Amazonian shamanism. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus ß-carboline alkaloids with monoamine oxidase-inhibiting properties. Increasing evidence from anecdotal reports and open-label studies indicates that ayahuasca may have therapeutic effects in treatment of substance use disorders and depression. A recent study on the psychological effects of ayahuasca found that the tea reduces judgmental processing and inner reactivity, classic goals of mindfulness psychotherapy. Another psychological facet that could potentially be targeted by ayahuasca is creative divergent thinking. This mode of thinking can enhance and strengthen psychological flexibility by allowing individuals to generate new and effective cognitive, emotional, and behavioral strategies. The present study aimed to assess the potential effects of ayahuasca on creative thinking. METHODS: We visited two spiritual ayahuasca workshops and invited participants to conduct creativity tests before and during the acute effects of ayahuasca. In total, 26 participants consented. Creativity tests included the "pattern/line meanings test" (PLMT) and the "picture concept test" (PCT), both assessing divergent thinking and the latter also assessing convergent thinking. RESULTS: While no significant effects were found for the PLMT, ayahuasca intake significantly modified divergent and convergent thinking as measured by the PCT. While convergent thinking decreased after intake, divergent thinking increased. CONCLUSIONS: The present data indicate that ayahuasca enhances creative divergent thinking. They suggest that ayahuasca increases psychological flexibility, which may facilitate psychotherapeutic interventions and support clinical trial initiatives.

Subjective aggression during alcohol and cannabis intoxication before and after aggression exposure.

RATIONALE: Alcohol and cannabis use have been implicated in aggression. Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated. OBJECTIVES: This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication. METHODS: Heavy alcohol (n = 20) and regular cannabis users (n = 21), and controls (n = 20) were included in a mixed factorial study. Alcohol and cannabis users received single doses of alcohol and placebo or cannabis and placebo, respectively. Subjective aggression was assessed before and after aggression exposure consisting of administrations of the point-subtraction aggression paradigm (PSAP) and the single category implicit association test (SC-IAT). Testosterone and cortisol levels in response to alcohol/cannabis treatment and aggression exposure were recorded as secondary outcome measures. RESULTS: Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments. CONCLUSIONS: It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively.