Key words psychedelics - psilocybin - whole-brain models - neuroplasticity - LSD
Introduction
Classic psychedelics, or serotonergic hallucinogens, comprise three main chemical
classes: the indoleamines such as N,N-Dimethyltryptamine (DMT) contained in
plants [1 ], psilocybin and its active
metabolite psilocin contained in several mushroom species [2 ], the phenylalkylamines such as mescaline
contained in several cacti [3 ], and synthetic
“amphetamines” such as 2,5-Dimethoxy-4-iodoamphetamine (DOI) and
2,5-dimethoxy-4-bromoamphetamine, and the semisynthetic ergolines such as lysergic
acid diethylamide(LSD) [4 ]. They produce
profound alterations in perception, cognition, emotion, and self-consciousness [5 ]
[6 ]
[7 ]
[8 ]. Given these intense mind-altering
properties, naturally-occurring psychedelics have been used by humans for millennia
for spiritual and medicinal purposes [3 ]
[9 ].
During the 1950s and 1960s, the clinical potential of LSD and psilocybin was
extensively investigated for the treatment of different psychiatric disorders
including depression and alcohol use disorder. Although these early clinical studies
had serious methodological flaws by current standards, systematic reviews suggest
that repeated low doses of psychedelics in combination with psychotherapy
(psycholytic or “mind loosening” model) or a few high doses with
psychological support (psychedelic or “mind-manifesting” model)
resulted in impressive improvement rates in the treatment of various forms of
depression, anxiety, and alcohol dependence [10 ]
[11 ]
[12 ]. The association of psychedelics with the
counterculture and concerns over misuse led to the placement of LSD and related
drugs in a restrictive regulated drug category (Schedule I) in 1976 in the United
States and most other countries. Hence, human research with psychedelics declined,
leaving many questions about the mechanism of action and clinical efficacy of
classic psychedelics unexplored [13 ].
However, in the early 1990s, human psychedelic research with psilocybin, mescaline,
and DMT resumed in healthy volunteers by employing different new brain imaging
techniques and concepts borrowed from cognitive neurosciences [14 ]. Since then, an increasing number of
molecular and neurophysiological underpinnings of various psychological effects of
psilocybin, LSD, and DMT have been identified in healthy volunteers that allow
firmer inferences about the potential mechanisms of psychedelic drug action.
Recent behavioral and neuroimaging studies demonstrated that psychedelics produce
their psychological effects primarily via agonist action at 5-HT2A receptors in the
brain [15 ]
[16 ], although modulatory downstream effects upon the gamma-aminobutyric
acid (GABA)ergic [17 ], dopaminergic [18 ] and glutamatergic [17 ] systems also seem to be implicated [19 ]. Current psychological and cognitive
studies of psychedelics drug effects in combination with functional human brain
imaging in healthy volunteers suggest that psychedelics can profoundly change the
sense of self, often experienced as a dissolution of the ordinary boundaries between
the self and the world, enhance mood and shift emotion processing to the positive,
and facilitate prosocial behavior [19 ]
[20 ] which is accompanied by modulation of
neural circuits that are implicated in mood and affective disorders [21 ]
[22 ]
[23 ]
[24 ]
[25 ].
Psychedelics have also been shown to increase glutamate-driven neuroplastic
adaptations in animals [26 ] which may provide
a novel mechanism for the lasting beneficial outcomes reported in non-clinical and
clinical populations [27 ].
In this review, we first outline the phenomenology and key psychological dimensions
of psychedelic-induced altered states of consciousness as measured by standardized
psychometric scales and then review potential state and trait predictors of the
acute responses to psychedelics. We have summarized the potential mechanism of
action of classic psychedelic drugs at the molecular, cellular, and circuitry
levels. Then, neural correlates of psychedelic-induced alterations of
self-consciousness and emotion regulation have been reviewed and the relevance of
these findings for the treatment of affective disorders has been discussed. A better
understanding of the biological and neurocognitive mechanisms underlying the
psychedelic experience and their long-term impact on the mind and brain shall help
to develop more specific intervention strategies for improving well-being in health
and disease.
Phenomenology and Predictors of Psychedelic States
Phenomenology and Predictors of Psychedelic States
Classic psychedelics produce multifaceted altered states of consciousness,
characterized by profound changes in self-consciousness and interrelated
psychological functions: altered perception, including visual illusion,
(pseudo-)hallucinations, and synesthesia, alterations in mood and cognitive
capacities, and transcendence of time and space [6 ].
The profound transient alteration in self-consciousness, experienced as a dissolution
of the sense of self/ego and a breakdown of the boundaries between the self
and the world, appears to be one of the core features of the psychedelic experiences
(the term self and ego are used synonymously in these studies) [28 ]
[29 ].
However, the phenomenon of ego-dissolution is neither an all or nothing affair nor
does it occur on its own [30 ]
[31 ]. The experience of ego-dissolution arises
dose-dependently along a perception-hallucination continuum associated with
increased sensory and emotional arousal, distinct changes in cognitive functions,
the release of emotions, often with the recall of emotionally loaded autobiographic
memories, and increased capacity for introspection [6 ]. Empirical research has repeatedly shown that in a supportive and
controlled setting, medium to high doses of psychedelics (i. e.,
psilocybin<25 mg, LSD<200 µg) can trigger
with relatively high incidence a pleasurable self-dissolution associated with bliss,
feelings of oneness, and insightfulness [32 ]
[33 ]
[34 ]
[35 ]
[36 ]. Such unitive experiences
can sporadically also occur during deep mediative states or spontaneously in
religious exaltation and have been referred to as states of selflessness [37 ] or mystical-type experiences, respectively
[38 ]
[39 ]
[40 ]. Although in this dose
range the sense of being a self, or “I” distinct from the world, is
diminished or briefly abolished, some remnant “self-observer”
(self-awareness) remains preserved in most, if not all, psychedelic states [6 ]. In fact, memories of such experiences can
apparently be formed and reported [41 ]
[42 ]. However, at larger doses, the same dose of
a given psychedelic (e. g., psilocybin 30 mg) might induce a
pleasurable “mystical-type” experience, or under certain
circumstances, a more psychologically challenging or psychotic-like response
characterized by fear of losing control over thinking and one’s autonomy,
delusions of grandeur, impairment of reasoning, and anxiety or panic [42 ]
[43 ]
[44 ]. This clinical observation
is underscored by a recent placebo-controlled dose-response study with psilocybin
demonstrating that a 30 mg/70 kg psilocybin dosage compared
to 20 mg/70 kg markedly increased the incidence for fear and
paranoid thinking [33 ]. Likewise, when
comparing dosages of LSD, the ratings for pleasurable “oceanic”
self-dissolution increased with dosages of 25, 50, and 100 µg of LSD
but plateaued at the highest dose of 200 µg, which also
substantially increased the ratings for anxious ego-dissolution [36 ].
Although the intensity of the psychedelic experience depends most critically on the
dosage [32 ]
[33 ]
[36 ]
[45 ]
[46 ],
it is generally thought that several non-pharmacological factors categorized as the
“set” (i. e., the individual’s expectations,
personality traits) and the “setting” (i. e., the
therapeutic interventions, the physical and social environment) are important in
shaping the quality of the acute psychedelics experience [32 ]
[42 ]
[47 ]
[48 ]
[49 ]
[50 ].
To date, however, only a few prospective studies including controlled conditions
[47 ]
[48 ]
[49 ]
[51 ]
[52 ]
[53 ]
[54 ]
[55 ]
and a meta-analysis pooling data from 23 controlled studies involving 409 psilocybin
administrations to 261 healthy volunteers [32 ], have investigated the impact of non-pharmacological predictors of the
acute response to psychedelics. In most of these studies, the well-validated Altered
State of Consciousness Questionnaire (5D-ASC) was employed to measure the broad
spectrum of the psychedelic experiences along the five core dimensions (factors):
‘‘oceanic self-boundlessness’’(OB), “dread
of ego dissolution’’(DED) ‘‘visionary
restructuralisation’’(VIS), ‘‘auditory
alterations’’(AA), and ‘‘vigilance
reductions’’ (VR). The dimension OB assesses the blissfully
experienced self-dissolution including feelings of oneness and insightfulness, while
the dimension DED assesses the more distressing reaction associated with thought
disorders, fear of losing control, and anxiety. The dimension VIS measures altered
perception, changed meaning, and facilitated recall of memories and imagination. The
dimensions OB, DED, and VIS can be further described along 11 second-order scales
(11-ASC) [31, 56 ]
.
The OB-related blissful “mystical-type” experience can also be
measured by the Mysticism Scale (M-Scale) [57 ]
or by the Mystical Experience Questionnaire (MEQ30) [58 ]. Both scales yield a total score for mysticism comprising various
subscale scores, such as a sense of unity, ego-loss, transcendence of space and
time, ineffability, deeply-felt positive mood, feelings of sacredness, and noetic
insight [57 ]
[58 ]
[59 ]
[60 ]
. Notably, both the M-scale and MEQ30
total scores correlate highly with the OB score of the 5D-ASC scale [48 ]
[61 ]
suggesting that these scales assess an overall similar experience.
The results of these studies suggest that scoring high on the personality traits
including openness to experience [47 ]
[48 ], trait absorption [32 ]
[54 ],
optimism towards life [47 ]
[48 ], being well and relaxed the day(s) before
and during drug intake [32 ]
[47 ]
[48 ],
and using a mindful attention and emotion regulation strategy involving a
non-judgmental orientation of acceptance towards all emotions and thoughts arising
in the present moment predicted the magnitude of positive self-dissolution (OB) or
mystical-type experience (M-total score) [48 ]
([Fig. 1a ]). Pre-experience with altered
states [47 ]
[48 ], older age [32 ]
[47 ], and a pleasant environment and the
application of music during drug intake were also found to contribute to a blissful
experience of OB [32 ]
[62 ] or beneficial outcomes [51 ]
[53 ].
Finally, scoring high on cognitive-emotional re-appraisal capacity seems to buffer
from distressing aspects of psychedelic experiences indexed as DED in mediation
experts during a group retreat, which may arise with higher doses of psilocybin
[48 ]. However, further research in
mediation novices is needed to disentangle the interaction of mindfulness training
and group setting. On the other hand, high neuroticism, younger age, and an
impersonal laboratory setting predicted unpleasant and anxious reactions to
psilocybin [32 ]. A high absorption capacity
also predicted heightened visual perception [54 ], reduced stimulus-color consistency during synesthetic-like
experiences [55 ], and together with esthetic
sensibility VIS, included facilitated imagination and changed meaning [32 ]
[47 ]
([Fig. 1a ]). Notably, absorption has also
been identified as a predisposing trait for hallucinatory and mystical-type
experiences [63 ] and linked to the binding
potential (BP) of the 5-HT2A receptor [64 ],
suggesting that the assessment of 5-HT2A BP may provide a predictor of the overall
psychedelic drug effects [65 ]
[66 ].
Fig. 1 Empirical described predictors of acute and long-term effects
of Psychedelics. The Altered State of Consciousness Questionnaire (5D-ASC)
[31 ]
[79 ] and the Mysticism Scale (M-Scale)
[58 ]
[59 ] are usually administered shortly
after the acute psychedelic experience. Red arrows=positive
correlations; blue arrows=negative correlations: a : Scoring
high on trait openness [47 ]
[48 ], absorption [32 ]
[54 ], and optimism about life [47 ]
[48 ], being relaxed the
day(s) before drug intake intake [32 ]
[47 ]
[48 ], using a non-judgmental emotion
regulation strategy [48 ],
pre-experience with ASCs [47 ]
[48 ], older age [47 ], and a pleasant ambiance [32 ], supportive music [51 ]
[53 ]
[62 ], and meditation
practice [49 ] were predictive for a
positive psychedelic experience (e. g., “Oceanic
Boundlessness”) in healthy volunteers (HVs). High emotional
re-appraisal capacity reduced the occurrence of distressing experiences
(e. g., “Dread of ego-dissolution”) [48 ]. On the other hand, high
neuroticism, young age, and an impersonal laboratory setting predicted
unpleasant and anxious reactions to psilocybin in healthy volunteers [32 ]. In addition, high absorption
capacity and esthetic sensibility predicted changes in visual perception and
altered meaning of percepts (VIS) [32 ]
[47 ]. b :
Mysticism Total Score (M-Scale or MEQ30) predicted persisting increases in
trait openness [67 ]
[68 ], mood, well-being, attitudes and
psychosocial behaviors in healthy volunteers [48 ]
[67 ]
[69 ]. The M-Scale
subdimensions “unity” and “sacredness”
predicted persisting increases in self-acceptance and appreciation for life
in healthy volunteers [48 ], while
“ego dissolution” predicted lasting increases in openness
and mood [80 ].
However, given the current experimental limitations (e. g., small sample
sizes, homogenous samples) further studies yet need to replicate these findings by
using well-power, placebo-controlled designs, and more diverse populations. The
impact of other important potential predictors, such as the participant’s
expectations, the experimenter’s mindset, the number and quality of
preparation sessions, or the influence of the psychological interventions during
drug intake, is not known and needs to be empirically investigated.
A better understanding of the influence of non-pharmacological variables seems not
only to be crucial for the fine-tuning of the acute experience but also for
producing enduring beneficial effects after drug intake [48 ]. A few recent studies have emphasized that
the mystical-type experience (MEQ30, M-total or OB score) mediates the persisting
positive changes in trait openness [67 ]
[68 ], mood, well-being, attitudes, and
psychosocial behaviors in healthy volunteers [48 ]
[67 ]
[69 ] as well as the enduring antidepressant
effects in patients with major depression [70 ]
and terminal cancer patients [71 ]
[72 ] ([Fig.
1b ]). However, not every study found an increase in openness as a
personality trait [73 ] or a correlation
between the overall mystical experience and the enduring therapeutic effects in
patients [74 ]
[75 ]. A recent prospective study with psilocybin reported that the M-Scale
subscale scores for ‘unity’ and ‘sacredness’ were
the strongest predictors of the increases in “self-acceptance” and
“appreciation for life” at a four-month follow-up in healthy
meditation experts [48 ] ([Fig. 1b ]). Thus, the specific contribution of
the different dimensions of the psychedelic experience, including the release and
working-through of distressing emotions, to the long-term outcomes, remains to be
systematically investigated [41 ]
[70 ]
[76 ]
[77 ]
[78 ].
Neurobiology of Psychedelics
Neurobiology of Psychedelics
Receptor activation and pharmacological effects of psychedelics
Classic psychedelics such as psilocybin, DMT, or LSD act as partial agonists upon
5-HT1, 5-HT2, 5-HT6, and 5-HT7 receptors [4 ]. LSD and other ergolines also act upon dopaminergic (D1, D2) and
adrenergic receptors [4 ], while mescaline
and DOI are selective agonists at 5-HT2A, 5-HT2B, and 5-HT2C sites [81 ]. Activation of 5-HT2A receptors located
in cortical and subcortical structures seems to be a key mechanism in mediating
many of the behavioral and psychological effects of psychedelics in animals
[82 ] and humans [15 ]
[16 ]. Blocking 5-HT2A/5-HT2C receptors with ketanserin
abolished virtually all of the subjective effects of psilocybin, LSD, and DMT in
humans [6 ]
[15 ]
[16 ]
[83 ]
[84 ]
[85 ]
[86 ]
[87 ]. The intensity of psilocybin-induced subjective effects
correlated with 5-HT2A receptor occupancy in the prefrontal cortex and other
cortical regions [66 ]
[88 ]. In addition, pre-treatment with the
5-HT1AR agonist buspirone significantly reduced the visual effects of psilocybin
in healthy volunteers [89 ], while the
5-HT1AR antagonist pindolol significantly increased the psychological responses
to DMT [90 ], suggesting a modulatory
effect of the 5-HT1AR system on 5-HT2-mediated psychedelic effects. The 5-HT1AR
has also been thought to contribute to the attention-disrupting effects of
psilocybin in humans [91 ].
Psilocybin was also found to increase striatal dopamine concentrations, which
correlate with euphoria and depersonalization phenomena in humans [18 ]. Blocking of D2 receptors with
haloperidol partially diminished the psilocybin-induced positively experienced
depersonalization but not the visual alterations and working memory impairments,
and even increased anxious derealization phenomena in healthy volunteers [15 ]. While psilocybin does not act directly
on dopamine receptors, LSD shows high intrinsic activity at dopamine D2
receptors which may be responsible for the more psychotic-like effects in humans
[4 ]. However, studies specifically
blocking dopaminergic receptors after LSD administration are currently lacking.
A recent animal study showed that high doses of LSD known to produce
psychotic-like behavioral effects in rodents [92 ], but not low doses, modulated dopaminergic activity in the
ventral tegmental area via activation of trace amine-associated receptors 1
(TAAR1) [93 ]. Hence, TAAR1 receptors may
provide a novel target for the treatment of LSD-induced psychotic-like symptoms.
In addition, hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists such
LSD and lisuride differentially activate intracellular signaling pathways in
cortical neurons [94 ], and only
hallucinogenic agonists such as LSD and DOI increased the expression of the
early genes EGR1 and EGR-2 [95 ]. This
functional selectivity remains to be further investigated and maybe a reference
for the development of novel compounds with specific therapeutic properties.
Neuroplastic effects of psychedelics
Several preclinical studies have shown that LSD and DOI increase cortical
glutamate levels and layer 5 pyramidal cell activity in the prefrontal cortex
[96 ]. The increase in glutamate is due
to recurrent network activity triggered by activation of postsynaptic 5-HT2A
receptors located in deep layer 5 or 6 pyramidal neurons that project to layer 5
pyramidal neurons. This glutamate release subsequently activates postsynaptic
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors
located in the apical dendrites in the same neurons which in turn is suggested
to increase the gene expression of brain-derived neurotrophic factor (BDNF), a
protein known to promote neuronal growth and neuroplasticity. DOI administration
was found to increase BDNF expression in the prefrontal cortex and hippocampus
in rodents [97 ]. In recent, DOI, LSD,
psilocybin, and DMT produced both structural and functional neuronal plasticity
in prefrontal cortical neurons in vitro and in vivo [98 ]
[99 ]
[100 ]
[102 ]. The increased synaptogenesis appears
to be mediated through activation of 5-HT2A, tropomyocin receptor kinase B
(TrkB), and mTOR signaling pathways [98 ],
given that the spine remodeling in cortical layer V pyramidal neurons was
abolished by antagonism of TrkB, BDNF’s primary target, and activator or
mTOR, or by blocking 5-HT2A receptors with ketanserin [98 ]. However, a recent study conducted in
mice [102 ] showed that blocking of 5-HT2A
receptors with a ketanserin dose (1 mg/kg), sufficient to
completely abolish head twitch responses, did not block psilocybin-induced
structural plasticity [102 ]. Another study
similarly found that ketanserin (2 mg/kg) almost completely
reduces the ability of psilocybin to induce head twitches but not its
neuroplastic and antidepressant-like behavioral effects in mice [103 ]. The findings suggest that the spine
remodeling and antidepressant-like effects of psychedelics in animals may not or
only partially depend on 5-HT2A receptor activation but may also involve the
activation of other serotonin receptors and signaling pathways [4]. However,
given that different routes of administration and dosage were used in these two
studies, further dose-response research may be necessary to clarify the role of
the 5-HT2A receptor in these processes. Whether psychedelics exert their
neuroplastic effects and potentially associated therapeutic consequences via
5-HT2A receptor agonism and/or polypharmacological action remains to be
investigated.
To date, only a few studies have investigated the relevance of this
psychedelic-induced increase of glutamate-driven AMPA receptor throughput and
associated neuroplastic adaptations for the behavioral effects in animals and
humans. In mice, low-dose psilocybin has been shown to facilitate the extinction
of fear memory associated with a tendency to increase hippocampal
neuroplasticity [104 ]. Similarly, DOI
administration in mice led to fast-acting dendritic spine structural plasticity
in prefrontal pyramidal neurons and acceleration of fear-extinction via the
5-HT2A receptor [100 ]. In another in vivo
study, DOI produced a long-lasting depression of evoked AMPA excitatory
postsynaptic currents in layer V pyramidal neurons in mice as an index of
synaptic plasticity [105 ]. In a recent
study on mice, repeated LSD administration (but not a single dose) selectively
enhanced prosocial behavior without eliciting antidepressant effects by
increasing medial prefrontal cortex (mPFC) excitatory neurotransmission through
activation of 5-HT2A/AMPA receptors and mTOR signaling [106 ]. The inactivation of the mPFC
excitatory neurons inhibited social interactions and nullified the social
effects of LSD [106 ]. Using multiple
measures of behavior, a recent study found that psilocybin produced fast
antidepressant-like behaviors accompanied by strengthened synaptic transmission
in the hippocampus of mice [103 ].
Intriguingly, neither the behavioral nor the electrophysiological responses were
prevented by pretreatment with the 5-HT2A/C antagonist ketanserin,
suggesting that the behavioral and synaptic effects of psilocybin are
independent of 5-HT2A receptor activation, at least in these paradigms tested so
far. The authors concluded that psilocybin may promote restoration of synaptic
connectivity in cortico-mesolimbic circuits processing reward and emotions
without involving 5-HT2AR-dependent psychedelic effects, which has to be
confirmed in further studies. With regards to neuroplasticity effects in humans,
one clinical trial of ayahuasca for depression found a correlation between BDNF
plasma levels 48 hours post-treatment and symptom improvements [107 ]. However, in a recent study,
200 µg LSD significantly increased plasma BDNF levels
6 hours post-treatment, while there were only nonsignificant increases
in plasma BDNF after 25, 50, and 100 µg LSD or after ketanserin
with LSD treatment in healthy volunteers [36 ]
[108 ]. A crucial limitation
of such studies is that BNDF concentration cannot be directly assessed in the
brain. Further studies including alternative approaches to brain plasticity are
needed to investigate if and how the neuroplastic effects seen in animals relate
to the long-lasting symptom improvements reported in recent clinical studies
[27 ].
Functional Network Models of Psychedelic States
Functional Network Models of Psychedelic States
Recent human neuroimaging studies into psychedelic-induced changes in brain activity
and connectivity patterns during resting state gave rise to various hypotheses
regarding the neural underpinnings and widespread functional network disruptions
underlying acute psychedelic states. Empirical evidence supports changes in thalamic
gating, signal diversity of cortical activity, between- and within functional
network integration, and temporal dynamics induced by psychedelic compounds.
Thalamic gating model
Alteration of information processing within
cortico–striato–thalamo-cortical (CSTC) feedback loops is one
mechanism that has been proposed to underly the psychedelic experience. The
thalamus within this circuit is crucial in gating external and internal
information to the cortex and, thereby, in the regulation of the level of
consciousness and attention [109 ]
[110 ]
[111 ]). Thalamic gating is under the control of glutamatergic
cortico–striatal and cortico-thalamic pathways that project to specific
and nonspecific nuclei of the thalamus and under the modulatory influence of
serotonergic and dopaminergic projections arising from the raphe and ventral
tegmentum to several components of the CSTC loops. The CSTC model proposes that
psychedelics disrupt thalamocortical information flow through the stimulation of
5-HT2A receptors located on cortical pyramidal cells and/or GABA
interneurons in several parts of the CSTC loop, resulting in an information
overload of the cortex and subsequent disruption of cortico-cortical integration
of distributed neuronal activity. This could ultimately cause the increased
sensory perception, cognitive disturbances, and ego-dissolution that arise in
psychedelic experiences [109 ]
[112 ] ([Fig. 2 ]). This hypothesis is also compatible with the suggested
increase of bottom-up information flow and relaxed priors proposed in the
relaxed beliefs under psychedelics (REBUS) model described below [113 ].
Fig. 2 Working hypothesis of psychedelic drug effects on
cortico-striato-thalamo-cortical and cortico-cortical circuits of
information flow: The schema in [Fig.
2 ] comprises central brain networks on the effects of
psychedelic drugs responsible for bottom-up sensory input via the
thalamus to the cortex and top-down cortico-striato-thalamic,
cortico-thalamic and/or cortico-cortical control of information
processing. The model is based mostly on data obtained on the action of
LSD and DOI in animals as well as from some studies with LSD and
psilocybin in humans. The 5-HT2A receptors are highly expressed in the
apical dendrites of layer 5 pyramidal (L5p) neurons in the cortex and
are particularly enriched in the prefrontal cortex (PFC) [129 ]
[130 ]
[131 ]. A smaller proportion is
located pre-synaptically on thalamocortical afferents projecting to the
neocortex [96 ]. 5-HT2ARs are also
expressed on GABAergic interneurons in the cortex and subcortical
structures [131 ]. LSD and DOI both
increase extracellular glutamate levels via activation of post-synaptic
5-HT2A receptors on deep layers 5 and 6 pyramidal neurons (L5p) (stage
1) and on Lp6 (stage 2) neurons projecting to L5p neurons [96 ]
[132 ]
[133 ] as well as
via activation of pre-synaptic 5-HT2A receptors on specific (SP) and
non-specific (NSP) thalamocortical afferents [96 ]
[134 ]. Psychedelics such as LSD can also stimulate 5-HT1A
receptors on the hillock on Lp5 and Lp6 neurons (stage 4) and cortical
GABAergic interneurons (stage 5) resulting in both inhibition and
disinhibition of prefrontal pyramidal cell activity [132 ]
[135 ]
[136 ]. Furthermore, LSD or DOI are
also potent partial agonists at cortical (stage 6) and subcortical
(striatal, pallidal or thalamic) (stage 7) 5-HT2A receptors in GABAergic
interneurons [137 ]
[138 ]. Despite this partially
inhibitory mechanisms, this LSD- or DOI-induced increased glutamate
release produces a striking net-excitatory effect on L5p neurons [139 ]
[140 ]
[141 ] and promotes synaptic
plasticity via AMPA and NMDA receptor-dependent mechanisms [98 ]
[105 ]
[106 ]
[133 ]
[142 ]. L5P neurons affect both
thalamic and cortical processing and have the unique ability to couple
thalamo-cortical (stage 8) and cortico-cortical loops (stage 9) of
information streams with each other [143 ]. This is thought to provide a mechanism through which
the state and content of consciousness are functionally coupled [134 ]. Psychedelics appear to affect
this extended thalamic-cortical broadcasting system and thus
consciousness as a whole, by simultaneously producing sensory flooding
and arousal via reduced thalamic gating of interoceptive and
exteroceptive stimuli and by altering the meaning and attachment of
percepts due to disrupted cortico-cortical interactions [19 ]
[109 ]. In this model, thalamic gating is thought to be under
the control of glutamatergic cortico-striatothalamic and
cortico-thalamic loops projecting back to the cortex, in addition to
being under the modulatory influence of serotonergic (and dopaminergic)
projections from the raphe (and the VTA) to several parts of the
CSTC.
The CSTS model is supported by the recent finding that LSD dose-dependently
reduced the firing activity of reticular thalamus GABAergic neurons accompanied
by disinhibition of mediodorsal thalamus relay neurons and increased firing
activity of infralimbic prefrontal pyramidal neurons in mice [114 ]. Infusion of DOI into the dorsal
pallidum in rodents and systemic administration of psilocybin, LSD, and DMT in
humans disrupts sensorimotor gating and is associated with cognitive impairments
in a 5-HT2A -dependent manner [34 ]
[115 ]
[116 ]
[117 ]. Two neuroimaging
studies reported that LSD increased functional connectivity between the thalamus
and sensory-somatomotor cortical regions in healthy volunteers [118 ]
[119 ]. LSD increased directed excitatory connectivity from the
thalamus to the posterior cingulate cortex (PCC) and concomitantly decreased
functional connectivity to the temporal cortex [120 ]. In line with the CTSC model, LSD also decreased control of the
ventral striatum over the thalamus [120 ].
These results indicate that LSD differentially affects thalamo-cortical
connectivity and does not lead to an undifferentiated increase in cortical
information flow [120 ]. According to the
hypothesis that disruption of thalamic gating may result in a sensory overload
of the frontal cortex (“hyperfrontality”) [121 ], two positron emission tomography
studies reported increased prefrontal glucose metabolism after psilocybin
administration in healthy volunteers [121 ]
[122 ] which also remained
evident after normalizing for global effects of psilocybin [123 ]. Similar frontal-dominated effects
were shown with DMT and mescaline measuring cerebral blood flow (CBF) with
single-photon emission computed tomography [124 ]
[125 ]. However, using
arterial spin labeling to investigate changes in brain perfusion, LSD was found
to increase CBF in the visual cortex [126 ]
while psilocybin produced brain-wide hypoperfusion in healthy subjects [127 ]. This latter result was replicated by
Lewis et al. [128 ], but after adjusting
for unspecific global effects, psilocybin was found to increase CBF in frontal
and temporal regions and decrease CBF in subcortical and occipital regions.
These findings are consistent with the hypothesis that reduced thalamic gating
leads to overactivity of prefrontal brain regions, and also illustrate that the
interpretation of such changes depends on the analytical methods used. It is
also conceivable that modern imaging techniques are unable to determine the
delay between changes in brain activity and signal acquisition and how
temporally dynamic thalamic gating may be. Future studies are warranted to
investigate whether differential effects on thalamic subregions or other
subcortical structures may provide a more detailed model and their linkage with
specific psychological alterations of psychedelic states.
The functional state of CSTC loops can be inferred by perturbational imaging
(e. g., electroencephalography, EEG combined with transcranial magnetic
stimulation, TMS) to assess drug-induced changes in brain state in real-time
[146 ]. Perturbational imaging reveals
the synchronized neuronal firing mediated by receptor kinetics [147 ] and can be used to describe the
functional state of the brain. TMS-pulses induce a phase-reset of several
endogenous cortical oscillations and can therefore also be used as a biomarker
of the physiological state and to compare across physiological conditions [146].
TMS-EEG is currently being used to probe psychedelic-induced changes in
cortico-thalamo-cortical dynamics in humans (unpublished). This unique approach
to characterizing the effect of psychedelics on regional interactions at
millisecond resolution is expected to clarify the relationship between
phenomenological state and brain-state. The role of receptor kinetics in the
TMS-evoked response, in combination with the ability to infer
cortico-thalamo-cortical interactions using this technique, offers the
possibility to model the relationship between pharmacodynamics and
psycho-physiological responses.
Neural Entropy model
The “entropic brain hypothesis” (EBH) proposes that the variety
of altered states of consciousness can be indexed through the
information-theoretic measure of the entropy of key parameters of brain activity
[113 ]
[148 ]. The EBH together with the ‘free-energy
principle’ has recently been integrated to formulate the “REBUS
and the anarchic brain” model [113 ]. In brief, this model states that psychedelics increase the
entropy of spontaneous cortical activity and consequently reduce the precision
of high-level priors (expectations or beliefs about the world), and thereby
liberating bottom-up information flow [113 ]. This renders recurrent cortical information processing more
sensitive to the ascending information flow resulting in increased entropy or
complexity of the underlying neuronal activity. Recent empirical research has
identified increased entropy or signal diversity as a signature of psychedelic
states [149 ]. Recent neuroimaging studies
with magnetoencephalography (MEG) and EEG showed that LSD, psilocybin, and DMT
increased the Lempel-Ziv complexity, a measure of signal diversity and
approximation to entropy, which correlated with the overall intensity of the
psilocybin and DMT-induced psychedelic experience [150 ]
[151 ]. Furthermore, in an fMRI study, LSD increased sample entropy in
sensory and some higher-order networks [80 ]. An increased repertoire of different brain states including
rapid brain dynamics and functional connectivity was reported after the
administration of psilocybin and LSD in the same set of healthy individuals
[148 ]
[152 ]. Increased Shannon entropy, broadly defined as the amount of
information in a variable, was also reported in seven participants after
ayahuasca [153 ]. A recent mechanistic
simulation model of the entropic effects of LSD suggests that 5-HT2A receptor
activation leads to an increase in the overall entropy of the neural signals,
but also that the entropy changes are not uniform across brain regions. Entropy
increased in some cortical regions and decreased in some subcortical regions as
a result of 5-HT2A receptor activation, suggesting a reconfiguration of the
topographical distribution of entropy. Intriguingly, at the whole-brain level,
this change was poorly explained by 5-HT2A receptor density, but correlated
strongly with local connectivity strength [154 ]
The REBUS model proposes that the increase in entropy under psychedelics reflects
a relaxation of the precision weighting of high-level priors, leading to
decreased top-down and increased bottom-up information flow. In support of this
view, LSD reduced the electrophysiological responses to surprising stimuli in an
auditory mismatch paradigm [155 ]. Analysis
by Dynamic Causal Modeling (DCM) revealed that this effect was best explained by
reduced top-down information flow from the frontal cortex [155 ]. However, other studies with
psilocybin [156 ]
[157 ]
[158 ] or DMT [159 ] did not
reveal reductions in auditory mismatch processing. On the other hand, a recent
fMRI-EEG study using a tactile mismatch paradigm revealed that psilocybin
reduced the blood oxygenation level dependent (BOLD) signal responses to
surprising tactile stimuli in frontal cortex regions, visual cortex, and
cerebellum, as well as the electrophysiological responses in frontal cortical
regions correlating with the experience of disembodiment and altered meaning of
percepts [160 ]. Hence, it is conceivable
that increased bottom-up information flow, presumably by altered
cortico-thalamo-cortical gating and impaired top-down cortical integration [109 ]
[113 ]
[149 ], may underlie the
reduced sensation of body touch and thus the experience of disembodiment [160 ]. Further research is needed to unravel
the extent to which alterations in bottom-up and top-down information transfer
contribute to the topology of entropy changes and signal diversity observed in
psychedelic states.
Models of this nature are an important tool for interpreting neurophysiological
changes induced by psychedelic drugs. They act as a conceptual lens for
explaining how the induced psychological states may be causally linked with
physiological states. Distinguishing correlation from causation remains a
challenge for neuroscience in general [161 ]. Approaches like the REBUS model, which conceptualize the brain
as having properties of a Bayesian process (i. e., updating high-level
priors), have proven to be predictive in many areas of cognitive research [162 ]. However, confidently mapping Bayesian
objects, such as priors, onto the dynamic activity of neuronal populations
remains ongoing research [163 ]. As models
of information processing and neuronal population coding are developed and
aligned, our understanding of psychedelic states will continue to expand. When
borrowing nomenclature from other disciplines, such as
“entropy”, “complexity”,
“information” and “noise”, it is important to
anchor terminology to signal properties and the experimental paradigm used.
Experiments that investigate brain activity can either deliver a controlled
stimulus and record the (causally known/trial-invariant) signals
elicited, or they can record unconstrained (spontaneous) brain activity.
Properties such as “signal” and “noise” are
easier to define in the context of controlled stimuli because activity can be
parsed based on stimulus invariance. Spontaneous activity, on the other hand,
used to support the REBUS model, is the preferred terminology, and could be
considered by these criteria to be structured noise and therefore a measure of
signal diversity such as entropy. Entropy may be the most appropriate
description for scenarios when brain activity changes in unpredictable
directions and the only consistent outcome following drug administration is
unconstrained change.
Effects of Psychedelics on Brain Network Integration
Effects of Psychedelics on Brain Network Integration
Several neuroimaging studies have investigated the impact of psychedelics on brain
network dynamics by measuring resting-state functional connectivity changes between
and within intrinsic networks [119 ]
[126 ]
[127 ]
[164 ]
[165 ]
[166 ]
[167 ]
[168 ]. Two studies exploring the effect of LSD
and psilocybin on global brain connectivity (GBC) using a graph-based measure of
intrinsic whole-brain network connectivity and global signal correction (GSR) found
that both drugs increased connectivity of brain region in sensory and somatomotor
networks and decreased connectivity of brain regions in associative networks
including the Default Mode Network (DMN) [119 ]
[169 ]. The DMN is a large-scale
network – consisting of brain regions such as the medial prefrontal cortex,
posterior cingulate cortex, precuneus, and angular gyrus - that is activated when
one is awake, but not involved in any specific mental exercise [170 ]. Moreover, the regional GBC changes
correlated significantly with the topography of HTR2A gene expression [119 ]. These results are in line with the
finding that psilocybin decreased expression of the frontoparietal control network
(that is, a decreased probability of the occurrence of a recurrent phase-locking of
BOLD signal over time), and concomitantly increased occurrence of a globally
coherent brain state [171 ]. However, two other
studies investigating the effects of LSD on GBC, although without using GSR,
reported no overlapping results [118 ]
[172 ], except for increased functional thalamic
connectivity [118 ]
[164 ]
[172 ]. The decision to use or forgo GSR to adjust for shared variance across
brain regions as well as for physiological-, movement- and scanner-related artifacts
[173 ] remains a point of contention, and
there is essentially no single "right" way to process resting-state
data [173 ]. Together, these findings suggest
that increased (bottom-up) sensory processing and reduced top-down integration
capacity due to diminished associative network integrity may underlie psychedelic
experiences. Notably, a recent whole-brain model using the dynamical mean-field
quantitative description of excitatory and inhibitory neuronal populations as well
as the associated synaptic gain function suggests that the effect of LSD on global
brain connectivity can be best explained by the regional distribution and density of
5-HT2A receptors located on cortical pyramidal neurons [174 ]. A similar approach employing a
transcriptomics-informed large-scale cortical model, including the expression level
of various serotonergic and dopaminergic genes also found that modulation of
pyramidal cell gain by 5-HT2A receptor activation accurately captures the
LSD-induced GBC changes [119 ]
[144, 145 ]. In addition, fitting to GBC
in individual subjects revealed that the model also captures patterns of individual
differences in LSD response that predict different aspects of the psychedelic
experience [144 ]. Thus, it appears that the
integration of bio-physical modeling and empirical neuroimaging data provides a
promising framework to further unravel circuit mechanisms through which psychedelics
alter cortical functional topography. Future work may also incorporate 5-HT2A
receptors located in high density within the claustrum [175 ] and to a lesser extent in subcortical
structures [138 ], but may also include other
types of neuroreceptors such as the dopamine D2 [93 ]
[138 ]
[176 ], AMPA [98 ]
[105 ]
[106 ]
[133 ]
or NMDA receptor [142 ], all of which have been
shown to contribute to the emotional and cognitive effects of psychedelics as
described above.
Some studies also reported that psychedelics alter functional network connectivity
which is the strength of typical anticorrelations between the DMN and other
intrinsic networks [168 ]. Although psilocybin
decreased DMN – Task Positive Network orthogonality [165 ], this finding was not replicated in
another study after the administration of the DMT-containing drink Ayahuasca [167 ]. Psilocybin [166 ] and LSD [126 ]
[168 ] were also found to induce
widespread changes in between-network connectivity, although no uniform pattern of
changes has emerged so far [168 ].
A consistent finding of several studies that have explored within-network functional
connectivity (FC) is that psilocybin, LSD, and DMT decrease FC in or between
structures of the DMN, [119 ]
[126 ]
[127 ]
[167 ]
[168 ]
[177 ]. For example, psilocybin [69 ]
[127 ] and LSD [126 ] decoupled FC between the medial prefrontal (mPFC) and the posterior
cingulate cortices (PCC) - two major hubs of the DMN that have been implicated in
self-other distinction, self-related cognition, and inward- versus outward-directed
mentalizing [178 ]. Notably, a recent study
found that the decrease in mPFC – PCC FC, two days after psilocybin
administration, correlated with the intensity of the acutely experienced
self-dissolution (OB) and predicted positive changes in psychosocial functioning in
healthy volunteers four months later [69 ].
However, similar decreases in FC between the nodes of the DMN have also been
reported after the administration of selective serotonin reuptake inhibitors [179 ] and the serotonin-releaser N-Methyl-3,
4-methylenedioxyamphetamine (MDMA) [180 ].
Changes in DMN activity have been reported for several conditions, including
meditation [181 ] and task-positive behaviors
[182 ]. Hence, identifying DMN changes
specific to psychedelic drugs and the contribution of decreased DMN FC to the
subjective effects of psychedelics remains to be further investigated.
The concerted interaction of brain networks and brain regions is also reflected by
brain oscillations [183 ]
[184 ]. They are characteristic features of the
cortical dynamics implicated in the modulation of perception and cognitive
functions, which can be measured via resting-state MEG/EEG recordings [185 ]. MEG/EEG studies reveal that
psilocybin, LSD, and DMT reduce spontaneous oscillatory power of low-frequency
signals including the delta, theta, beta, and alpha (1–12.5 Hz)
frequency bands. The reduction of alpha power in the DMN including the ACC and PCC
[177 ]
[186 ], in parahippocampal regions [186 ], and parieto-occipital and posterior association cortices [177 ]
[186 ]
[187 ]
[188 ]
[189 ]
was the most consistent finding after administration of psychedelics. Alpha
oscillations reflect cortical inhibition of neuronal ensembles [190 ]. Thus, the decrease in alpha power may
indicate a bias of the cortical excitation/inhibition balance towards
excitation. DCM applied to MEG data suggests that the reduction in PCC alpha power
after psilocybin administration is consistent with increased L5p neuron activity,
which also correlated with ego-dissolution [127 ]. In another study, lagged phase synchronization of delta
oscillations between the orbitofrontal cortex, the parahippocampus, and the
retrosplenial cortex correlated with the psilocybin-induced spiritual experience and
insightfulness [186 ]. Psilocybin and DMT also
increased low gamma oscillations in the PCC [186 ] as well as low and high gamma power in frontal, temporal, and
parieto-occipital cortices [189 ]. However,
decreases in gamma power in prefrontal, sensory and somatomotor areas have also been
reported [177 ]. Gamma oscillations are thought
to provide a neuronal mechanism to bind coherently distributed cooperating neuronal
assemblies for representation, storage, and retrieval of information [184 ]
[191 ]. The range of cognitive processes in which gamma synchronization has
been implicated suggests that its presence may reflect an array of simultaneous
processes at work [192 ]. Changes in gamma
synchronization would then reflect changes in information processing, including
endogenously-generated states. Hence, alterations in gamma synchronization may well
contribute to changes in processes like autobiographical memory retrieval [193 ] and awareness of one’s own
internal state during the psychedelic experience [194 ]
[195 ].
Neural Correlates of Altered Self- and Emotion-Processing in the Psychedelic
States
Neural Correlates of Altered Self- and Emotion-Processing in the Psychedelic
States
Early clinical observations in psychedelic research suggested that psychedelics
induce regression of the self, lowering of rational thinking, increased affectivity,
and facilitated recall of memory blocks. This gave rise to the hypothesis that these
are important psychological mechanisms that contribute to the restructuring of the
self and self-related functions, as well as the changes in emotion regulation, and
thus to the clinical efficacy of psychedelic-assisted psychotherapy [41 ]
[76 ]
[196 ]
[197 ]
[198 ]. Building upon these findings, several studies have investigated the
neural correlates of psychedelic-induced alterations in self-experience, cognition,
mood, and emotion processing.
Self-Processing
Psychedelics profoundly alter various aspects of the ordinary coherent
self-experience [6 ]. This is often
described as a loosening of self-boundaries, an experience of oneness,
disembodiment, a loss of authorship of thought, emotions, and actions, and
dissolution or disintegration of the experiential “I” or
“ego” [6 ]
[199 ]. To date, several studies have
attempted to capture the neural correlates of these phenomena by correlating
psychometrically assessed subjective alterations in self-experience with brain
imaging data. So far, different constructs – ranging from dimensional
(e. g. “oceanic boundlessness” [119 ]
[200 ] to sub-dimensional (e. g. “unity” [6 ]
[201 ] and to single item-based approaches (e. g., “I
experienced a disintegration of my self or ego” [126 ]
[172 ]
[177 ]
[202 ]
[203 ] – have been used to measure the complex multi-layered
alterations of self-experience in psychedelic states.
In an fMRI study, the LSD-induced loss of self-boundaries correlated with
increased global brain connectivity in the somatomotor network [119 ], while in another study the subjective
reports of ego-dissolution correlated with increased global FC in the angular
gyrus and the insula [172 ]. In a
subsequent analysis of the later study [172 ], the LSD-induced ego-dissolution also correlated with decreased
seed-based functional connectivity within the DMN and between the
parahippocampus and retrosplenial cortex as measured by fMRT and with decreased
delta and alpha power as measured by MEG [126 ]. By focusing on the time-dependent effects of LSD on functional
connectivity, another analysis of this study [172 ] revealed that the feeling of ego dissolution correlated with the
increased weighted small-world propensity (organization) during the dynamic
sub-state of high global integration [203 ]. Concerning the effect of psilocybin, one study noted that the
self-reported ego-dissolution correlated with decreased alpha power in the PCC
[177 ], and in the same participants,
with a reduction of FC between the medial temporal lobe (MTL) and high-level
cortical regions, a “disintegration” of the salience network
(SLN), and a reduction of interhemispheric communication [202 ]. In another study, the
Psilocybin-induced spiritual experience and insightfulness – two
subdimensions of OB – correlated with the lagged phase synchronization
of delta oscillations between the retrosplenial cortex, the parahippocampus, and
the orbitofrontal cortex [186 ].
Recent neurocognitive approaches to the self suggest that self-referential
processing of internal and sensory stimuli in cortical midline structures
constitute a core concept of one’s self [204 ]
[205 ]
[206 ], a phenomenal self as the subject of
experience, also referred to as a self-model [7 ]
[28 ]. The representation of
the self as a solid entity includes in parallel the processing of internal
stimuli from one’s own body with emotions and cognition which are also
examined through self-reference and bound to that entity [7 ]
[207 ]. This complex multi-layered representation of the self has
various features such as a sense of being, ownership of a body, temporal order,
spatial location, ownership and authorship of thoughts, emotions and actions,
and a history [208 ]. Along this line, a
recent EEG-ERP study using an auditory self-monitoring task found that
psilocybin abolished self-stimuli encoding via a P300 mechanism associated with
current source density changes in the supragenual anterior cingulate cortex and
right insula [209 ]. Notably, the extent of
the P300 effect significantly correlated with the intensity of the experience of
unity (‘oneness with the surroundings’) and changed the meaning
of percepts, assessed psychometrically. Moreover, in accordance with predictive
coding principles [210 ], psilocybin also
reduced tactile mismatch processing in prefrontal cortex regions that correlated
with the extent of disembodiment and changed meaning in a combined EEG-fMRT
study in healthy volunteers [160 ]. The
phenomenon of reduced mismatch processing has been interpreted as reflecting an
impairment of predictive coding or, more generally, the “Bayesian
brain” notion that the brain continuously updates a hierarchical model
to infer the causes of its sensory inputs [162 ]. Thus, this study provides the first evidence to the hypothesis
that the profound alteration of the bodily-self as an aspect of self-dissolution
during psychedelic states is due to a dysfunctional integration of bodily states
and sensory inputs with prior beliefs [211 ]. However, more research is warranted to further investigate the
detailed hierarchical and temporal dynamics of psychedelics-induced disruption
of belief updating within the framework of predictive coding [212 ].
Taken together, these disparate findings regarding the neuronal correlates of
altered self-experience or ego-dissolution appear to reflect different facets
and layers of the dynamics of self-loss in psychedelic states, but may also be
due to the different methods, metrics, and doses used across studies. The
participant’s widely different understanding of ambiguous terms such as
“ego”, “sacredness” or “spiritual
experience” may also have contributed to the variability of present
results [213 ]
[214 ]. More differentiated
operationalization and fine-grained psychometric instruments are needed to
conclusively identify specific neural correlates of altered self-experiences
across future studies. However, the present data also suggest that the self
should be understood as a complex matrix of representations involving different
structures and functions rather than a single entity that could be readily
abandoned in psychedelic states. The investigation of self-referential
processing may offer a promising alternative operationalized approach to unravel
the neural correlates of altered self and ego-dissolution.
Beyond the scope of getting a deeper insight into the different organizing
principles and processing levels that constitute our self, these studies are
important because alterations in self-processing are considered to be crucial
for the efficacy of psychedelic-assisted therapy [41 ]
[197 ]
[198 ]. So far, positively
experienced self-dissolution (e. g., OB) or mystical-type experiences
were correlated with the treatment success in an open-label study of major
depression [215 ] and two controlled
studies of depression and anxiety in palliative care [71 ]
[72 ]. Clinical observations suggest that the transient dissolution of
self-boundaries and the reduction of self-referential processing leads to
decentering [41 ]
[48 ]
[216 ]
[217 ]
[218 ], which is a process of stepping
outside of one’s own immediate experience enabling a person to realize
that their thoughts and emotions are not unchangeable facts, but only a
constructed reality of the self [219 ]
[220 ]. This shift in perspective facilitates
more appropriate reactions and adaptions to one’s own cognitions and
negative attribution of emotions and reduces dysfunctional attitudes towards the
self [48 ]
[219 ]. Increased self-focus and reduced attention to others and the
environment are characteristic features of depression - presumably due to
increased DMN resting-state activity and altered balance between DMN and
executive network activity [24 ]
[221 ] – therefore, it is conceivable
that the transient self-dissolution associated with reduced DMN activity leads
to reduced and more flexible cognitive reactions, especially in depressed
patients suffering from negative self-attribution and ruminative thinking [22 ]
[23 ]. Consistently, LSD and psilocybin acutely increased emotional
empathy [222 ]
[223 ], facilitated social adaptation [224 ], and reduced rejection sensitivity and
feelings of social exclusion [20 ]
[201 ]. Hence, reduced self-processing may
also promote improvements in social cognition [20 ], thereby contributing to the emotional attunement which is
important in (psychedelic-assisted) psychotherapy of depressed patients [11 ]
[41 ]
[198 ]. However, these
hypotheses remain to be tested in clinical studies.
Emotional Processing
Several studies in healthy volunteers have shown that psychedelics also acutely
alter emotion processing, and particularly reduce the response to negative
emotional stimuli. For example, psilocybin and LSD dose-dependently attenuated
the recognition of negative facial expression in healthy volunteers [84 ]
[223 ]
[225 ]
[226 ]. Intriguingly, psilocybin reduced both
non-conscious and conscious structural encoding of fearful faces, although
somewhat more pronounced during conscious processing [226 ], suggesting that emotional awareness
may enhance psychedelic-mediated emotion regulation (for an opposite view see
[103 ]). Furthermore, psilocybin and
LSD reduced the neuronal response to negative stimuli in the amygdala correlated
with the increase in the positive mood [227 ]
[228 ]. Subsequent
correlation analyses revealed that psilocybin reduced directed connectivity from
the amygdala to the primary visual cortex during threat processing [229 ] and decreased the functional
connectivity between the amygdala and the striatum during angry face
discrimination [230 ]. In a recent study,
reduced amygdala response to negative stimuli was observed one week after
psilocybin administration but returned to baseline one month after
administration [231 ].
Negative cognitive and emotional biases, as well as increased amygdala reactivity
to negative stimuli, are characteristic features of depression [22 ]. Hence, it is conceivable that
psychedelics may acutely abolish this negative cognitive and emotional bias by
reducing amygdala reactivity, allowing a cognitive-emotional re-adaption from a
decentered stance. To what extent this process on its own or in combination with
psychotherapy may contribute to the enduring symptom reductions reported in
psychedelic-assisted therapy is hardly understood. So far, a recent open-label
study in depression reported increased amygdala reactivity in response to
fearful stimuli and decreased amygdala-prefrontal cortex FC one day after
psilocybin administration [215 ]
[232 ]. This discrepancy may be because
increased amygdala reactivity in these depressed patients was measured prior to
psychological integration work [215 ].
Further longitudinal studies are needed to explore the long-term effects of
psychedelics on amygdala reactivity and its clinical relevance.
Conclusion
Elucidating the biological mechanisms of classical psychedelic drugs, while hindered
by a complex socio-political history, persists as a promising research endeavor for
neuropsychopharmacology. Realizing the full potential of psychedelic compounds as an
effective and reliable clinical tool will require a continuous understanding of
their interdependent effects at many biophysical and psycho-social levels.
Psychedelic experiences have broadly defined phenomenological trajectories, which
makes their contents accessible to researchers via psychometrics. Standardized
questionnaires currently exist to quantify aspects of these drug-induced alterations
in consciousness, which lends to quantification and correlation with biomarkers and
measures of physiological state. The diversity of receptor targets is
well-characterized, affecting primarily serotonergic receptor subtypes and mediated
by several other neuromodulatory receptors. Through these known mechanisms, aspects
of psychedelic experiences in humans can be modified by administering other drugs
concomitantly to target specific receptor subtypes. The affected receptor sites are
situated within neuronal pathways necessary for cortico-thalamic and
cortico-cortical feedback circuits. By modulating excitatory-inhibitory balance in
these circuits, psychedelic drugs can participate in neuroplasticity within
structures critical for information processing in the brain. These insights have
laid a foundation for several, non-conflicting, theories about the
multi-system-level changes induced by psychedelic drugs. They predict altered
pathways in brain structures associated with the integration of information relevant
to sensation, cognition, emotions, and the narrative of self. These theories also
converge to explanations inspired by biological (statistical) thermodynamics, using
the concepts of entropy and information, in combination with the necessary
receptor-mediated dynamics. Moreover, modern approaches to causal inference applied
to imaging techniques (like DCM and perturbational imaging) are helping to forge
models directly relevant to neuropsychiatry which will hopefully become prognostic
tools. Neurophenomenological metrics for transient and long-lasting effects of
psychedelic drugs on healthy volunteers and patients continue to be discovered, and
those which best predict clinical outcomes of psychedelic-assisted therapies are an
ever-expanding field and show great promise.
