Chapter 1 sketches the need for a novel treatment option for mood-related disorders. It was highlighted that efforts to find such a treatment option have been made through research on both ketamine as well as the psychedelic substance psilocybin. Moreover, previous research highlights that other psychedelics such as ayahuasca and 5-methoxydimethyltryptamine (5-MeODMT) are worthy of further investigation. However, as the legal status of psychedelic substances worldwide makes it rather difficult to conduct (clinical) research, several naturalistic observational studies were designed for this doctoral dissertation to further investigate the effects of both ayahuasca and 5-MeO-DMT on mental health-related variables. The studies described in Chapter 2-3 investigated the pharmacological and nonpharmacological impact of ayahuasca ingested in a naturalistic, (neo)shamanic setting. The studies in the following Chapters 4-6 investigated the effects of 5-MeO-DMT on psychological and biomedical processes in humans. Specifically, the within-subject study in Chapter 2 examined the post-acute and longer-term effects of ayahuasca in users in Colombia and the Netherlands (N=57). It was hypothesized that ayahuasca would evoke betterment in mental health related symptoms, and that changes would correlate with the degree of ego dissolution evoked by the psychedelic experience. Assessments were made before, the day after, and 4-weeks after the ayahuasca ceremony and included a test-battery designed to assess symptoms of affect, well-being, mindfulness related capacities and creativity. Relative to baseline, there was a significant reduction in self-reported level of depression and stress that persisted for 4-weeks. Additionally, convergent thinking improved post-ayahuasca up until 4-weeks follow-up. Satisfaction with life and several mindfulness related capacities improved the day after the ceremony but failed to reach significance 4 weeks after. Moreover , changes in affect, satisfaction with life, and mindfulness were correlated with the level of ego dissolution experienced during ayahuasca, and unrelated to previous experience with ayahuasca. Thus, it was concluded that ayahuasca produces sub-acute and long-term improvements in affect and cognitive thinking style in non-pathological users. The placebo-controlled, within-subject study in Chapter 3 explored whether the post-session effects on mental health related variables (affect, cognition and empathy) were pharmacologically produced by ayahuasca (matter), or due to set (mind). Assessments were made pre and post-ayahuasca ingestion in participants of ayahuasca retreats of naturalistic, neo-shamanic origin hosted in The Netherlands, Spain and Germany. Assessments involved the distribution of a test-battery including standardized measures of affect and cognition as well as an objective task of empathy. Participants were randomized into two treatment groups that ingested capsules containing ayahuasca (N=14) or placebo (N=16). It was predicted that that ‘set’ and ‘setting’ would impact both groups, while the pharmacological effects of ayahuasca would be most prominent in the group that received ayahuasca. Results suggest that participants overall reported low ratings of the experience of ego dissolution and altered states of consciousness in retrospect of the session. Moreover, relative to baseline, a repeated measure analysis revealed that betterment of depression, stress, and anxiety symptoms were related to non-pharmacological factors of the ceremony, while an increase in implicit arousal to negative stimuli (emotional empathy) was pharmacologically related to ayahuasca. It was concluded that subjective improvements in affect (depression, anxiety and stress) of participants of naturalistic ayahuasca ceremonies can be driven by non-pharmacological factors such as expectations and intentions (mind-set). Furthermore, improvement in implicit arousal to negative stimuli (empathy) was related to the pharmacological treatment with ayahuasca (matter). The within-subject study in Chapter 4 sought to investigate the sub-acute and long-term effects of the inhalation of vapor from dried toad secretion containing 5-MeO-DMT. Assessments were made before, after the session, and 4 weeks later in users (N=42) at various European locations (Spain, The Netherlands and Czech Republic) through the distribution of a questionnaire designed to assess symptoms of affect, mindfulness and cognition. It was expected that symptoms of affect, such as depression, anxiety, stress and somatization reported by participants at baseline would be ameliorated by use of the vapor from dried toad secretion containing 5-MeO-DMT through means of inhalation, and that measures of, cognition, such as creative thinking and mindfulness related capacities, would improve. It was expected that such changes would persist over time and would still be measurable at 4 weeks after intake. 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. All in all, this study suggests that a single inhalation of vapor from toad secretion containing 5-MeO-DMT produces, rapid and persistent improvements in satisfaction with life, mindfulness and psychopathological symptoms, and that these changes are associated to the strength of the psychedelic experience. The within-subject study in Chapter 5 assessed the effects of synthetic 5MeO-DMT inhalation on salivary biomarkers, as well as mental health related variables such as affect and mindfulness. Eleven participants were assessed using a test-battery before, immediately post-session, and 7 days following a session where they inhaled vapor of synthetic 5-MeO-DMT at location in Prague, The Czech Republic. Additionally, salivary samples were collected before and within 2 hours of their session. It was predicted that symptoms of depression, anxiety, and stress would decrease, and ratings of satisfaction with life would increase, from before to after inhalation of vaporized synthetic 5-MeO-DMT. It was found that inhalation of synthetic 5-MeO-DMT vapor significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgement significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgement. Taken together, it was concluded that inhalation of vaporized synthetic 5-MeO-DMT produced significant changes in inflammatory markers, improved affect, and non-judgement in volunteers. The within-subject study described in chapter 6 aimed to assess w hether intramuscular injection (IM) and vaporization of 5-MeO-DMT induced different reactivation rates (flashback), changes in satisfaction with life, as well as ratings of the experience with ego dissolution and the mystical experience. An assessment was made using an online-survey designed to explore the effects of 5-MeO-DMT in retrospect of the 5-MeO-DMT experience of 27 individuals ( Mage=32. SD=1.40; males=18; North America=19) who had either vaporized (N=13) or intramuscularly injected (N=14) 5-MeO-DMT. There was no significant difference between either group regarding demographics or subjective measures. Of the 14 participants in the IM group, 3 (21%) reported reactivations; in contrast, of the 13 participants in the vaporization group, 9 (69%) reported reactivations. Redosing (more than 1 dose) occurred more frequently in the vaporization group (N=8) (1-6 times with 3-35mg of 5-MeO-DMT), relative to the IM group (N=2) (1-5 times with 5-10 mg of 5-MeO-DMT). All participants in the IM group experienced release of physical tension, compared to 8 participants in the vaporization group. Participants in the IM group reported longer time of onset of acute effects (between 1-3 [N=6] and 4-6 minutes [N=6]), relative to the vaporization group where the majority (N=11) reported a rapid onset of 1-50 seconds. It was concluded that compared to vaporization, the IM route of administering 5-MeO-DMT is associated with lower and less doses, lower frequencies of reporting reactivation, a higher frequency of physical tension release, and longer onset of acute effects. Finally, in Chapter 7 the key findings of all the studies are discussed in a broader perspective, and implications as well as recommendations for future research is provided. The studies presented in this dissertation give direction to future placebo-controlled research with ayahuasca and 5-MeO-DMT and endorses studies into their potential as a novel treatment method of mood related disorders.