The potential of 5‐methoxy‐N,N‐dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action

Abstract

Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic‐assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4–12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short‐acting psychedelic 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5‐MeO‐DMT. Primarily, 5‐MeO‐DMT is able to induce mystical experiences and ego‐dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood‐related comorbidities consistent with the negative reinforcement and self‐medication paradigms. In addition, preliminary evidence indicates that 5‐MeO‐DMT modulates neural oscillations that might subserve ego‐dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5‐MeO‐DMT is characterized by neuroplasticity, anti‐inflammation, 5‐HT_2A receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood‐related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.

1. ALCOHOL USE DISORDER

Alcohol use disorder (AUD) can be defined as a pattern of compulsive heavy alcohol use and a loss of control over alcohol intake despite adverse consequences. ¹ Moreover, AUD is characterized by neuroadaptations in three major neurocircuits (i.e., basal ganglia, extended amygdala, and prefrontal cortex [PFC]) that result in dysfunction in (1) incentive salience, (2) negative affect, and (3) executive function systems, respectively. ² In most countries, AUD remains one of the most prevalent psychiatric disorders ¹ with recent estimates of 23 million people in the European Union ³ and 32.6 million people in the United States. ⁴ , ⁵ Moreover, AUD is the leading risk factor for global disease burden ⁶ with approximately 3 million annual deaths, ⁷ detrimental effects on general health, ⁸ and high amount of disability‐adjusted life years. ⁹ In 2010, it was estimated that AUD costs the United States $249 billion, ¹⁰ including $28 billion in healthcare, $179 billion in workplace productivity, $13 billion in collisions, and $25 billion in criminal justice. ¹¹ Moreover, the range and magnitude of harm of AUD extends beyond the individual, as it affects families, occupation, and crime and disorder. ¹² , ¹³ Currently available treatments for AUD consist of various pharmacological and/or psychosocial interventions ¹ , ¹⁴ with modest efficacy and high relapse rates. ¹⁵ , ¹⁶ Most notably, few new medications have been approved in the past 20 years ¹⁷ and AUD remains characterized by a significant treatment gap (untreated percentage) that has increased from 78.1% in 2004 ¹⁸ to 82.7% in 2021, ¹⁹ despite multiple earlier recommendations from the World Health Organization to address this issue. ²⁰ , ²¹ , ²² Ultimately, this necessitates the investigation of novel treatments for AUD.

2. PAT IN THE TREATMENT OF AUD

In the past decade, numerous authors have alluded to the potential of psychedelic‐assisted therapy (PAT) for the treatment of addiction. ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ For instance, the classic psychedelic lysergic acid diethylamide (LSD) has been explored for AUD in the mid‐20th century ²⁹ , ³⁰ and contemporary reviews have shown efficacy in reducing drinking behaviour after only one dose. ³¹ , ³² Other recent reviews also show preliminary evidence for psilocybin in the treatment of AUD. ³³ , ³⁴ Currently, there is a general consensus that the acute subjective experience induced by high doses of classic psychedelics (e.g., LSD and psilocybin) during PAT mediate the therapeutic response in a variety of psychiatric disorders, ³⁵ , ³⁶ , ³⁷ , ³⁸ including AUD. ³⁹ , ⁴⁰ Yet, this experience lasts approximately 4 to 12 h, ⁴¹ which requires a significant amount of time investment regarding therapeutic input during dosing sessions leading to high costs and impeding implementation of PAT. ⁴² , ⁴³ Accordingly, there is an increasing interest in the clinical investigation of the classic psychedelic 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT), in particular due to its rapid onset and short duration (15–20 min) that could make PAT more cost‐effective. ⁴⁴ , ⁴⁵ , ⁴⁶ The current paper offers a first look at potential therapeutic mechanisms for AUD by giving an overview of the extant literature of 5‐MeO‐DMT (see Table 1).

TABLE 1.

Overview of (pre)clinical studies with 5‐methoxy‐N,N‐dimethyltryptamine and potential therapeutic mechanisms of action in the treatment of alcohol use disorder.

Human studies
	Design	Population	Mechanism	Potential symptom improvements
Davis et al. 47	Survey (n = 515)	General	Mystical experience	AUD, MDD, PTSD, anxiety, and SUD
Barsuglia et al. 48	Case study (n = 1)	Veteran	Mystical experience	AUD and PTSD
Kervadec et al. 49	Retrospective survey (n = 160)	General	Mystical experience	AUD
Davis et al. 50	Survey (n = 362)	General	Mystical experience	MDD and anxiety
Cox et al. 51	Survey (n = 99)	General	Mystical experience	PTSD
Ragnhildstveit et al. 52	Case study (n = 1)	PTSD	Mystical experience	PTSD, hopelessness, and suicide risk
Uthaug et al. 53	Observational (n = 42)	General	Ego‐dissolution	MDD, stress, and satisfaction with life
Uthaug et al. 53	Observational (n = 42)	General	Mindfulness (nonjudgement and awareness)	Not related to symptom improvement or subjective effects
Uthaug et al. 54	Observational (n = 11)	General	Mindfulness (nonjudgement)	MDD, anxiety, and stress
Davis et al. 55	Retrospective (n = 51)	Veterans	Psychological flexibility	MDD, PTSD, anxiety, and cognitive functioning change
Kervadec et al. 49	Retrospective survey (n = 160)	General	Psychological flexibility	AUD
Armstrong et al. 56	Prospective (n = 51)	Veterans	Psychological flexibility a	AUD, PTSD, and cognitive functioning change
Uthaug et al. 54	Observational (n = 11)	General	Anti‐inflammation (decrease in IL‐6)	Not related to symptom improvement or subjective effects
Reckweg et al. 57	Phase 1/2 trial (n = 16)	TRD	NA b	MDD
Acosta‐Urquidi et al. 58	EEG study (n = 23)	Healthy volunteers	Increases in gamma, theta, and coherence in all frequency bands	AUD, MDD, and anxiety
Barsuglia et al. 48	SPECT (n = 1)	Veterans	Increases in brain perfusion in bilateral caudate nuclei, left putamen, and right insula, as well as temporal, occipital, and cerebellar regions	AUD and PTSD

Animal studies
	Design	Population	Mechanism	Potential symptom improvements
Riga et al. 59	Open field test	KO2A and wild‐type C57BL6 mice	Modulation of neural oscillations (increases in theta in PFC and beta band coherence between all areas)	MDD and AUD
Winne et al. 60	Open field test	C57BL6 mice	Modulation of neural oscillations (increases in theta and slow gamma oscillations in ventral hippocampus and medial PFC)	Anxiety
Vargas et al. 61	In vivo analysis	Wild‐type mice and knockout mice	Neuroplasticity with increases in dendritic spine density in layer V pyramidal neurons of PFC	MDD
Jefferson et al. 62	Head‐twitch response, social ultrasonic vocalization, and longitudinal in vivo two‐photon microscopy	C57BL6J mice for behavioural experiments and Thy1 GFP line M mice for imaging experiments	Neuroplasticity with long‐lasting increases (1 month) in dendritic spine density in medial frontal cortex	MDD
Lima de Cruz et al. 63	In vivo analysis	C57BL6J mice	Neuroplasticity (more complex dendritic morphology) and neurogenesis (newborn granule cells) in dentate gyrus of hippocampus	MDD
Dakic et al. 64	In silico analysis	Human cerebral organoids	Neuroplasticity (long‐term potentiation and the formation of dendritic spines) through NMDAR, AMPAR, and Eprhin B2 signalling	MDD
Dakic et al. 64	In silico analysis	Human cerebral organoids	Anti‐inflammation through inhibition of NF‐κB signalling pathway (no mention of any cytokines)	MDD and AUD
Szabo et al. 65	In vitro analysis	Human monocyte‐derived dendritic cells	Anti‐inflammation through decreases in pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α, and chemokine IL‐8) and increases in anti‐inflammatory cytokines (IL‐10) through sigma‐1 receptor signalling	MDD
Cameron et al. 66	Forced Swim Test and Sucrose Preference Test	C57BL6J and knockout mice	Activation of 5‐HT2A receptors	MDD
Dakic et al. 64	In silico analysis	Human cerebral organoids	Downregulation of metabotropic glutamate receptor 5	SUD

Abbreviations: AUD, alcohol use disorder; EEG, electroencephalography; MDD, major depressive disorder; PFC, prefrontal cortex; PTSD, post‐traumatic stress disorder; SPECT, single‐photon emission computed tomography; SUD, substance use disorder; TRD, treatment‐resistant depression

^a Indicated by self‐reported changes assessing how bothered individuals were by their cognitive and PTSD symptoms. ⁵⁶

^b Subjective effects of 5‐methoxy‐N,N‐dimethyltryptamine will be published in a separate paper. ⁵⁷

3. Incilius alvarius : 5‐MeO‐DMT

5‐MeO‐DMT is a natural psychoactive indole alkylamine found in a variety of plants ⁶⁷ and the parotid gland secretions of the toad species I. alvarius ⁶⁸ , ⁶⁹ , ⁷⁰ and can be produced synthetically. ⁷¹ The acute subjective effects of 5‐MeO‐DMT are most often induced through the inhalation of vapour from dried secretions of I. alvarius reaching peak effects within seconds that last for approximately 15–20 min. ⁴⁵ Other well‐documented routes of administration include intramuscular injection ⁷² and intranasal administration, ⁷³ which are featured by a slower onset (1–7 min) and prolonged subjective effects (~60 min).

Compared with classic psychedelics, the subjective experience of 5‐MeO‐DMT has been described as very distinct with feelings of transcendence that often involve ego‐dissolution, nondual awareness, and an increased range and intensity of emotions, spanning the feeling of love, unity, and awe to panic and terror. ⁴⁴ Notably, 5‐MeO‐DMT has been reported to lack visual effects, ⁷⁴ possibly due to its high binding affinity for the 5‐HT_1A receptor ⁷⁵ , ⁷⁶ and the observation that the partial 5‐HT_1A receptor agonist buspirone is able to reduce the acute visual effects of psilocybin. ⁷⁷ Accordingly, 5‐MeO‐DMT is often described as a content‐free experience associated with a loss of sense of self and bodily awareness, including sensory deprivation described as “all‐white light” or “all‐black” with descriptors such as “emptiness,” “nothingness,” or “void.” ⁷⁸ A rudimentary framework of the complete 5‐MeO‐DMT experience is presented by James Oroc in Tryptamine Palace that include (1) dissolution into fractals of white light upon exhalation of 5‐MeO‐DMT, (2) transportation via white light and potential appearance of spirit guides and various manifestations, (3) sense of unity and that love is the principle that organizes the universe, (4) complete dissociation with ego‐identity and any concept of time, (5) reassertion of identity (return of “my” ego), (6) repossession of the physical body, and (7) return to baseline. ⁷⁹ This framework serendipitously overlaps with the seven stages reported in The Toad of Dawn and how the 5‐MeO‐DMT experience seemingly progresses from beginning to end. ⁸⁰ Importantly, however, Oroc (2009) emphasizes that “an infinite variety of experiences for any given individual are possible” (p. 13), which indicates that this framework needs to be confirmed in future clinical trials with follow‐up in‐depth interviews and robust qualitative research methodologies (e.g., Grounded Theory). ⁸¹

An overview of observational studies shows that the acute effects of 5‐MeO‐DMT are associated with mild to moderate physiological and psychological adverse events (e.g., fear, sadness, anxiety, confusion, fatigue, crying, paranoia, trembling, vomiting, nausea, headache, pressure on the chest or abdomen, and loss of body perception). ⁴⁵ Recent clinical trials involving healthy volunteers ⁸² and individuals with treatment‐resistant depression ⁵⁷ demonstrate that adverse events are generally transient in nature and resolve spontaneously when 5‐MeO‐DMT is administered in a controlled and supportive environment. However, anecdotal evidence also indicates that 5‐MeO‐DMT can result in so‐called “possession states” with extreme motor outbursts, which can be contained when adhering to various precautions (e.g., having “ground control” or humming soothing incantations). ⁷³ Others report that only a very small percentage of 5‐MeO‐DMT users suffer from severe physical reactions (e.g., bodily tension), but also intense physical “calm,” and that this is a promising area of future research. ⁷⁹ Furthermore, survey studies show that individuals can experience so‐called reactivations of the acute subjective effects (i.e., flashbacks) 1 week following 5‐MeO‐DMT administration, but these have primarily been reported as either a positive or neutral experience. ⁸³ Most recently, reactivations are estimated to occur in 27% to 73% of individuals. ⁷² , ⁸⁴ Finally, reports of psychosis are rare ⁷³ , ⁸⁵ and might be caused when used in conjunction with ayahuasca. ⁸⁶ Potentially, this is because ayahuasca contains a monoamine oxidase‐A inhibitor (i.e., Psychotria viridis Banisteriopsis caapi) that has been shown to alter 5‐MeO‐DMT pharmacodynamics. ⁸⁷

4. POTENTIAL THERAPEUTIC MECHANISMS OF ACTION OF 5‐MeO‐DMT IN THE TREATMENT OF AUD

4.1. The mystical experience

Similar to the other classic psychedelics, ⁸⁸ , ⁸⁹ 5‐MeO‐DMT reliably occasions so‐called mystical experiences ⁴⁴ , ⁴⁵ that are broadly defined as “a sense of unity” or “the experience of becoming one with all that exists.” ⁹⁰ Notably, one review has identified the psychedelic‐induced mystical experience as the strongest mediator of therapeutic efficacy in addiction ²³ and has been considered a significant part of traditional 12‐step facilitation programmes, such as Alcoholics Anonymous. ⁹¹ Consistently, one large survey study demonstrated that the 5‐MeO‐DMT‐induced mystical experience is associated with improvements in alcoholism within 66% (n = 340/515) of respondents. ⁴⁷ Another case study involving a 31‐year‐old veteran showed that the 5‐MeO‐DMT‐induced mystical experience was associated with reduced craving to alcohol 5 days post‐treatment, which were sustained at 1 month, with a partial return to mild alcohol use at 2 months. ⁴⁸ Most recently, a retrospective online survey (n = 160) demonstrated that the reduction in alcohol consumption was significantly associated (p = 0.03) with the intensity of the mystical experience. ⁴⁹

Furthermore, survey studies demonstrate that the 5‐MeO‐DMT‐induced mystical experience is associated with improvements in symptoms of depression, ⁴⁷ , ⁵⁰ post‐traumatic stress disorder (PTSD), ⁴⁷ , ⁵¹ , ⁵² and anxiety. ⁴⁷ , ⁵⁰ This indicates that 5‐MeO‐DMT could alleviate psychiatric mood‐related comorbidities that are highly prevalent in AUD. ⁹² Notably, recent studies employing Mendelian randomization indicate that psychiatric mood disorders as major depressive disorder (MDD) ⁹³ and PTSD ⁹⁴ have a causal effect on AUD. This provides support for the so‐called self‐medication hypothesis in which patients consume alcohol to alleviate negative affect. ⁹⁵ , ⁹⁶ , ⁹⁷ Clinically, this is significant as psychiatric mood disorders are considered as one of the most significant predictors for relapse, ⁹⁸ potentially due to their implication in craving ⁹⁹ , ¹⁰⁰ , ¹⁰¹ that impedes successful alcohol rehabilitation. ¹⁰² Ultimately, 5‐MeO‐DMT‐induced mystical experiences could improve symptoms of AUD due to the alleviation of mood‐related comorbidities.

4.2. Ego‐dissolution

Ego‐dissolution highly correlates with the mystical experience and refers to a reduction or loss of one's sense of self or personal identity. ⁸⁸ , ¹⁰³ Recent reviews suggest that psychedelic‐induced ego‐dissolution plays a significant role in mediating therapeutic efficacy in several psychiatric disorders. ¹⁰⁴ , ¹⁰⁵ To date, only one survey study (n = 42) has shown that high levels of 5‐MeO‐DMT‐induced ego‐dissolution were associated with lower ratings of depression and stress together with increases in life satisfaction. ⁵³ Many authors argue that psychedelic‐induced ego‐dissolution triggers a psychological change through “changes of the sense of self” that helps to reshape one's “self” or identity from a detached standpoint. ¹⁰⁴ , ¹⁰⁶ Others refer to this as a narrative “inflection point” ³⁵ that ultimately affords the individual to realize alternative pathways of thought and behaviour. ¹⁰⁵

This could provide a novel perspective on the well‐established negative reinforcement framework ⁹⁹ , ¹⁰⁰ and self‐medication hypothesis. ⁹⁶ Specifically, the notion that negative self‐perception underlies mental health problems has a long history in psychology ¹⁰⁷ and has been corroborated in a meta‐analysis of 226 effect sizes demonstrating that self‐focussed attention is associated with negative affect (e.g., depression and anxiety). ¹⁰⁸ Ego‐dissolution could be beneficial for AUD and attenuate negative reinforcement mechanisms, as it challenges negative self‐perception characterized by significant alterations in narrative selfhood, ¹⁰⁹ reducing public self‐consciousness ¹¹⁰ and increasing self‐compassion. ¹¹¹ Most notably, this notion is consistent with the prominent RElaxed Beliefs Under pSychedelics model, which is a unified theoretical framework positing that psychedelics primarily work by weakening the precision weighting of high‐level Bayesian priors (i.e., having deep‐seated beliefs about the self or ego). ¹¹²

4.3. Mindfulness and psychological flexibility

Mindfulness and psychological flexibility are two highly related psychological constructs that are here defined as the ability to be in the present moment with nonjudgement and to act in accordance with one's goals and values. ¹¹³ , ¹¹⁴ One observational study (n = 11) suggests that 5‐MeO‐DMT increases nonjudgement that significantly correlated with improvements in symptoms of MDD, anxiety, and stress. ⁵⁴ Another observational study (n = 42) found significant increases in nonjudgement and awareness but reported no significant relationship with the observed significant decreases in depression, anxiety, and stress at 4 weeks follow‐up. ⁵³ Regarding psychological flexibility, one study with war veterans (n = 51) demonstrated that 5‐MeO‐DMT was associated with significant and large increases in retrospective reports of psychological flexibility that were strongly associated with symptoms of PTSD, MDD, anxiety, and cognitive functioning change. ⁵⁵ Similarly, a recent retrospective survey demonstrated that increases in psychological flexibility are a significant predictor of reducing alcohol consumption. ⁴⁹ Finally, another prospective study with war veterans is suggestive of increases in psychological flexibility following 5‐MeO‐DMT, as it asked participants to what degree they were bothered by their symptoms of PTSD and cognitive impairments and found significant decreases in these measures and alcohol use when comparing responders (n = 19) to nonresponders (n = 26). ⁵⁶ In other words, this finding suggests an improvement in acceptance, which is one of the six core psychological flexibility processes. ¹¹⁴

Addiction is suggested to be characterized by significant experiential avoidance, the opposite of acceptance, whereby individuals consume substances (e.g., alcohol) to avoid or suppress unwanted internal or external experiences. ¹¹⁵ Again, this aligns with the self‐medication hypothesis ⁹⁶ and negative reinforcement paradigm. ⁹⁹ , ¹⁰⁰ Consistently, several reviews are beginning to demonstrate the therapeutic potential of mindfulness and psychological flexibility‐based interventions in the treatment of AUD, ¹¹⁶ , ¹¹⁷ particularly to reduce mood‐related comorbidities and levels of perceived craving. ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹

4.4. Neuroimaging 5‐MeO‐DMT

There is an increasing literature of neuroimaging studies on classic psychedelics that have provided novel insights into brain mechanisms that potentially underly their therapeutic effects. ¹⁰⁵ , ¹²⁰ , ¹²¹ , ¹²² Currently, there are only two 5‐MeO‐DMT neuroimaging studies. ⁴⁸ , ⁵⁸

The first neuroimaging study conducted electroencephalography in healthy volunteers (n = 23) and hints towards three potential (sub)acute therapeutic mechanism of action for AUD. ⁵⁸ First, it found significant acute fronto‐parietal increases in gamma (38–40 Hz). Extensive evidence shows that increases in gamma occur during various meditation practices, ¹²³ , ¹²⁴ particularly during self‐dissolution meditation. ¹²⁴ Accordingly, this could reflect a neurological correlate of psychedelic‐induced ego‐dissolution ¹⁰⁵ and the aforementioned narrative “inflection point” where individuals disidentify with certain thoughts, emotions, or behaviour. ³⁵ , ¹⁰⁵

Second, the study found significant acute increases in theta (6–8 Hz) in most subjects during 5‐MeO‐DMT. ⁵⁸ Again, several reviews demonstrate parallels with (sub)acute effects of meditation, where increases in theta are associated with anxiolytic effects ¹²⁴ that signify a state of relaxed alertness conducive to mental health. ¹²⁵ Moreover, increases in theta in frontal midline regions (i.e., PFC and anterior cingulate cortex) are positively related to increased parasympathetic activity and decreased sympathetic activity with implications for cognitive control. ¹²³ Consistently, two recent studies with opioid users indicate how (sub)acute theta increases in frontal midline regions result in altered self‐referential processing and reduced opioid use over time due to enhanced cognitive control. ¹²⁶ , ¹²⁷ Notably, a recent study demonstrated that a single dose of the classic psychedelic psilocybin led to significant increases in theta power compared with placebo 2 weeks after administration that correlated with antidepressant effects in MDD. ¹²⁸ Together, this suggests that increases in theta oscillations following 5‐MeO‐DMT might improve inhibitory control and negative affect in AUD with implications for craving.

Third, the study found a significant (reversible) increase in coherence across frequency bands. ⁵⁸ Coherence refers to the degree of coupling of a particular frequency between two different brain regions and can be used as an indicator of functional connectivity. ¹²³ Various meditation practices are known to increase theta, alpha, and gamma coherence. ¹²³ , ¹²⁴ , ¹²⁹ Regarding AUD, one study demonstrated higher theta and alpha coherence in long‐term abstinent alcoholics (n = 20) compared with healthy controls (n = 21) that reflects enhanced top‐down executive control (i.e., inhibitory control and emotion regulation). ¹³⁰ Moreover, several cross‐sectional studies indicate that executive control is amenable to adaptation as the amount of years of abstinence increases. ¹³⁰ , ¹³¹ , ¹³² Potentially, 5‐MeO‐DMT could reorganize executive control networks after one or several doses, which would be consistent with the neuroplasticity hypothesis of classic psychedelics ¹³³ , ¹³⁴ , ¹³⁵ and meditation. ¹³⁶

The second neuroimaging study conducted single‐photon emission computed tomography and found increases in brain perfusion in various regions of interest associated with AUD 3 days after 5‐MeO‐DMT. ⁴⁸ Moreover, the authors speculate how 5‐MeO‐DMT's prominent affinity for serotonin receptors, particularly 5‐HT₁ and 5‐HT₇, ⁷⁶ could have implications for the treatment of AUD. Specifically, 5‐HT₁ is involved in chronic alcohol exposure through the striatum ¹³⁷ , ¹³⁸ and glutamatergic and GABAergic neurotransmission that modulate the cingulate cortex and default mode network, ¹³⁹ whereas 5‐HT₇ has been purported to mediate alcohol consumption and seeking/craving behaviour in the ventral tegmental area and striatum. ¹⁴⁰ Yet, this report remains highly speculative, as it concerns a case report who also received ibogaine 2 days prior to 5‐MeO‐DMT that confounded the results. ⁴⁸

4.5. Preclinical animal studies and potential neurobiological mechanisms

Preclinical studies hint towards five potential neurobiological mechanisms of action in AUD (see Table 1). First, preliminary evidence indicates that 5‐MeO‐DMT increases theta (4–6 Hz) and gamma (30–60 Hz) frequencies in the medial PFC and ventral hippocampus and beta band coherence across brain areas. ⁵⁹ , ⁶⁰ These results are broadly consistent with the aforementioned neuroimaging study ⁵⁸ and the extensive literature of meditation where increases in theta, gamma, and coherence have potential implications for antidepressant and anxiolytic effects ¹²⁴ , ¹²⁵ but also antiaddictive effects due to improvements in inhibition. ¹²³ , ¹²⁶ , ¹²⁷

Second, several studies demonstrate that 5‐MeO‐DMT induces neuroplasticity. Most recently, a single dose of 5‐MeO‐DMT was demonstrated to increase dendritic spine density in layer V pyramidal neurons of the PFC in wild‐type mice compared with 5‐HT_2A knockout mice. ⁶¹ Others have shown neuroplastic effects in the medial frontal cortex with increases in dendritic spine density lasting for 1 month, ⁶² whereas others showed both neuroplastic effects and neurogenesis in the dentate gyrus of the hippocampus with more complex dendritic morphology and newborn granule cells, respectively. ⁶³ Moreover, 5‐MeO‐DMT has modulatory effects on proteins in human cerebral organoids with long‐term potentiation and the formation of dendritic spines (i.e., cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization) through several plasticity‐related intracellular pathways, such as NMDAR, AMPAR, and Eprhin B2. ⁶⁴ Accordingly, many other authors posit that the neuroplastic effects account for the observed antidepressant effects in human use of 5‐MeO‐DMT, ⁶¹ , ⁶² , ⁶³ particularly due to the widely established observation of structural and functional alterations in key brain regions (i.e., medial frontal cortex and hippocampus) involved in the pathophysiology of MDD ¹⁴¹ , ¹⁴² and AUD. ² , ¹⁴³ , ¹⁴⁴

Third, 5‐MeO‐DMT is able to induce anti‐inflammatory effects through inhibition of the NF‐κB signalling pathway ⁶⁴ and the sigma‐1 receptor that inhibited pro‐inflammatory cytokines (i.e., IL‐1β, IL‐6, TNFα, and IL‐8) and increased anti‐inflammatory cytokines (i.e., IL‐10). ⁶⁵ Both signalling pathways are considered as pivotal regulators of anti‐ and pro‐inflammatory responses. ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ Accordingly, 5‐MeO‐DMT could be of therapeutic significance as inflammation has been extensively documented in MDD ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ and AUD‐associated neuropsychological impairment. ¹⁵¹ , ¹⁵² Indeed, other researchers have recently considered anti‐inflammation as another emerging and promising therapeutic area for psychedelics. ¹⁵³ , ¹⁵⁴ Currently, one small observational study (n = 11) has shown anti‐inflammatory effects in humans following 5‐MeO‐DMT, but these were not significantly related to changes in ratings of mental health or psychedelic experience. ⁵⁴

Fourth, it seems that 5‐MeO‐DMT's antidepressant effects are particularly mediated by agonism of the 5‐HT_2A receptor. ⁶⁶ The 5‐HT_2A receptor is found in cortical layer V pyramidal neurons and purported to be the main mechanism of action for inducing the acute subjective effects of classic psychedelics. ¹⁵⁵ It is widely distributed across the brain that could account for classic psychedelics' and 5‐MeO‐DMT's effects on various perceptual, cognitive, and emotional systems, ¹²¹ which seems to be consistent with findings from the current review (i.e., mystical experiences, ego‐dissolution, and mindfulness/psychological flexibility).

Finally, 5‐MeO‐DMT is associated with major downregulation of metabotropic glutamate receptor 5, ⁶⁴ which is highly implicated in the rewarding effects of alcohol. ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ Ultimately, these preclinical findings are broadly consistent with the aforementioned human studies and the main hypothesis of the current review, namely, that 5‐MeO‐DMT could reduce symptoms of AUD through alleviating psychiatric mood‐related comorbidities.

5. DISCUSSION

As suggested by earlier reviews, ⁴⁴ it is important to note that the therapeutic potential of 5‐MeO‐DMT remains hypothetical as most reported studies were conducted in the general population and primarily comprise observational designs unable to establish causality. Moreover, it is argued that the fundamental mechanism responsible for clinical change remains unknown. ⁴⁵ Accordingly, the current paper has offered a first look at various potential therapeutic mechanisms for AUD (see Table 1). Future randomized placebo‐controlled clinical trials with several follow‐up assessments have to be conducted to establish causality and the clinical significance of each purported mechanism. The current paper will conclude by providing several recommendations for future researchers.

The current review provides the most evidence for 5‐MeO‐DMT's ability to induce mystical experiences, where decreases in AUD symptoms are potentially mediated through the alleviation of negative affect. ⁹⁶ , ⁹⁹ , ¹⁰⁰ Yet, the assessment of AUD symptoms in the extant literature lacks methodological rigour. Accordingly, it is highly recommended that future research implements well‐established assessment tools, such as the Alcohol Use Disorder Identification Test, ¹⁵⁹ Timeline Follow‐Back, ¹⁶⁰ and the Penn Alcohol Craving Scale. ¹⁶¹ Furthermore, 5‐MeO‐DMT is associated with ego‐dissolution that highly correlates with the mystical experience. ⁸⁸ , ¹⁰³ Ego‐dissolution triggers a psychological change in the sense of self that affords the individual to realize alternative pathways of thought and behaviour. ³⁵ , ¹⁰⁵ Negative self‐perception and negative affect are significantly associated with the sense of self. ¹⁰⁷ , ¹⁰⁸ The current review hypothesizes that the sense of self forms another salient negative reinforcement/self‐medication mechanism in AUD and that ego‐dissolution induced by 5‐MeO‐DMT along with changes in the sense of self could improve therapeutic efficacy. This should be explored in future clinical trials by assessing the degree of 5‐MeO‐DMT‐induced ego‐dissolution through the Ego Dissolution Inventory ¹⁰³ and whether this moderates the therapeutic response in AUD, such as reductions in craving and decreases in alcohol consumption assessed through the Penn Alcohol Craving Scale and Timeline Follow‐Back, respectively.

The purported therapeutic salience of the mystical experience and ego‐dissolution prompts the question whether their frequency and/or intensity would provide another argument for the therapeutic use of 5‐MeO‐DMT when compared with other psychedelics. For instance, one study indicates that a “light‐to‐common” dose of 5‐MeO‐DMT (5–7 mg) is already statistically equivalent to a high dose of psilocybin (30 mg/70 kg) when comparing the intensity of mystical effects. ¹⁶² Generally, the subjective effects of classic psychedelics are dose‐dependent, ⁴¹ which suggests that 5‐MeO‐DMT‐induced mystical experiences and ego‐dissolution should increase with higher doses. Indeed, one phase‐I study of 5‐MeO‐DMT that used individualized dosing regimens (2, 6, 12, and 18 mg) seems to support this. ⁸² Yet, this dose‐dependent relationship simultaneously negates the purported significance of extra‐pharmacological factors (e.g., set and setting) that modulate the psychedelic experience and therapeutic response. ¹⁶³ , ¹⁶⁴ , ¹⁶⁵ , ¹⁶⁶ Ultimately, future research should investigate this intricate relationship of (extra‐)pharmacological factors and how it potentially demarcates the therapeutic of a particular classic psychedelic within a clinical setting.

Furthermore, there is preliminary evidence that 5‐MeO‐DMT is associated with subacute increases in mindfulness and psychological flexibility. Generally, these constructs are cultivated through mindfulness‐based interventions (MBIs), such as Acceptance Commitment Therapy (ACT). ¹¹⁴ Several reviews posit that the therapeutic efficacy of MBIs and ACT is similar to conventional AUD treatments, ¹¹⁶ , ¹¹⁷ particularly due to decreases in mood‐related comorbidities and levels of perceived craving. ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ Accordingly, some authors posit that MBIs and ACT should be integrated with PAT due to potential synergistic effects. ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹ , ¹⁷⁰ However, various scholars consider the Western implementation of MBIs to be inadequate due to its failure to integrate the fundamental and essential teachings of Buddhism from which mindfulness originated. ¹⁷¹ , ¹⁷² Specifically, these include the Four Noble Truths, the Noble Eightfold Path (the Middle Way), and the Five Precepts, which are posited to be of particular therapeutic significance in addiction recovery. ¹⁷³ Buddhist recovery peer‐support programmes have integrated these Buddhist teachings, including Refuge Recovery, ¹⁷⁴ Recovery Dharma, ¹⁷⁵ and Eight Step Recovery. ¹⁷⁶ Furthermore, psychodynamic therapy could also be promising as it targets various functions of the ego ¹⁷⁷ that potentially facilitates the psychological changes in the sense of self. ³⁵ , ¹⁰⁵ Ultimately, future research should explore these therapeutic frameworks and whether their implementation in conjunction with 5‐MeO‐DMT could further facilitate the therapeutic response in AUD by alleviating psychiatric mood‐related comorbidities.

It is important, however, to remember that AUD is a multifactorial psychiatric disorder that is comorbid not only with psychiatric mood disorders but also with attention deficit hyperactivity disorder. ⁹² Such comorbidity increases AUD severity due to various neuropsychological risk factors with worse treatment outcome ¹⁷⁸ and increased risk of relapse. ⁹⁸ Indeed, there is extensive evidence that AUD is comorbid with various neuropsychological impairments (i.e., attention, executive functioning and [working] memory, and social cognition) with significant clinical implications, particularly due to their effect on motivation, decision‐making, complex learning, and interpersonal relationships. ¹⁷⁹ , ¹⁸⁰ Notably, several authors posit that abstinence of alcohol leads to (partial) recovery of neuropsychological functioning. ¹⁸¹ , ¹⁸² Yet, others argue that impairments persist even after sobriety. ¹⁸³ This discrepancy in recovery could be explained by differences in length of abstinence and the cognitive function targeted ¹⁸⁴ but also the degree of polysubstance abuse, number of previous detoxifications, and duration of dependence. ¹⁸² The literature on potential neuropsychological improvements following classic psychedelics is scant. Preliminary evidence shows an association between the DMT‐containing brew ayahuasca and subacute improvements in executive functioning, ¹⁸⁵ which is an important domain for treatment outcome. ¹⁸⁶ There are, however, no reports of 5‐MeO‐DMT and its potential effects on neuropsychological improvement. Accordingly, it is recommended that future clinical trials should conduct pre‐post neuropsychological assessments in AUD to assess whether 5‐MeO‐DMT leads to subacute improvements in neuropsychological functioning and whether this moderates treatment outcome (e.g., decreases in alcohol consumption due to improved executive functioning). Specifically, researchers should use the Hayling Test, Wisconsin Card Sorting Test, and the Iowa Gambling task to assess various components of executive functioning (e.g., inhibition, problem solving, and decision‐making) that are the most sensitive for alcohol effects. ¹⁸⁶

Furthermore, animal and human studies indicate that 5‐MeO‐DMT is associated with modulation of neural oscillations. It is argued that observed increases in gamma frequency could reflect a neurological correlate of ego‐dissolution and changes in the sense of self, whereas increases in theta frequency might improve parasympathetic activity, negative affect (e.g., anxiety), and cognitive control. Another observation is that 5‐MeO‐DMT modulates coherence (i.e., functional connectivity) across frequency bands that potentially reorganizes executive control networks with improved inhibitory control and emotion regulation. Future researchers should conduct multimodal neuroimaging studies prior to and following the administration of 5‐MeO‐DMT. First, electroencephalography can confirm the reported increases in theta, gamma, and coherence and should assess whether these effects are sustained during follow‐up assessments. Second, task‐based functional magnetic resonance imaging (fMRI) paradigms can explore whether 5‐MeO‐DMT has sustained effects on brain circuits involved in (1) incentive salience, (2) negative affect, and (3) executive function systems that are highly implicated in the pathophysiology of AUD. ² Respectively, these brain circuits can be assessed by task‐based fMRI methods, such as (1) alcohol cue reactivity paradigms or monetary incentive delay task, (2) negative/emotional stimuli sets, and (3) the Go/No‐Go, Stop Signal Task, or Delay Discounting Task. ¹⁸⁷ Such task‐based fMRI paradigms also allow to corroborate whether 5‐MeO‐DMT improves neuropsychological functioning and further exemplifies which therapeutic working mechanisms are deemed most significant in the treatment of AUD. Third, resting‐state fMRI should be conducted prior to and following the administration of 5‐MeO‐DMT including systems‐level dynamical assessments (e.g., brain signal complexity, metastability, and criticality). ¹⁸⁸ , ¹⁸⁹ Findings could corroborate the RElaxed Beliefs Under pSychedelics framework and the current paper's related argument of how rigid negative beliefs (i.e., high‐level Bayesian priors) of self‐perception mediate drinking behaviour. Moreover, findings can be related to other clinically relevant (neuro)psychological outcome measures (e.g., brain signal complexity and inhibitory control). ¹⁹⁰

Finally, animal studies suggest that 5‐MeO‐DMT has several neurobiological mechanisms. Primarily, 5‐MeO‐DMT induces neuroplasticity in the medial PFC and hippocampus that could alleviate symptoms of MDD ¹⁴¹ , ¹⁴² and AUD. ² , ¹⁴³ , ¹⁴⁴ Some implicate NMDAR, AMPAR, and Eprhin B2 to be involved in 5‐MeO‐DMT's neuroplastic effects, ⁶⁴ whereas others hint to the 5‐HT_2A receptor ⁶¹ or do not mention any signalling pathways at all. ⁶² , ⁶³ Recently, preclinical findings with classical serotonergic psychedelics (i.e., psilocybin, LSD, DMT, and DOI) indicate that neuroplasticity primarily involves TrkB and mTor receptors ¹⁹¹ , ¹⁹² , ¹⁹³ and that TrkB‐signalling with psilocybin and LSD is independent of 5‐HT_2A activation. ¹⁹¹ Future research should exemplify whether 5‐MeO‐DMT is involved in TrkB‐signalling due to its promotion of brain‐derived neurotrophic factor and subsequent antidepressant effects following the atypical psychedelic ketamine ¹⁹⁴ , ¹⁹⁵ and conventional antidepressants. ¹⁹⁶ , ¹⁹⁷ Similarly, mTor‐signalling should be investigated due to its regulation of neuronal development and plasticity. ¹⁹⁸ Furthermore, animal studies show that 5‐MeO‐DMT has anti‐inflammatory properties mediated by the NF‐κB signalling pathway ⁶⁴ and the sigma‐1 receptor ⁶⁵ with implications for MDD ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ and AUD‐associated neuropsychological impairment. ¹⁵¹ , ¹⁵² Preliminary evidence indicates that 5‐HT_2A receptor agonism is implicated in 5‐MeO‐DMT's antidepressant effects and that downregulation of metabotropic glutamate receptor 5 could reduce craving. It is highly recommended to amalgamate these final findings by conducting animal models of addiction, in particular those that have high and direct translational value to AUD in humans ¹⁹⁹ , ²⁰⁰ and ideally assess incentive salience, negative affect, and executive function systems implicated in the pathophysiology of AUD. ² Indeed, results can be juxtaposed to the aforementioned (neuro)psychological and neuroimaging designs that potentially corroborate the (reverse) translation ²⁰¹ and establish the therapeutic effects of 5‐MeO‐DMT in the treatment of AUD.

6. CONCLUSION

In conclusion, there is preliminary evidence that 5‐MeO‐DMT could have potential for the treatment of AUD, particularly through the alleviation of psychiatric mood‐related comorbidities that reduce craving and improve successful rehabilitation. The current review offers a first look at several therapeutic mechanisms of action and provides recommendations for future research, including robust AUD assessment tools, exploring the intensity of the mystical experience and extra‐pharmacological factors, assess different therapeutic frameworks, neuropsychological assessment, neuroimaging studies with task‐based and resting‐state fMRI, and investigate neurobiological signalling pathways (e.g., TrkB and/or mT) together with animal models of addiction.

AUTHOR CONTRIBUTIONS

Stephan Tap is the lead author that has contributed to the present review paper.

CONFLICT OF INTEREST STATEMENT

The author has nothing to declare. The review paper was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Tap SC. The potential of 5‐methoxy‐N,N‐dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action. Addiction Biology. 2024;29(4):e13386. doi: 10.1111/adb.13386

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analysed in this study.