Psychedelic drugs as a long-needed innovation in psychiatry

T he field of psychiatry is facing unprecedented challenges. Despite recent important innovations, several mental disorders continue to lack effective treatment. After briefly exploring some of the current challenges, we suggest that the therapeutic use of psychedelic drugs in psychotherapeutic settings represents a promising and integrative treatment with enduring effects for mental health patients. We then propose that psychedelic psychotherapy could be an important innovation in the field, providing a treatment that combines complex pharmacological action with enhanced psychotherapeutic interventions.

A relevant effect of most psychedelic drugs is their recently discovered enhancement of neurogenesis and neural plasticity. T he activation of 5-HT 2A receptors has been associated with neurogenesis [49,50], and neuronal plasticity [51]. Remarkably, DMT and other psychedelics have been termed "psychoplastogens" due to their promotion of rapid structural and functional neural plasticity [52]. T his emphasis on the modulation of neural circuits through fast-acting psychoplastogens, instead of rectifying chemical imbalances using long-term treatments, suggests a considerable paradigm shift and fertile ground for further research not only regarding psychiatric disorders but also neurodegenerative conditions. Psychedelic drugs have also been recently discovered to have anti-inflammatory effects.
T his could have implications not only for psychiatric disorders in which inflammation is an essential component, but also for various physical conditions and neurodegenerative disorders [45]. Although serotonin acting via 5-HT 2 receptors produces proinflammatory actions [53] psychedelic drugs such as LSD and 2,5-Dimethoxy-4iodoamphetamine (DOI) primarily show potent anti-inflammatory effects [54]. In the case of DOI, it seems to be an extraordinarily potent anti-inflammatory agent, since it has an EC50 of 15 picomolar in preventing T umor Necrosis Factor alpha (T NF-α) mediated inflammation in aortic smooth muscle cells [54]. Interestingly, the therapeutic dose is much lower than the dose capable of producing behavioral effects.
T he effects of psychedelic drugs could also be explained in terms of alterations to functional connectivity in brain networks. A disintegration of the Default Mode Network (DMN) has been observed after administering either psilocybin [55], LSD [56], or ayahuasca [57]. In the case of psilocybin, it also caused decreased activity and connectivity in the medial prefrontal cortex (mPFC). T his is especially relevant since this region shows enhanced activity in depressed patients [58], which is attenuated after depression treatment [59]. It has been suggested that psychedelic drugs can weaken well-established brain networks and at the same time reduce the degree of segregation between them. Due to this general effect, the normal organization of brain networks is disrupted, and thereafter strong, topologically long-range functional connections not previously present can emerge, and brain networks are reconnected in a "healthier" way [44,60]. Our group has also published an article that suggests there is a need to study the therapeutic effects of psychedelic drugs from the polypharmacology perspective . Indeed, most psychedelic drugs currently used in clinical settings are derived from natural sources (psilocybin, DMT ), so they have a multi-target profile that should not be ignored when attempting to elucidate their mechanisms of action.

Psychological effects
In therapeutic settings, the drug (generally psilocybin, LSD, or ayahuasca) is used on one or a few occasions during psychotherapy sessions, helping an individual to overcome obstacles and to catalyze the therapeutic experience [37]. In this manner, psychedelic drugs can trigger meaningful personal experiences [64,65], facilitate introspective insights [37] and enhance the relationship between the therapist and the patient [66].
T he psychedelic experience itself offers important therapeutic effects [43]. Indeed, the best outcomes in the clinical trials where psychedelic drugs were administered were obtained in those patients reporting intense mystical-type or peak experiences [67][68][69].
Interestingly, it would not always be necessary to achieve these powerful experiences in order to obtain useful personal and interpersonal insights, since it has been observed that emotional breakthroughs that commonly occur in psychedelic therapy are essential to the process as well [70].
T he experiences induced by psychedelic drugs in therapeutic contexts seem to change an individual's personality structure into a healthier one [71], and these changes have been related to pro-environmental behaviors [72] and lower levels of intimate partner violence [73]. T hus, beyond individual benefits, we can also expect associated social and community benefits as a result of psychedelic-assisted psychotherapy.  [74][75][76], anxiety in cancer patients [77][78][79][80], addictions [81], social anxiety in autism [82], and PT SD [83][84][85][86][87]. See T able 1 for more details. Indeed, beyond the mere demonstration of efficacy, it has been suggested that some of these treatments could represent the first evidence-based and pharmacologically-mediated cures for mental disorders to be found in psychiatry [88]. In addition to these substances, the therapeutic potential of ibogaine for the treatment of addictions is also remarkable, mostly in terms of the treatment of opioid dependence [89], as it offers a potential solution to the opioid crisis occurring in many countries. T wo randomized controlled trials in which ibogaine will be administered to patients with alcoholism and patients included in Methadone Maintenance Programs will begin this year (ClinicalT rials.gov Identifiers: NCT 03380728 and NCT 04003948, respectively).   [91,92]. In this manner, the "treatment" goes far beyond the ritual itself, constituting a long and complex process. In the case of modern psychedelic psychotherapy, maybe we would have to look for a treatment that goes far beyond the "administration" of drugs as well.
T he central role of community in the process of healing has been systematically neglected in Western psychiatry, which has adopted an individualistic approach to mental health. In this regard, it has been observed that community-based interventions can have a more positive psychological impact than individualistic approaches [93][94][95]. T hus, it could be a good idea to consider expanding the complexity of psychedelic psychotherapies further, where a (poly)pharmacological action and psychological effects enhancing therapeutic interventions are combined with strategies that promote social connection. A good option may be the administration of psychedelic drugs to groups instead of individual sessions, as some authors have been testing [96].
T his approach is sensible considering that social isolation and loneliness are now considered major public health concerns, with some studies concluding that extreme loneliness predicts greater severity of symptoms, a slower recovery, and worse treatment outcomes in people affected by depression, bipolar disorder, and anxiety [97], increasing the risk of premature death by more than 20% [98]. Additionally, the greater focus on social support and social bonds is in accordance with suggestions recently published by the Special Rapporteur of United Nations, in support of the replacement of the biomedical model with a human rights-based approach, as previously mentioned [11]. We should remember that there is a growing tendency towards the ritualistic and communal use of plants like ayahuasca [99]. In contrast with clinical trials, the notion that psychedelic drugs are harmful is challenged when we examine real-world situations.

Undesired effects of psychedelic drugs
Psychedelic drug use is associated with a lower rate of mental health problems [100] and with reduced psychological distress and suicidality [101] in population studies. Preliminary evidence from a public health perspective [102] showed that the long-term ritualistic use of psychedelic drugs was associated with a higher positive perception of health and a healthy lifestyle. Additionally, 56% of the sample reduced their use of prescription drugs due to their use of ayahuasca.
Despite the apparent safety and associated advantages, we must not forget the limitations of psychedelic-assisted psychotherapy. Current evidence is limited, so more studies are needed in order to better describe potentially serious adverse events and the effectiveness of treatments. Additionally, not all patients would be candidates. For instance, psychedelic-assisted psychotherapy should not be used to treat patients with a personal or family history of nonpsychotic mania or a psychotic disorder, since psychotic episodes can occur due to the use of psychedelic drugs [103]. Additionally, some published cases have shown that subjects without previous symptoms also developed psychopathological crises [103]. For this reason, patients who are administered psychedelic drugs should be properly screened using strict inclusion / exclusion criteria [104].

Conclusion
T he need for innovative treatments in psychiatry could be responded to in part through the greater introduction of psychedelic psychotherapies. T hey represent an integrative approach to mental health, involving the use of pharmacological tools that can be combined with enhanced psychotherapeutic interventions and, as we propose, community-based interventions. Furthermore, in contrast to the majority of psychiatric medications, only a few administrations would be necessary, so this could mean important savings for public health systems in terms of both direct and indirect costs.
T his is highly relevant considering the claims made by Nesta and other organizations regarding poor outcomes related to biomedicine investment. However, we should remember that psychedelic psychotherapy is far from being a panacea. Potential risks exist, and patients with psychotic or bipolar disorders will have to continue seeking out other kinds of treatments. Nonetheless, psychedelic drugs represent an exciting and   (7), 604-612.