Psychiatric are very prevalent medical conditions nowadays. These constitute a public health concern as they often lead to disability, with a high associated sanitary cost. Among these disorders, it is estimated that between 1.0 and 16.9% of the world population suffer from depression (1) and around 3.8–25% have anxiety (2). The number of incident cases of depression worldwide increased by 49.9% from 1990 to 2017 (3) and it is also a major risk factor for suicide. Although there are several clinically tested and authorized medicines and protocols to treat these illnesses, about 50% of patients suffering from major depressive disorder receiving treatment fail to respond (4). When patients fail to respond to two or more antidepressants, it is considered that they suffer from treatment-resistant depression (5).

In addition, patients who respond to classic antidepressant treatment suffer from undesirable and frequent side effects, and many discontinue treatment (6). Furthermore, due to their late-onset clinical effect (7), these medications are not an ideal treatment for certain cases of anxiety and depression, so alternative treatments are highly sought after. Moreover, from the beginning of this century, fear-related disorders such post-traumatic stress disorder (PTSD) and specific phobias have also raised their prevalence. These disorders are also accompanied by a decrease in quality of life and by severe depression and anxiety (8, 9).

Psychedelic substances have been used for millennia since the dawn of humanity for magic-religious rituals to communicate with divinities, the spiritual world of the deceased and to obtain knowledge and healing (10). These substances were consumed from vegetal and animal preparations. Classical examples of these drugs are ayahuasca, peyote and magic mushrooms. Psychedelic effects include an altered state of consciousness characterized by distortions of perception, hallucinations, visions, dissolution of self -boundaries and “the experience of union with the world” (11). During the 20th century, the advances in chemistry led to the isolation and structural elucidation of the active molecules of these natural drugs and to the synthesis of a great number of analogs. Such structures included tryptamines (N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), psilocybin) and indole alkylamines (e.g., lysergic acid diethylamide, LSD). On the other hand, a great number of amphetamine derivatives was synthetized due to their vasomotor, psychostimulant, and anorectic effects, from which we highlight 3,4-methylenedioxymethamphetamine (MDMA) (see Figure 1 for representative chemical structures).

Many of these substances, such as LSD, were tested for possible medical uses during the 1950s and 1960s, demonstrating that they could be used to treat anxiety and depression (12). However, as some of them spread into the illicit recreational market, the Food and Drug Administration (FDA) banned any pharmacological research into them in 1970 by classifying these substances in Schedule I, the most restrictive category of drugs (13). Similarly, for MDMA, uncontrolled published reports suggested that, when administered in conjunction with psychotherapy, it could provide substantial benefits for those afflicted with a variety of mental disorders and so was used in the United States from 1977 to 1985, when it became scheduled under the Controlled Substances Act (CSA) (14).

However, the need of alternatives to clinical drugs and based on such previous evidence fueled efforts to re-take clinical studies with these scheduled substances, although most of them were denied regulatory approval. Thus, clinical trials with MDMA and several psychedelics such as LSD, psilocybin and DMT on depression, anxiety and PTSD have been carried out with promising results, even in treatment-resistant cases (15, 16). Such studies demonstrate the psychotherapeutic utility of these compounds and encourage to carry on with these studies but, as it also happens with clinically approved medicines, these drugs may have side effects, contraindications and some non-optimal pharmaceutical properties that claim for the search of alternatives which, retaining the therapeutic activity, overcome these issues.

Consequently, several associations raised to promote the research on the clinical use of psychedelic drugs to enlarge the therapeutic arsenal to treat several mood disorders. These include the Multidisciplinary Association for Psychedelic Studies (MAPS),¹ a non-profit organization that was founded in 1986 to increase the knowledge base of psychedelic substances; the Heffter Research Institute, a non-profit organization founded in 1993 that promotes research with classic hallucinogens and psychedelics, predominantly psilocybin; and the Beckley Foundation, which promotes the use of psilocybin for depression and LSD for pain.

The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were initially synthetized with therapeutical purposes and were withdrawn for concrete reasons that did not make these substances appropriate for the purposed medical use (e.g., adverse effects, improper pharmacological profile, etc.). NPS include a range of chemical structures which intend to act as replacements to classical banned substances (e.g., cocaine, MDMA, LSD, cannabis, opioids, etc.), so that they can be initially freely sold in presentations “not intended for human use” such as bath salts, plant food, incense, research chemicals, etc. (17). Moreover, as they are classified and banned, they are replaced by a new generation of non-controlled molecules enlarging the library of compounds that might, under a clinical setting, be used in therapeutics. The possibilities of therapeutic uses of synthetic cathinones and synthetic cannabinoids have been cited and summarized in a recent review (18), which also warns about the undesirable effects of these substances, which may preclude such therapeutic uses.

In this review we will focus in two groups of NPS, namely synthetic cathinones and psychedelics, as they share at least part of their mechanism of action with psychotherapeutic drugs (e.g., antidepressants) and may provide additional actions that contribute to the therapeutic effect. In fact, there is already evidence of clinical trials with some of these substances. We will discuss the pharmacodynamic requirements, review the previous evidence and the properties expected in a new drug to become useful in therapeutics of mood disorders.

Although it cannot strictly be considered an NPS, MDMA is one of the most representative examples of the use of a recreational illicit substance for therapeutic purposes. Although it had been synthesized by the pharmaceutical company Merck in 1912, MDMA never got officially to be tested as a therapeutical drug (63). In 1978, Alexander Shulgin, a Californian chemist, synthesized and tested the drug, being the first to describe that MDMA was a psychoactive drug in humans. MDMA induces changes in mood, lowering emotional defensiveness and increasing the ability to open to others, breaking boundaries in communication and increasing empathy and self-acceptance without producing marked hallucinogenic effects (64, 65). Therefore, it is not a “classic” psychedelic drug, but an “entactogen,” producing a gentler and easily tolerated state compared to LSD. Then MDMA was rescued and adopted by many underground therapists during the remaining 1970s and 1980s as an adjuvant of psychotherapy, reporting beneficial effects (66–68). Unfortunately, the enormous success that MDMA (also known as “ecstasy” and “Molly” in the street market) reached as a recreational drug due to its euphoric, pro-social and empathetic effects, led to its progressive placement in the most restrictive category of controlled substances worldwide. In spite of this, MDMA became one of the most widespread illegal drugs in the dance-club and rave party’s scenes, especially during the late 1980s and along 1990s, with numerous intoxication case reports and even some fatalities attributed to its consumption (69, 70).

However, after its scheduling and due to the previous evidence about its utility in psychotherapy, placebo-controlled studies conducted from the beginning of the 2000s provided preliminary safety and efficacy data on the use of MDMA in assisting psychotherapy for treatment-resistant PTSD (71–75). Later, phase 3 trials have been carried out to confirm the efficacy and safety to establish MDMA as a prescription medicine for the use in psychotherapy for PTSD (16). Approval could come as early as by the end of 2023.

In this phase 3 trial (16), patients with PTSD were subjected to three 8 h-experimental sessions of manualized psychotherapy spaced approximately 4 weeks, in which they received 80 mg MDMA orally, plus 40 mg after 1.5–2.5 h in the first session and 120 mg plus 60 mg in the second and third sessions. The comparison group received a placebo instead of MDMA, combined with the same psychotherapy. Each experimental session was followed by three 90-min integration sessions that were spaced ∼1 week apart to allow the participant to understand and incorporate their experience.

The patients were monitored for several vital constants (e.g., blood pressure, heart rate, body temperature, etc.) during the development of the sessions and, in general, systemic effects of MDMA were mild (transient systolic and diastolic blood pressure and heart rate, some reported muscle tightness, decreased appetite, nausea, hyperhidrosis, feeling cold…). Interestingly, no increase in adverse events related to suicidality was observed in the MDMA group.

The results demonstrate that these three doses of MDMA given in conjunction with manualized psychotherapy over the course of 18 weeks results in a significant and robust attenuation of PTSD symptoms and functional impairment, and that this attenuation is higher than in the placebo group. Moreover, the benefits seem to be bigger than the FDA-approved first-line pharmacotherapies sertraline and paroxetine, which have both exhibited smaller effect sizes in pivotal studies (76) and to whose many patients fail to respond. Long term assessments are warranted to evaluate the duration of the outcome.

MDMA is hypothesized to support and enhance psychotherapy by facilitating the ability of the subject to access emotionally upsetting material, modulating the associated level of arousal, and strengthening the therapeutic alliance (77). It has been suggested that “MDMA may catalyze therapeutic processing by allowing patients to stay emotionally engaged while revisiting traumatic experiences without becoming overwhelmed” (16).

MDMA possesses a unique combination of pharmacological properties that contribute to its overall psychotherapeutic effects [see ref. (78) for a review]. It is not the only monoamine releaser with particularly prominent effects on serotonin, but it also increases dopamine and noradrenaline and elevates serum oxytocin through activation of hypothalamic 5-HT_1A receptors (79, 80). Oxytocin is a neuropeptide believed to play a role in affiliation and bonding in mammals. However, the contribution of such increase in the entactogenic effect of MDMA is still a matter of controversy (78, 81). Mithoefer et al. (75) mentioned that MDMA may reopen an oxytocin-dependent critical period of neuroplasticity that typically closes after adolescence, thus facilitating the processing and release of particularly intractable, potentially developmental, fear-related memories. This, combined with therapy, may produce a “window of tolerance,” in which participants are able to revisit and process traumatic content without becoming overwhelmed or encumbered by hyperarousal and dissociative symptoms. Brain imaging studies found that activity in the amygdala, the brain structure that acquires and stores fearful memories (81), is reduced after MDMA administration, and shows changes in the response to angry and happy facial expressions (83, 84).

Also, cortisol concentrations significantly increase by 100–150% from baseline levels with MDMA ingestions of 0.5 and 2.5 mg/kg of body weight in the absence of physical exertion (85). These increased concentrations have been suggested to contribute to the fear extinction process when combined with psychotherapy (86).

Moreover, MDMA has also been demonstrated to induce neuroplasticity in rats across the corticolimbic circuitry. It stimulates the expression of the early gene transcription factor c-fos in the amygdala, hippocampus and cortex (87–89), which is an early marker of neuroplastic changes. Acute MDMA also raises brain-derived neurotrophic factor (BDNF) in cortical areas of rodents (90, 91) which leads to an increase in neurites and spines in cortical neurons (92, 93). MDMA can also induce neuroplasticity in the hippocampus of rats but, in this case, it requires chronic exposition (94). Neuroplasticity is necessary for the neurochemical rewiring which is supposed to account for the psychotherapeutic effect of this drug and other psychedelics, and this effect seems to be triggered after activation of 5-HT_2A receptors (95, 96).

Concerns on the clinical use of MDMA include potential side effects such as cardiovascular events, especially in elderly patients or those with previous cardiac conditions, and potential serotonergic neurotoxicity, although it has been reported that MDMA used under a clinical environment is unlikely to be neurotoxic (97, 98). Indeed, the results of the recent phase 3 trial (16) indicate that the MDMA regimen used in psychotherapy was not harmful in patients who did not meet the exclusion criteria, which included uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. Under this controlled scenario, MDMA was safe and reported adverse effects were, in general, not severe.

Taken together, it can be stated that MDMA is one of the most evident examples that an NPS might, when used properly, be useful in psychiatry. It would also be a good starting point to design or screen substances that, having similar properties, present more favorable pharmacodynamics and less undesirable effects at therapeutic doses, as well as lack of neurotoxic effects after clinical use (98). The latter is fundamental for a drug to be approved for medical use by the regulatory authorities. In this line, MDMA analogs such as 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDEA) have also been explored for psychotherapeutic use (99–101). On the other hand, patients with a history of chronic MDMA consumption may not benefit from its therapeutic effects at the doses commonly used due to tolerance. Therefore, only drugs that do not have cross tolerance with MDMA could be used in these patients (78).

Finally, another field to explore is the stereochemistry, as isomers of the same compound can account for different effects. For example, in the case of MDEA, the S-isomer is responsible for its entactogenic effects, whereas the R-isomer produces dysphoria and depressive symptoms and is responsible for its neurotoxic effects (102).

Synthetic cathinones, also known as β-ketoamphetamines, are a class of substituted amphetamines characterized by the presence of a carbonyl group at the β-position of the basic phenethylamine structure (see Figure 1 for representative chemical structures). Such modification approaches this structure to endogenous monoamines such as epinephrine and NE, which have a hydroxyl group at the β position. They are synthetic derivatives of cathinone, a natural alkaloid found in the shrub khat (Catha edulis Forsk), whose fresh leaves are traditionally chewed by population of the horn of Africa and the Arabian Peninsula to obtain stimulant and euphoric effects, as well to reduce hunger and fatigue and to ease social interaction (103, 104).

Synthetic cathinones are, together with synthetic cannabinoids, the most popular NPS and this correlates with the number of new substances appearing every year, although the prevalence of use of each individual substance is low compared with more classical drugs (105). Their consumption increased by the end of the first decade of 2000 when the production and purity of MDMA pills decreased due to the strong control on this drug and their synthesis precursors as well. However, not all the cathinones are NPS, as is the case of bupropion, which is a cathinone used as antidepressant and as an aid in smoking cessation, as will be mentioned below.

These compounds exert their effects targeting DAT, SERT and NET (106–115), mainly inhibiting monoamine uptake but some can act as substrates of the transporters and interact with the synaptic vesicles, inducing neurotransmitter release (106–115). These actions potentiate the effects of the monoamine/s involved and lead to strong psychostimulation. Also, depending on the serotonergic effects, some distortion of perceptions and entactogen effects can occur. For these reasons, synthetic cathinones are used as substitutes for amphetamines, MDMA or cocaine and have abuse potential. However, and according to the monoaminergic hypothesis of depression explained above, cathinones with an adequate profile of activity on the different transporters and lower addictive potential might also be candidates for antidepressant medications.

In fact, there is a published study carried out in mice assessing the acute antidepressant effects of the ethanolic extract of khat (116) showing a decrease in the immobility time in both the tail suspension test and the forced swim test. These results suggest antidepressant potential, at least in these animal models. However, other studies report schizophrenic-like symptoms in mice after subchronic oral administration of the extract (117) and the addictive potential of this natural drug is widely recognized (118), precluding any therapeutical use. Moreover, methcathinone was used in Russia as an antidepressant in the 1930s and 1940s although it was replaced by newer and safer drugs (119).

When looking for a possible therapeutic utility of existing cathinones, their pharmacological profile on different monoamine transporters must be carefully examined. The first generation cathinones mephedrone and methylone have DAT/SERT ratios between 0.1 and 10, which are higher than those obtained for MDMA (0.08) and in the range of that for cocaine (3.1) (115). High selectivity on DAT with > 10 DAT/SERT ratios may suggest increased abuse potential, especially given that DA has been related to reinforcing effects (120). For this reason, more favorable (lower) DAT/SERT ratios would be desirable for a cathinone to be considered as a therapeutic candidate, as it would also have predominant entactogenic effects over psychostimulant properties.

Bupropion, a dual DA and NE reuptake inhibitor and releaser, is a derivative of cathinone that was developed in the 1980s as an atypical antidepressant and has been prescribed in some cases of major depressive disorder (121) and as a smoking cessation agent. It has also been used to enhance the therapeutic response to noradrenergic and/or serotonergic antidepressants, decreasing sexual side effects and the weight gain induced by these drugs. It has negligible activity on SERT (IC₅₀ > 10,000 nM) (122) and the fact that it is administered orally implies a pharmacokinetic profile that reduces its rewarding effects (123). However, abuse of bupropion through another administration routes (e.g., insufflation or injection of crushed bupropion tablets) has been described (124, 125).

Apart of considering the possibility that some specific cathinones, as bupropion, may be used in the chronic treatment of depression, some have been reviewed as potential candidates to be used as MDMA, namely in a few sessions, low doses and combined with psychotherapy because of their entactogenic effects. These included methylone, butylone and ethylone but, among them, methylone seems to better combine the desired properties (78).

Due to being the β-keto analog of MDMA, similar pharmacological effects would be expected for methylone, although noticeable differences have been reported. For example, in vivo 5-HT synthesis inhibition fully antagonizes the hyperlocomotion induced by MDMA but not that by methylone (107, 126). Methylone inhibits DAT and NET at approximately half the potency of MDMA and inhibits SERT at about one-third of its potency (107). However, unlike MDMA, methylone is not as potent inhibiting the vesicular monoamine transporters (VMAT2) at supposedly therapeutic concentrations (107, 127), which suggest lower releasing capabilities. On the other hand, methylone induces DA and NE release in rat brain synaptosomes and in HEK cells transfected with the human monoamine transporters with similar potency than MDMA, but it has lower potency for 5-HT release (111, 128, 129).

Methylone exhibits a lower potency than MDMA for 5-HT_2A receptors (130) and is a partial agonist at the 5-HT_1A receptor, with weak antagonist effect on 5-HT_2C receptors, where MDMA behaves as a partial agonist. However, other contemporary studies (115, 129) reported that methylone did not have significant affinity for any of these receptors.

In spite of everything, methylone consumers report sensations very similar to those experienced after taking MDMA, with subtle differences such as a shorter action, greater clarity of thought and a lower but noticeable increased desire to socialize and feelings of closeness to others. These perceptions suggest that it also has entactogenic effects (131) and that VMAT2 inhibition does not seem to be a requisite to induce such effects in humans (78). To note, these effects have been reported at doses of around 125 mg, which are around half the doses reported to induce some negative mood alterations (131).

A matter of concern about the therapeutic use of methylone may be the possible serotonergic neurotoxic effects reported from experiments in rats exposed to repeated doses [i.e., four doses of 25 mg/kg at 3-h intervals in 1 day (132) or 30 mg/kg, twice daily for 4 days (133)]. However, these effects were obtained after a binge dosing, which would not be the case if methylone was used therapeutically. In fact, MDMA has also been demonstrated to be neurotoxic after repeated administration (134) but, as mentioned above, the doses used in psychotherapy are far from these dosing regimens and unlikely to produce such deleterious actions. Moreover, Baumann et al. (111) examined post-mortem tissue concentrations of monoamines in rats following a schedule of a more moderate repeated dosing of mephedrone, methylone (three doses of 3 or 10 mg/kg every 2 h) and MDMA (three doses of 2.5 or 7.5 mg/kg every 2 h). In this case and in contrast to MDMA, neither mephedrone nor methylone depleted the monoamine content, which might represent a favorable aspect for methylone.

Overall, the most studied synthetic cathinones exert similar uptake inhibition at monoamine transporters as MDMA (127), but with slightly lower selectivity for SERT and overall lower potency (78). Moreover, they have very low potency inhibiting VMAT2 function, suggesting a scarce monoamine releasing effect and that the subjective entactogenic effects that some of them exert is due to a slightly different mechanism than MDMA (135). For this reason, such entactogenic effect deserves to be investigated to establish whether it can be useful to enhance the effects of psychotherapy on mood-related disorders. Also, designing drugs with a desired profile based on these previous findings is a promising option for obtaining new therapeutic compounds.

5-HT-releasing drugs have been used in the past as appetite suppressants and some are currently being evaluated for being used as anxiolytics or antidepressants (136, 137). In this line, synthetic cathinones displaying hybrid DA reuptake inhibition and 5-HT releasing activities have been suggested as potential therapeutic drugs (137, 138). This is feasible because certain chemical structures can bind to a given monoamine transporter (e.g., DAT) and block uptake whereas they can be substrate of another (e.g., SERT) and induce 5-HT release. Although some of such substances have already been synthesized and tested in vitro for such dual effects, in vivo experiments should confirm the appropriate potency and kinetics on every target to be tested for therapeutic purposes (138).

In this line, specific changes in the cathinone structure have been reported to change the mode of action on the monoaminergic targets to obtain drugs with the properties cited above. It is known that the addition of a 3,4-methylenedioxy group or substitutions on the phenyl ring, especially in para- position, of methcathinone generally shifts selectivity toward SERT and even can behave as partial 5-HT releasers (127, 128, 140–145). For example, it has been reported that trifluoromethyl-substitution of methcathinone in the para-position dramatically shifts the selectivity of methcathinone toward SERT (146), becoming a SERT-selective partial releaser. This effect has been suggested to be produced because these modified cathinones trap a fraction of SERTs in an inactive state by occupying a specific locus in the transporter called the S2-site. Moreover, these findings define a new mechanism of action for partial releasers, which is distinct from the other two previously known binding modes underlying partial release, such as that of MDMA analogs (acting on the S1-site) (147) or that of other phenethylamine derivatives, which trap the transporter in an inward facing conformation (148).

All this progress in the knowledge of monoamine transporters’ function and the structure-activity relationships concerning interaction with the different transporter binding sites can be the basis for the development of synthetic cathinones suitable for therapeutic use in psychiatry.

Psychedelics are a class of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of conciousness. This causes specific psychological, visual and auditory changes, and often a substantially altered state of conciousness. Apart from MDMA and ketamine, psychedelics constitute the main group of substances with ongoing clinical trials in search of new pharmacotherapies for mood disorders (153) (see Figure 1 for representative chemical structures).

The psychiatric effects of psychedelics are explained by their ability to bind and activate serotonergic receptors, which exist pre- and/or post-synaptically (154). Central serotonergic pathways, which originate from the raphe nuclei, are spread to most brain structures, especially the cortex, modulating the activity of a wide range of neurons (e.g., glutamatergic and dopaminergic) and many mood-related processes (155). Among the plethora of 5-HT receptor subtypes, 5-HT_2A is the main subtype attributed to be responsible for such effects, as it has been shown to be involved in reconsolidation of contextual fear, object recognition and conditioned food aversion memories, which are processes affected in psychiatric disorders such as depression, PTSD, anxiety and even drug addiction [see refs. (156, 157) as reviews]. Thereby, psychedelics may help with neurocircuitry rewiring addressing negative emotional processing and negativity bias, which can lead to more rumination, a common symptom of MDD (158).

The neurocircuitry rewiring induced by psychedelics is a complex process that is starting to be understood using functional magnetic resonance imaging (fMRI) (159–161). Psychedelics increase connectivity in high-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus while desynchronize and decrease what is called the “default-mode nertwork” connectivity (159, 160), which appears to be altered in mood diseases. This allows a new synchronous connectivity and rewiring responsible for the therapeutic effect. The cortical areas involved overlap with a map of 5-HT_2A receptor densities, which confirm its major role. The increase in global connectivity observed under psychedelics correlated with subjective reports of “ego dissolution” which is described as a sense of oneness with the universe or the experience of relaxed boundaries between the self and the world (162) and is related with a decrease in feelings of depression, anxiety, and stress, as well as with an increase in mindfulness-related capacities.

In fact, patients who participated in clinical trials assaying the effects of psychedelics on depression and reported amelioration of their disorder, related it as sense of connectedness to others (social connectedness), to the world and to past values, pleasant activities and hobbies, and felt more integrated, embodied and at peace with themselves and their troubled backgrounds (163).

Moreover, activity on 5-HT_1A receptor has also been reported to contribute to the therapeutic effects of psychedelics while counteracting some of the undesirable effects such as increased heart rate, vasomotor tone and blood pressure (164, 165). In fact, 5-HT_1A receptors have also been implicated in mood regulation (166) and are targets for drugs already approved for anxiety and depression such as buspirone or trazodone.

Below we will briefly review the psychedelics that have been investigated and used in the treatment of mood disorders, with the aim of extracting common characteristics required for new molecules which, keeping the therapeutic effects, might overcome some undesirable effects that may preclude their use in vulnerable patients.

In this article we have reviewed the properties of drugs useful to treat psychiatric disorders and we have highlighted the properties they share and that seem to be responsible for their therapeutic effects. Some of them had been initially used for recreational or ceremonial purposes but were reconducted to a clinical setting. As cited in the introduction, the continuous appearance of NPS, especially from the cathinone and the tryptamine families, can provide new chemical structures having the right combination of the desired properties. Those accomplishing these requirements may be tested in a clinical setting as new candidates for treating those disorders. It can also be highlighted that, although differing in their principal target, most of these drugs, directly or indirectly converge in the modulation of intracellular pathways contributing to the therapeutic effects (Figure 2).

There is no doubt that activation of 5-HT_2A receptors is an important requirement, either directly or indirectly (i.e., inducing 5-HT release) which is necessary for the neuroplastic properties and other effects, but there is evidence that, through molecular modeling, the affinity and neuroplastic properties of a molecule can be kept whereas hallucinogenic and other adverse effects may be removed.

For example, Cameron et al. (250), through careful chemical design, modified ibogaine (a non- conformationally restricted analog of 5-MeO-DMT, to a safer, non-hallucinogenic psychedelic compound variant (called TBG) with therapeutic potential for treating drug addiction. Most 5-HT_2A agonists also have activity on 5-HT_2B receptors, which can lead to cardiac valvulopathy (251) but, in this case, the compound TBG behaved as an antagonist on these receptors, thus bypassing this potential adverse effect. This is also an example that selectivity for the 5-HT_2A in front of other subtypes can be enhanced. The study of the pharmacological properties of the stereoisomers of a candidate molecule may also provide valuable information for enhanced potency and/or selectivity, as in the case of MDMA (102).

Nevertheless the 5-HT_2A receptor activation by the drug may be optimized in terms of potency and duration, in order to avoid excessive and negative sensations while keeping the beneficial effect. Also, pharmacokinetics can be improved by modifying properties such as lipophilicity and rapid metabolic inactivation. New tryptamine derivatives are continuously appearing in the NPS market and detected in consumers (252, 253) so their pharmacological properties should be studied to assess and provide information about their characteristics and about a possible therapeutic use in a clinical setting.

Also, bearing mild dopaminergic properties without exerting reinforcing effects may help to the therapeutic effect as occurs with classical antidepressants. On the other hand, affinity for sigma-1 receptors is another interesting property that is shared among these molecules and that has been suggested to be involved in the intracellular signaling processes in which they are involved (230). To note, several compounds with NMDA receptor antagonist properties have also affinity for sigma-1 receptors (e.g., dextromethorphan), both properties reported to contribute to the antidepressant effect.

Another interesting aspect that is being investigated is psychedelic microdosing. This consists in administering a 10th, or even less, of the usual therapeutic dose. Studies in rats report that chronic, intermittent, low doses of DMT produce antidepressant-like effects and enhanced fear extinction, without affecting working memory or social interaction (254). Also, recent studies in humans using two to four microdoses of LSD or psilocybin (255, 256) report an increase in positive mood, a decrease in depression, augmented energy, and improved work effectiveness. However, more research using double-blind placebo-controlled trials is needed to really confirm the efficacy of this dosing approach.

Finally, all the exposed above justifies the need to study, at different levels, the properties and effects of NPS as some of them may provide new therapeutic tools for psychiatric disorders.

DP, RL-A, and EE contributed to the conception and design of the study. DP wrote the manuscript draft. RL-A made the figures. All authors provided contents and references to be included in the review and critically read the manuscript and approved the submitted version.