Contents lists available at ScienceDirect
Medical Hypotheses
journa l homepag e:
The Psilocybin-Telomere Hypothesis: An empirically falsiable prediction
concerning the benecial neuropsychopharmacological eects of psilocybin
on genetic aging
Christopher B. Germann
Marie Curie Alumnus, United Kingdom
Cellular senescence
Genetic aging
Epigenetic clock
Life extension
We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has benecial eects
on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantiable
positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious
aging-related diseases). Our hypothesising follows the Popperian logic of scientic discovery, viz., bold (and
refutable) conjectures form the very foundation of scientic progress. The psilocybin-telomere hypothesis is
formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support
the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources
indicating that psilocybin has persistent benecial eects on various aspects of mental health (e.g., in the context
of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that
establish reliable correlations between mental health and telomere attrition (improved mental health is gen-
erally correlated with longer telomeres). Another pertinent component of our argument is based on recent
studies which demonstrate that meditative states of consciousness provide benecial eects on genetic aging.
Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically
signicantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose
of psilocybin can occasion life-changing transformative experiences ( 70% of healthy volunteers rate their
experience with psilocybin amongst the ve personally most meaningful lifetime events, viz., ranked next to
giving birth to a child or losing a loved one). We postulate that these profound psychological events leave
quantiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost eec-
tiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in
future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientic consilience via metho-
dological triangulation). In order to substantiate the psilocybin-telomere hypothesis potential neuropsycho-
pharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity,
hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT
receptor agonism, neuroplasticity/
synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4
serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary,
and it has deep ramications from a philosophy of science perspective as it connects the epistemic level (qua-
litative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the
long term, multidisciplinary and innovative investigations of the psilocybin-telomere hypothesis could con-
tribute to the improvement of senotherapeutic psychological interventions and the identication of novel ger-
oprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve
well-being and quality of life during the aging process.
A plethora of genetic and geroscience studies indicate that telomere
length is a reliable biomarker of cellular aging [1,2], i.e., telomeres are
regarded as a robust indicator of mitotic cell and possibly organismal
longevity [3]. Attrition/uncapping of telomeres is associated with the
Received 27 July 2019; Received in revised form 21 September 2019; Accepted 24 September 2019
This work was funded by the European Union Marie Curie Initial Training Network / Marie Curie Actions: FP7-PEOPLE-2013-ITN-604764. https://www.CogNovo.
eu Electronic supplementary material:
E-mail address:
Medical Hypotheses 134 (2020) 109406
0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
degeneration of multiple systems such as various organ failures, de-
pletion of the totipotent stem cell répertoire, tissue atrophy, impair-
ments in injury responses and various (neuro)restorative processes,
inter alia [4]. Furthermore, it has been proposed that telomeres function
as a psychobiomarker as they are partially regulated by psychological
factors [5,6]. In sensu lato, a healthy lifestyle and a positive outlook on
life are generally associated with longer telomeres while, vice versa,an
unhealthy lifestyle and a negative/pessimistic mindset are associated
with shorter telomeres [7,8]. There are numerous factors that in uence
telomere attrition, for instance, maternal genetic predispositions [9], in
utero stress-levels, quality of diet [10,11] and availability of ω 3 fatty
acids [12], alcohol consumption [13], tobacco smoking [14], sleep
patterns [15], a variety of social/interpersonal variables [1618], t-
ness and physical exercise [19,20], exposure to environmental toxins
such as trac pollution [21] and various chemical compounds found in
plastics [22], etc. pp. (for a comprehensive review see, [23]). Fur-
thermore, converging evidence indicates that telomeres are a ected by
psychological conditions such as chronic stress, depression, and re-
petitive negative thought patterns, viz., chronic rumination [3,2427]
and self-referential mind wandering
[28]. The pertinent literature
delineates the following dichotomous pattern: Positive psychological
states are correlated with longer telomeres, whereas depression,
chronic stress, and anxiety display a negative correlation [29].
In line with this empirical background, our primary hypothesis is
based on the major premise that psychological conditions aect telo-
meres. In addition, our hypothesis rests on the minor premise that the
therapeutic utilisation of psilocybin exhibits signicant benecial ef-
fects on various aspects of psychological health.
Rapidly accumulation
converging empirical evidence supports this claim [3034]. Speci-
cally, a substantial corpus of studies demonstrated that the therapeutic
utilisation of psilocybin reduces depression in various populations
[3537] and, for the sake of focus and parsimony, the present discus-
sion will be primarily concerned with this factor. However, similar
arguments could be articulated with respect to PTSD, various anxiety
disorders, behavioural and substance addictions, etc. (e.g., [38]). Given
the well-established comorbidity between these psychopathologies
[39], it is logically cogent to assume that the underlying cognitive,
emotional, and biochemical mechanisms are signicantly congruent in
numerous respects, e.g., in terms of characteristic neurotransmitter
dynamics and brain-wide network dynamics.
Hypothesis as a deductive syllogistic argument
Our hypothesis is based on the empirically grounded assumption
that neuropsychological factors inuence aging at the genetic level. We
postulate that benecial psychological conditions are associated with
telomeric health (i.e., longer telomeres via activation of the enzyme
telomerase reverse transcriptase which adds nucleotide sequences to
the ends of DNA). Consequently, we predict a priori that therapeutic
psychological and neurobiological changes induced by psilocybin are
quantiable by telomere analysis (but also via alternative biomarkers of
aging, as discussed subsequently). The primary hypothesis can be stated
as a deductive argument in form of a valid Aristotelian categorical
Syllogism #1
Major premise: Depression is associated with shorter telomeres.
Minor premise: Psilocybin reduces depression.
Conclusion: Ergo, psilocybin positively eects telomere length.
N.B.: According to syllogistic logic, each of the three distinct terms
represents a category, i.e.: [Depression] [Telomeres] [Psilocybin].
In Syllogism #1 the category [Telomeres] constitutes the major
term and [Psilocybin] represents the minor term. Crucially, the pre-
mises have a single term in common (the middle term)
that appears as
the subject or predicate of the categorical proposition, in casu, [De-
According to the principles of propositional logic, the conclusion
follows deductively
if the major and minor premise are accepted as
veridical. In the following sections we will thus provide empirical evi-
dence in order to substantiate the major and minor premise, i.e., 1) that
depression is associated with shorter telomeres and 2) that psilocybin
reduces depression. Note that our hypothesis could also be remodelled
in the framework of Bayesian epistemology. In this case the subse-
quently presented information can be utilised to calibrate/parametrise
informed priors which severe as a conditional probabilistic basis for
Bayesian prediction, viz., degrees of belief or credence.
Auxiliary hypothesis
We posit that negative psilocybin phenomenologies may not reliably
produce the a priori predicted genetic eects. Thus, our hypothesis is
directional (one-tailed) in the case of a positively valenced psilocybin
phenomenology, but bidirectional without any additional specication
as we assume that negatively valanced phenomenologies can cause
acute stress and anxiety. In the worst-case scenario such experiences
(colloquially referred to as bad trips) can induce lasting psychological
Ex hypothesi, negative psychological conditions facilitate
telomere attrition [40]. However, from a longitudinal perspective, a
prima vista seemingly negative psilocybin experience can exert bene-
cial longitudinal psychotherapeutic/cathartic eects which may take
substantial time to unfold (per analogiam to the occurrence of various
negative side-eects that frequently accompany physiological detox-
ication which can cause the release of deposited toxins that trigger
various seemingly negative side-eects which are in actuality con-
ducive to long-term healingsimilarly, psilocybin can render proble-
matic unconscious contents more accessible which may be acutely
problematic but conducive to longitudinal improvements of mental
health and quality of life). Negatively valenced phenomenologies
should therefore be investigated in a nuanced and diachronic fashion to
evaluate the psychotherapeutic developmental time course (e.g., by
Mind wandering has been associated with consistently shorter telomeres
across dierent immune cell types, i.e., granulocytes and lymphocytes [28].
The authors concluded that a present attentional state may promote a healthy
biochemical milieu and, in turn, cell longevity.
Contrary to wide spread public doxa [109], epidemiological data indicate
that psychedelics are not linked to psychopathology or suicidal behaviour
[[110], cf. [115]. The mass-media utilized propagandistic/PR methods à la
Bernays [117,113] in order justify the governmental War on Drugs (initiated
by the Nixon administration) which was clearly politically motivated, for in-
stance, in order to target Vietnam war opponents and racial minorities and to
serve the prison-industrial complex [119,115]. This juridically enforced in-
terregnum interupted the very promising psychedelic research agenda abruptly.
One can only speculate how much progress psychedelic science could have
achieved in the interim if research would not have been systematically in-
hibited by irrational polictical factors.
Recently, an anxiolytic function of endogenous tryptamines (i.e., N,N-
Dimethyltryptamine) has been hypothesised [see [116]] which may be perti-
nent for the hypothesis at hand (for instance, persistent stress reduction via
activation of the parasympathetic branch of the CNS).
The absence of the middle term in both premises leads to a syllogistic fal-
lacy, i.e., the logical fallacy of the undistributed middle (lat.: non distributio
D.M.: From a philological vantage point, the term deduction is etymolo-
gically derived from the Latin deducere to lead, to derive. Thus, the premises
(automatically) lead to the conclusion, i.e., the conclusion is logically derived.
This methodological approach exemplies the basis of the deductive-nomolo-
gical model (PopperHempel model) of scientic explanation [117].
The DSM-5® diagnosis Hallucinogen persisting perception disorder
(HPPD) has been applied in extreme cases (low incidence rate).
C.B. Germann
Medical Hypotheses 134 (2020) 109406
employing a longitudinal research design and appropriate analytic
procedures such as statistical time-series analysis).
In a generic presentment, the psilocybin-telomere hypothesis can
be reformulated in a more relaxed/exible semantic format as illu-
strated in Syllogism #2. However, for the sake of specicity (i.e., ex-
perimental operationalism/falsiability) we will focus the subsequent
discussion on the more concrete formalisation which focuses ex-
clusively on depression. Moreover, it is hitherto unclear whether psi-
locybin per se is sucient to induce benecial neuropsychological ef-
fects or if it is generally advisable to combine it with psychotherapy to
harness its full psychological potential. The open question is thus: Is
psilocybin intrinsically therapeutic (as various indigenous cultures
would purport)
or is additional psychotherapy indicated to guide the
process and to facilitate post festum integration in order to improve the
psychological and medical eectiveness of the intervention? This is an
empirical question which should be investigated in a controlled
manner. Future research should also elucidate the synergistic eec-
tiveness of psilocybin (cf. [41]) when combined with dierent psy-
chotherapeutic treatment modalities, e.g., cognitive behavioural
therapy, somatic therapy, transpersonal therapy, psychoanalysis, music
therapy, meditation, mindfullness training, inter alia. We maintain that
the transcendental/spiritual phenomenological aspects are pivotal to
the therapeutic eects of psilocybin (cf. the etymological meaning of
the composite lexeme psychology; i.e., derived from the Greek ψυχή
psyche, hence, in its original root meaning psychology refers to the
study of the soul/spirit/breath). However, a genuine appreciation of
this reconceptualisation requires a Kuhnian paradigm shift in main-
stream scientic thought (viz., a holistic/integral perspective which
supersedes dogmatic material reductionism and epiphenomenalism).
Syllogism #2
Major pre-
Benecial neuropsychological changes positively eect telomere
Minor pre-
Psilocybin has quantiable benecial neuropsychological eects.
Conclusion: Ergo, psilocybin positively eects telomere length.
It should be emphasised that we selected depression as a representative
exemplar to demonstrate a much broader line of thought. Psilocybin has
multi-layered eects on psychological health and the predicted genetic/
epigenetic eects are thus likely complex and multifactorial and not
exclusively restricted to telomeres. However, telomeres are a con-
venient biomarker which is readily quantiable with modern labora-
tory methods (e.g., PCR-based assays). Ergo, the psilocybin-telomere
hypothesis allows for the straightforward construction of an experi-
mentum crusis (a decisive experiment which allows for direct
falsication), i.e., a controlled experiment based on the ceteris paribus
principle (viz., an experimental design in which all known potential
confounding variables are rigorously controlled across experimental
conditions in an attempt to isolate a cause= > eect relationship be-
tween psilocybin and telomeres). For a more synoptic test of the psi-
locybin-telomere hypothesis enzymatic telomerase activity should be
measured and alternative methods to quantify the aging process should
be employed. Other biological clocks are, for example, transcriptomic
predictors, proteomic predictors, metabolomics-based predictors, and
composite biomarker predictors [42]. Data indicates that dierent
biomarkers measure dierent (unrelated) aspects of biological aging
For instance, in addition to telomere analysis, epigenetic clock
analysis based on DNA methylation data could be utilised as a com-
plementary measure [44]. Telomere length and the epigenetic clock are
independently associated with chronological age and mortality [45]
and could therefore be utilised in a cross-validating manner.
It has
been proposed that DNA methylation age quanties the cumulative
eect of an epigenetic maintenance system and that this novel epi-
genetic clock can be used to address a host of questions in develop-
mental biology, cancer and aging research [46] and also questions
related to epigenetic reprogramming and rejuvenation [47]. Like
telomere analysis, epigenetic clock analysis shows correlations with
diet, exercise, education, and lifestyle factors.
Evidence in the support of the major premise: Depression is associated with
telomere attrition
Numerous studies indicate that depression has quantiable eects
on telomeres [4850] and animal models support this nding [51].
recent meta-analysis of 83 studies conrmed a signicant correlation
between depression and telomere length [149]. The pertinent literature
indicates a general pattern: Positive mental psychological states have
benecial eects on telomere length while the opposite holds true for
negative states such as stress, depression, and anxiety [40,52]. Accu-
mulating evidence thus indicates that depression accelerates genetic
aging (i.c., telomere attrition/senescence) and it has been hypothesised
that the link between depression and genetic aging is, inter alia, medi-
ated by the hypothalamicpituitaryadrenal axis (HPA axis) [53]. The
HPA axis is crucial for the elicitation of stress responses in reaction to a
given stressor, e.g., release of the stress hormones cortisol, epinephrine/
adrenalin, and norepinephrine. Inammation is another important in-
terrelated factor in the context of stress, depression, and genetic aging
[54]. The exact psychoneuroendocrinological mechanisms are a matter
of ongoing scientic debate (for an evolutionary account see [55]).
Another important factor associated with depression is oxidative stress
[56]. Again, it has been demonstrated that oxidative stress contributes
to genetic aging, i.e., it accelerates telomere attrition [57,58]. In fact,
inammatory and oxidative stress biomarkers can be regarded as
peripheral biomarkers in major depression (for a review see [56] ).
The role of psilocybin and structurally related tryptamines as anti-in-
ammatory agents is a topic which recently gained attention [59] and
particularly the role of the σ1 receptor in neuroinammation and
neurodegeneration is of interest in the present context.
Alterations in concentrations of various brain growth factors have
been associated with stress and depression. Specically, BDNF (brain-
derived neurotrophic factor) has been thoroughly investigated in this
Indeed, indigenous shamanic healers (alias doctores) refer to psychoactive
plants as immensely intelligent plant teachers or plant healers [118],a
piece of evidence from anthropological linguistics that corroborates the notion
that specic plants/fungi possess an inherent therapeutic potential because they
are living organisms endowed with a soul (not merely complementary Watson-
Crick base pairs to be manipulated by an omniscient LaPlacian scientist). This
much older and much more nature-bound primitive animistic Weltanschauung
is fundamentally incompatible with the almost ubiquitously adopted doxastic
philosophical axioms of mainstream reductive materialism and its unique
myopic perspective on the very question of what constitutes knowledge [119].
For example, attempts to reduce neurochemically induced transformative
transcendental experiences to specic synaptic and dendritic molecular pro-
cesses (e.g., 5-HT
agonism) may turn out to be a naïve reductionist fallacya
Zeitgeist bias that inuenced much of 20th century neuroscience in an irra-
tional and prejudiced manner towards a view that (unsuccessfully) attempts to
reduce psychology to physics, i.e., it is believed that material processes form the
causative foundation of psychology in its entirety (due to a misapplication of
the covering law model of explanation). However, the assumption that psy-
chology (and consciousness) can be in toto reduced to physics has de facto be-
come increasingly more implausible.
The Pearson correlation coecient with chronological age is r 0.96; for
telomeres length it is r ≈−0.53.
N.B.: For various quasi-Kantian ethical and moral reasons we are categori-
cally opposed to studies which harm or kill animals. Further, such studies are
specically problematic with respect to chemical compounds that alter con-
sciousness as animals presumably lack the complexity of consciousness human
beings possess (i.e., a lack of generalisability/external validity).
C.B. Germann
Medical Hypotheses 134 (2020) 109406
regard [60] and it appears to be decreased in clinically depressed po-
pulations [6163]. Lower BDNF-levels may be responsible for neuroa-
natomical changes that accompany depression. Particularly relevant for
the hypothesis at hand, it has been suggested that telomerase mediates
the cell survival-promoting actions of BDNF [64] . Consequently, it
would be of great interest to examine the eects of psilocybin on BDNF
concentrations [65] as this might provide basic insights into inter-
mediary biochemical mechanisms that mediate between psilocybin and
its postulated eects on genetic aging.
Research indicates that various forms of stress (including chronic
rumination as a symptom of depression) set in motion a psychoneur-
ochemical cascade of detrimental eects which negatively aect telo-
meres [6668]. Stress magnies various endogenous inammatory re-
sponses which in turn inhibit telomerase activity (see also [69]). Again,
the exact mechanisms are currently a topic of active research (see [6]).
It has been hypothesised that exposure to stress activates a broad and
complex array of interacting biological mediators which results in the
shortening of telomeres [70]. To recapitulate: Stress arousal increases
stress hormones, neuroinammation, and oxidative stress. Thesefactors
have been reliably associated with telomere attrition [67,71,72] .
There are several protective factors which modulate the detrimental
impact of chronic stress. For instance, certain neurosteroid hormones
counteract the negative eects of excessively high levels of cortisol. For
example, the endogenous steroid hormone dehydroepiandrosterone
(DHEA) has been shown to possess antiglucocorticoid properties which
oer protection against the deleterious eects of cortisol [73], thereby
reducing neurocognitive decits in depression. Likewise, BDNF induced
hippocampal neurogenesis has positive protective eects on chronic
stress levels [7477] and reduces social avoidance [78,79]. Important
for the present hypothesis is the empirical nding that psilocybin in-
duces neurogenesis in the dentate gyrus of the hippocampus and that it
facilitates fear extinction in animal models [80]. Studies have demon-
strated that stress and depression are associated with a reduction of
hippocampal volume due to atrophy and loss of neurons [75]. Several
studies indicate that hippocampal neurogenesis may be required for
some of the cognitive-behavioural eects of antidepressants [81].
Current evidence indicates that plasma BDNF levels are decreased in
unmedicated depressed patients and that antidepressant treatment
(e.g., SSRIs)
can increase BDNF to normal concentrations [82].In
addition to these mediators, there are several moderators which inu-
ence the eects of depression and stress on telomeres. Numerous studies
have investigated the moderating role of genetic predispositions that
are responsible for a heightened vulnerability to various life stressors.
Given that personality traits have a strong heritability component (as
indicated by twin studies [83]) it is not surprising that some individuals
are much more resilient when exposed to stress, compared to others
who are hypersensitive and show negative reactions even to minor life-
stressors. For instance, meta-analytic research indicates that a specic
polymorphism of the serotonin transporter promoter (5-HTTLPR)
moderates the correlation between stress and depression [84]. In ad-
dition to genetic dierences, epigenetic changes are thought to play a
moderating role (e.g., via DNA methylation which alters gene expres-
sion by inhibiting the binding of transcription factors; see [85]). In
contrast to genetic changes, epigenetic changes alter the expression of
genes (but, by denition, not the genetic code itself). Epigenetic
changes can be reversible and non-reversible depending on specic
conditions (also see [86]). We propound that that the psychologically
profound transformative transcendental experiences" that can be oc-
casioned by psilocybin are accompanied by specic/characteristical
epigenetic changes. That is, we predict that the qualitative phenom-
enological aspects of psilocybin are reected at the epigenetic level,
viz., we hypothesise a correspondence between phenomenology
A landmark study [144] experimentally demonstrated that a single
high dose of psilocybin is capable to induce long-lasting personality
changes in the basic personality trait Openness to Experience (as
measured by the widely used NEO Personality Inventory). This nding
is very intriguing because there is broad scientic consensus that basic
personality traits are relatively stable over time (i.e., a genetic basis is
assumed; [145]) and that they can only be altered by major life events
(e.g., [146]). Ergo, it is logically cogent to predict that the personality
changes induced by psilocybin are paralleled by epigenetic changes.
This line of thought connects neatly with the previously presented
empirical results. A genetic pilot study [87] found that OTE is related to
SERT polymorphism (5-HTTLPR which is associated with SLC6A4, the
serotonin transporter gene discussed previously in the context of de-
pression and PTSD). Based on this empirical background it is thus lo-
gically sound to assume that psilocybin has epigenetic eects on genes
related to serotonin dynamics. Specically, 5-HTTLPR is a plausible
candidate gene given its association with depression, anxiety-related
personality traits, and addiction (for a meta-analysis of the moderating
role of 5-HTTLPR in stress and depression see [84]). Given that psilo-
cybin has been utilised psychotherapeutically to treat all of these dis-
orders [88] a common genetic mechanism is thus predictable on an a
priori basis. To recapitulate: We provided evidence which substantiates
the major premise of Syllogism #1 (the predicate of the conclusion):
Telomere length is a reliable indicator of genetic aging and it has been
repeatedly demonstrated that telomeres are aected by psychological
conditions such as chronic stress, anxiety, and depression, inter alia.In
Given that 95% of 5-HT in the human body are found in the gut, and
given that the functioning of the gut-brain axis has been associated with de-
pressive states, it would be interesting to investigate if psilocybin alters the gut
microbiome (which is crucial for the maintenance of physiological homeostasis
and brain functioning). Further, it would be of interest to see if this hypothetical
correlation stands in any relation with endogeneous neurothrophic brain
growth factors (e.g., BDNF/NFG/CNTF/GDNF) and telomeres/telomerase ac-
tivity. Indeed, the possibility of a peripheral regulatory role for DMT and/or 5-
HO-DMT in gastrointestinal function has recently been suggested [120].
N.B.: There are numerous detrimental neuropsychological side-eects
associated with SSRIs which deserve constant emphasis, specically given the
highly biased lobbyism of Big Pharma [126123].
This line of thought is also revealing from a neurophenomenological van-
tage point which connects the 17/18th century Husserlian school of thought
(dened as German transcendental-idealist philosophy) with the methods and
technologies of modern neuroscience [129,125]. This approach emphasises that
phenomenology is subject to scientic inquiry and it further highlights the
importance of embodiment. Future psilocybin research should attempt to in-
tegrate principles derived from the embodied cognition framework into its
modelling eorts as current research on psychoactive compounds is almost
exclusively brain-centred (i.e., at the level of specic classes of neurons or
particular neuronal circuits). This brain-bias limits the scope of psilocybin
research in an irrational manner. To put it another way, it has been cogently
argued that the processes crucial for consciousness cut across the prima facie
assumed tripartite brain-body-world division which structures most of con-
temporary science at the most axiomatic level of analysis [126]. This insight
might turn out to be a crucial component in order to reconceptualise the ada-
mantine hard problem of consciousness”—the most fundamental and hitherto
completely unresolved scientic problem which has an intrinsic anity with
research on altered states of consciousness. We suggest that the transdisci-
plinary cybernetic concept of autopoiesis [132129] is of central pertinence in
this respect as psilocybin and related tryptamines can facilitate very productive
analytic/contemplative introspection on the relationship between percipient
and perceived (i.e., subject and object, mind and matter, psyche and physis).
This introspective phenomenological analysis allows for modications of the
modus operandi in which information is processed, e.g., modications of sti-
mulus appraisal (an important factors in depression and anxiety disorders [see
[130]). Subjective time perception (time conscientiousness) is a particularly
relevant topic in this regard [136,132]. We argue that intention is a variable
which interacts with the phenomenology (and hence the physiological eects)
of psilocybin. This psycho-physical interaction between intention and psycho-
biology deserves further investigation.
C.B. Germann
Medical Hypotheses 134 (2020) 109406
the next section we will provide a synopsis evidence which indicates
that therapeutic utilization of psilocybin exerts benecial eects on
various aspects of mental health. We will specically focus on its pos-
tulated eects on depression.
Evidence in support of the minor premise: Psychotherapeutic utilisation of
psilocybin reduces depression
has been reliably associated with numerous mental
health benets (e.g., in the context of anxiety, PTSD, OCD, addiction,
etc., for a systematic review see [150]). Rapidly accumulating evidence
demonstrates that psilocybin signicantly reduces clinical symptoms in
depressed populations [8991,93]. Further, it has been reported that
psilocybin improves emotional face recognition in treatment-resistant
patients [92]. This quasi-interpersonal improvement was statistically
signicantly correlated with a reduction in anhedonia, viz., decits in
the capacity to experience hedonic pleasure (including reduced in-
trinsic motivation). From a neuroanatomical point of view, the ob-
served reduction of depressive symptoms reported in [93] was asso-
ciated with increased resting-state functional connectivity (RSFC)
within the default-mode network (DMN; 5 weeks post-treatment as per
fMRI data). Furthermore, post-treatment response was associated with
increased ventromedial prefrontal cortex RSFC and bilateral inferior
lateral parietal cortex RSFC, in addition to decreased RSFC in the
parahippocampal-prefrontal cortex. Moreover, brain-wide analysis re-
vealed a post-treatment decrease in cerebral blood ow (CBF) in the
temporal cortex and the amygdala. Importantly, reductions in amyg-
dala CBF were statistically signicantly correlated with a reduction in
depressive symptoms. It should also be noted that the fMRI study (op.
cit.) demonstrated that the acute eects of psilocybin dier from the
longitudinal eects. In the following paragraphs we will primarily
concentrate on the involvement of the DMN and the amygdala in de-
According to the controversial Diagnostic and Statistical Manual of
Mental Disorders (DSM-5®) (but see [147]) published by the American
Psychiatric Association, one of thefeatures of depression is obsessive
rumination/brooding, i.e., repetitive thought patterns that cause long-
term organismic stress on multiple levels. In abstracto , "Psychological
Rumination" can be regarded as a non-somatic analogon to digestive
"Rumination Disorder" which involves the repeated regurgitation of
food materials over elongated periods of time. Similarly, rumination in
depression involves the chronic mental regurgitation of primarily ne-
gative emotionally laden psychological materials, i.e., a chronically
distressing inward-directed attentional focus that is not actively solu-
tion oriented but rather a passive and counterproductive coping-style
that is signicantly debilitating for the individual ("locus of control" and
self-ecacy are important moderating variables in this respect). Ru-
minative thought patterns are associated with various subconscious
cognitive biases that are based on negative, automatic, recyclic, and
self-centred cognitions.
It is of pivotal pertinence for the psilocybin-telomere hypothesis at
hand that rumination has been associated with telomere attrition [3].
Rumination, in turn, has been associated with hyperactivity of the de-
[94,95]. Experimental studies have demon-
strated that psilocybin signicantly downregulates DMN activity [93].
Interestingly, a recent experimental study indicated that psilocybin-
assisted mindfulness training modulates DMN connectivity with lasting
eects [41]. Ergo, we argue that the downregulation of DMN activity is
an important neuroanatomical component of the psilocybin-telomere
hypothesis. Rumination is a persistent symptom of depressive dis-
orders. Consequently, a reduction in rumination is likely to positively
aect telomere length. We suggest that the reduction of rumination is
an aspect which is common to psilocybin interventions, mindfulness
training, and mediation, i.e., these prima facie dierent methods predict
a similar outcome criterion, viz., a reduction in negative repetitive
thought motifs. Rumination is a cause for chronic stress which, in turn,
is associated with various inammatory processes and the down-
regulation of the immune system, factors that have been associated
with shorter telomeres [71,96,97].
Psilocybin can occasion the most profound transformative experi-
ences known to science. For example, in a longitudinal study 70% of
healthy volunteers rated their experience with psilocybin amongst the
ve most meaningful and signicant experiences of their entire live,
i.e., the neurochemically induced experience was on average ranked
next to the most formative lifetime events such as giving birth to a child
or to losing an intimate loved one [99] cf. [98]. We argue that these
experiential peak events have a quantiable genetic counterpart, i.e.,
the psilocybin-occasioned phenomenological apogee produces a unique
quantiable epigenetic footprint (epigenetically traceable qualia). The
underlying logic is based on the supposition that profound psycholo-
gical experiences are associated with equally profound genetic changes
(i.c., in proportion to the phenomenological valence). This ideas is
motivated by recent genetic studies which reintroduce quasi-La-
marckian elements into quantitative genetic biology and thereby chal-
lenge the central dogma of molecular biology
[100] which was for a
long time unchallengeable axiomatic to genetic research. For instance,
it has been shown that acquired olfactory conditioning can be epigen-
etically inherited by subsequent generations (at least up to F2) [101].
The odorant receptor ( Olfr151) was used to condition F0 mice and
subsequent generations (which were utterly naïve to the olfactory
conditioning paradigm) revealed CpG hypomethylation in the Olfr151
gene. We submit that if a simple Pavlovian olfactory conditioning
paradigm can cause quantiable quasi-Lamarckian epigenetic eects,
then it is predictable (with a high likelihood) that a profound and life-
changing psilocybin experience (cf. Griths et al., 2008) has equally
quantiable eects at the genetic level.
In their native language, Náhuatl, the Aztecs referred to the Psilocybe
mexicana fungi specimen as Teonanácatl, a composite lexeme which is ety-
mologically derived from teotl meaning god and nanácatl meaning
"fungus". In the chemical literature psilocybin was also referred to as a
teonanácatl hallucinogens [e.g., [133]]. Along the same philological lines, the
term entheogen has been introduced into the western scientic literature by
Ruck et al. [134]. Per denition, an entheogen is a chemical substance used in a
ceremonial, religious, shamanic, and/or spiritual contexts that has the potential
to produce profound psycho-spiritual insights and changes. The etymology of
the neologism entheo-gen is a Greek compound lexeme derived from νθεος
(entheos) and γενέσθαι (genesthai) and translates into generating the divine
within (cf. the cognate term enthusiasm). Indeed, the Greek Dionysian
Mysteries may be grounded in the utilisation of entheogenic biomaterial. The
ecstatic cult of Dionysus involved the consumption of Kykeon, a drinkable
concoction which potentially included tryptamine-like compounds. The Kykeon
possibly contained ergot-parasitized barley. The ergot [135] are a fungal
parasite of the barley or rye grain, which contains the alkaloids ergotamine and
ergonovine, i.e., precursors of LSD-25. The relation between spirituality and
aging has recently gained renewed attention [for a review see [136]].
Specically, various connectivity density dierences have been demon-
strated which dierentiate healthy individuals from individuals diagnosed with
major depressive disorder, i.e., more neural functional connectivity between
the posterior-cingulate cortex and the subgenual-cingulate cortex during rest
periods, but not during task engagement [but see [93]].
The obvious question is: Should science ever be dogmatic? [cf. [137]].
The pineal indole hormone melatonin (N-acetyl-5-methoxy tryptamine) is a
tryptaminergic structural relative of psilocybin and it has been suggested that
melatonin acts as an antioxidant geroprotector [138,139]. For instance, long-
itudinal supplementation of melatonin increased longevity in D. melanogaster.
The interactions between psilocybin and the melatonin system are therefore a
topic of great interest, particularly in regard to immunosenescence [140] and
neuroinammation [141], but also from a depth-psychological point of view,
given the peculiar properties of the photoreceptive parietal third eye [142]
and its pivotal role in basic circadian regulation (biochronology) and dream-
C.B. Germann
Medical Hypotheses 134 (2020) 109406
We suggest that genes associated with the serotonins system (e.g.,
SLC6A4 gene associated with sodium-dependent serotonin transporter)
are a likely genetic locus for planned comparisons (speci cally in the
context of depression and anxiety). For instance, it has been reported
that individuals with specic serotonin transporter (5-HTT) promoter
polymorphism (associated with reduced 5-HTT expression) exhibit
greater amygdala activity (fear and anxiety-related behaviours) as as-
sessed by BOLD functional magnetic resonance imaging ([102], cf.
[103]). Interestingly, it has been experimentally demonstrated that
psilocybin decreases amygdala reactivity and that this limbic down-
regulation correlates with enhancements in positive mood [103]. These
eects of psilocybin on emotional processing are specically relevant
for the hypothesis at hand because the central nuclei of the amygdala
are involved in the genesis of various fear responses such as the ght
ight response, ANS responses such as changes in heart rate, elevation
of blood pressure, and neuroendocrine responses such as cortisol re-
lease. A topically related study investigated the spatiotemporal brain
dynamics of emotional face processing and reported that psilocybin
modulates emotional processing presumably via agonism of the 5HT
serotonin receptor subtypes [104].
Taken together, the idea which connects genetic research to psy-
chological research is that cellular mechanisms (e.g., telomeres/telo-
merase activity) are intimately coupled with cognitive processes (an-
xiety, depression, mood, stress, etc.). To use a mnemonic sticky
formulation provided by Professor Elissa Eppel in a lecture at the
University of California in 2011: Our cells are listening to our thoughts .
We submit that therapeutic utilisation of psilocybin has signicant
benecial eects on various organismic levels and, specically, that the
therapeutic eects of psilocybin on the human mind-body complex are
of great interest against this empirical background. From our vantage
point, neuromechanistic accounts are complementary to metaphysical
perspectives on the eects of psilocybin and we will discuss the ther-
apeutic potential of transcendental experiences in forthcoming pub-
lications (e.g., discussing the therapeutic value of ego-dissolution/
nonduality; see also [148]).
We provided converging empirical evidence from a plurality of
sources in order to substantiate the stipulations entailed in the major
and minor premises of Syllogism #1. Based on this evidential back-
ground, we argue that the 'psilocybin-telomere hypothesis' warrants
systematic experimental testing. Specically, we argue that the con-
vergence of evidence indicates scientic consilience.
According to
this pivotal meta-scientic concept, strength of evidence increases
when multiple independent sources of evidence are in agreement. The
generalisability and robustness of converging evidence for a given lo-
gical conclusion is a function of the number of di erent research ap-
proaches in support of the conclusion. Furthermore, if equivalent con-
clusions are reached from multiple perspectives (e.g., dierent
disciplines/theorectical frameworks) this provides evidence in support
of the reliability and validity of the utilised research methodologies
themselves. Resilience thus reduces the impact of confounding factors
(e.g., method related measurement errors) because these errors do not
inuence all research methods equally. That is, resilience balances-
out method specic confounds. Perhaps more importantly, the same
principle also applies to logical confounds (e.g., logical fallacies and
unconscious cognitive biases). In the philosophy of science, this has
been termed consilience of inductions [105,106]. Inductive con-
silience can be described as the accordance of multiple inductions
drawn from dierent classes of phenomena. Or, in somewhat more
elaborate terms, the colligation of facts through superinduction of
conceptions [107]. The term has recently been adopted within neu-
roscience (e.g., [108]) where the converge of evidence from multiple
(hierarchically arrangeable) sources (molecular, cellular, neuroanato-
mical, cognitive, behavioural, social, etc.) plays a crucial role for the
development of meta-disciplinary (unifying) theoretical frameworks.
Following this line of thought, scientic experiments which investigate
the eects of psilocybin across multiple levels of analysis and ex-
planation would be of great value. The psilocybin-telomere hypothesis
provides impetus for this endeavour as it connects the epistemic and the
ontic level of analysis.
Multiple pathways may be involved in the eects of psilocybin on
telomeres (neurogenesis, neuroplasticity, downregulation of the de-
fault-mode network, modulation of the rich-club architecture of the
brain, enhanced functional interconnectivity between various brain
networks, anti-inammatory activity, changes in microbiota, im-
munomodulation, changes in cognitive and emotional appraisal, im-
provements in interpersonal relations, transpersonal/spiritual aspects,
etc.). From a neurochemical vantage point, the dierential involvement
of various 5-HT receptor subtypes is naturally of aprioristic interest as
serotonin participates in a multitude of physiological/psychological
processes. For instance, in order to systematically test for the involve-
ment of the 5-HT
receptor in the hypothesised eects of psilocybin on
telomeres, the non-selective antagonist Ketanserin could be utilised.
Repeated (sub-threshold) microdosing of psilocybin is yet another in-
teresting longitudinal research methodology in the context of the hy-
pothesis at hand. Furthermore, the di erential eects on telomeres of
various cell types should be systematically examined (specically given
the shortening at varying rates). In addition, phenomenological and
neurological similarities between meditation and psilocybin should be
systematically mapped in the context of genetic aging. Research sug-
gests that states of consciousness induced by meditation and those oc-
casioned by various tryptamines have signicantly congruent neuro-
chemical and neuroanatomical correlates. We conclude that future
studies that integrate phenomenological aspects of "higher states of
consciousness" with quantitative assessment methods have signicant
potential to advance and deepen our understanding of the interactions
between psychological, neuronal, and (epi)genetic processes.
Conict of interest
The author declares no conict of interest.
[1] Blackburn EH. Telomeres and telomerase: The means to the end (Nobel Lecture).
Angew Chemie Int Ed 2010;49:740521.
[2] Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, et al. An epige-
netic biomarker of aging for lifespan and healthspan. Aging 2018;10:57391.
[3] Epel ES, Daubenmier J, Moskowitz JT, Folkman S, Blackburn E. Can meditation
slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres. Ann N Y
Acad Sci 2009;1172:3453.
[4] Jaskelio M, Muller FL, Paik J-H, Thomas E, Jiang S, Adams AC, et al. Telomerase
reactivation reverses tissue degeneration in aged telomerase-decient mice. Nature
[5] Epel ES. Telomeres in a life-span perspective: A new psychobiomarker? Curr Dir
Psychol Sci 2009;18:610.
[6] Epel ES. Psychological and metabolic stress: A recipe for accelerated cellular
aging? Hormones 2009;8:722.
[7] Boccardi V, Paolisso G, Mecocci P. Nutrition and lifestyle in healthy aging: the
telomerase challenge. Aging (Albany NY) 2016;8:12 5.
[8] Lin J, Epel ES, Blackburn E. Telomeres and lifestyle factors: Roles in cellular aging.
(footnote continued)
states (note that psychoactive phenethylamines and tryptamines such as mes-
caline, DMT, and psilocybin induce comparatively similar dream-states [see
also [143]]).
From a philological point of view, the etymological root of the term con-
silience is derived from the Latin consilient, from com "with, together" and salire
"to leap, to jump". Hence, it literally means jumping together (i.e., of
knowledge). Scientic resilience is thus semantically synonymous with the
expression concordance of evidence.
C.B. Germann
Medical Hypotheses 134 (2020) 109406
Mutat Res - Fundam Mol Mech Mutagen 2012.
[9] Asghar M, Bensch S, Tarka M, Hansson B, Hasselquist D. Maternal and genetic
factors determine early life telomere length. Proc R Soc B Biol Sci 2015. https://
[10] Paul L. Diet, nutrition and telomere length. J Nutr Biochem 2011.
[11] Leung CW, Laraia BA, Needham BL, Rehkopf DH, Adler NE, Lin J, et al. Soda and
cell aging: Associations between sugar-sweetened beverage consumption and
leukocyte telomere length in healthy adults from the national health and nutrition
examination surveys. Am J Public Health 2014;104:242531.
[12] Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, et al. Omega-3
fatty acids, oxidative stress, and leukocyte telomere length: A randomized con-
trolled trial. Brain Behav Immun 2013.
[13] Pavanello S, Hoxha M, Dioni L, Bertazzi PA, Snenghi R, Nalesso A, et al. Shortened
telomeres in individuals with abuse in alcohol consumption. Int J Cancer 2011.
[14] Mirabello L, Huang WY, Wong JYY, Chatterjee N, Reding D, Crawford ED, et al.
The association between leukocyte telomere length and cigarette smoking, dietary
and physical variables, and risk of prostate cancer. Aging Cell 2009. https://doi.
[15] Lee KA, Gay C, Humphreys J, Portillo CJ, Pullinger CR, Aouizerat BE. Telomere
Length is Associated with Sleep Duration But Not Sleep Quality in Adults with
Human Immunodeciency Virus. Sleep 2014.
[16] Notterman DA, Mitchell C. Epigenetics and Understanding the Impact of Social
Determinants of Health. Pediatr Clin North Am 2015.
[17] Beatty Moody DL, Leibel DK, Darden TM, Ashe JJ, Waldstein SR, Katzel LI, et al.
Interpersonal-level discrimination indices, sociodemographic factors, and telomere
length in African-Americans and Whites. Biol Psychol 2019;141:19. https://doi.
[18] Needham BL, Carroll JE, Roux AVD, Fitzpatrick AL, Moore K, Seeman TE.
Neighborhood characteristics and leukocyte telomere length: The Multi-Ethnic
Study of Atherosclerosis. Heal Place 2014.
[19] Puterman E, Lin J, Blackburn E, ODonovan A, Adler N, Epel E. The power of
exercise: Buering the eect of chronic stress on telomere length. PLoS ONE 2010.
[20] Denham J, Nelson CP, OBrien BJ, Nankervis SA, Denni M, Harvey JT, et al.
Longer Leukocyte Telomeres Are Associated with Ultra-Endurance Exercise
Independent of Cardiovascular Risk Factors. PLoS ONE 2013.
[21] Hoxha M, Dioni L, Bonzini M, Pesatori AC, Fustinoni S, Cavallo D, et al.
Association between leukocyte telomere shortening and exposure to trac pol-
lution: a cross-sectional study on tracocers and indoor oce workers. Environ
Heal 2009.
[22] Pavanello S, Pesatori AC, Dioni L, Hoxha M, Bollati V, Siwinska E, et al. Shorter
telomere length in peripheral blood lymphocytes of workers exposed to polycyclic
aromatic hydrocarbons. Carcinogenesis 2010.
[23] Shammas MA. Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab
Care 2011;14:2834.
[24] Gotlib IH, LeMoult J, Colich NL, Foland-Ross LC, Hallmayer J, Joormann J, et al.
Telomere length and cortisol reactivity in children of depressed mothers. Mol
Psychiatry 2015;20:61520. .
[25] Puterman E, Epel ES, Lin J, Blackburn EH, Gross JJ, Whooley MA, et al.
Multisystem resiliency moderates the major depression-Telomere length associa-
tion: Findings from the Heart and Soul Study. Brain Behav Immun 2013;33:6573.
[26] Price LH, Kao HT, Burgers DE, Carpenter LL, Tyrka AR. Telomeres and early-life
stress: An overview. Biol Psychiatry 2013;73:1523.
[27] Verhoeven JE, Révész D, Wolkowitz OM, Penninx BWJH. Cellular aging in de-
pression: Permanent imprint or reversible process?: An overview of the current
evidence, mechanistic pathways, and targets for interventions. BioEssays
2014;36:96878. .
[28] Epel ES, Puterman E, Lin J, Blackburn E, Lazaro A, Mendes WB. Wandering minds
and aging cells. Clin Psychol Sci 2012;1:7583.
[29] Hoge EA, Chen MM, Orr E, Metcalf CA, Fischer LE, Pollack MH, et al. Loving-
kindness meditation practice associated with longer telomeres in women. Brain
Behav Immun 2013;32:15963.
[30] Bogenschutz M. Mood, craving, and self-ecacy in psilocybin-assisted treatment
of alcoholism. Neuropsychopharmacology 2015.
[31] Bogenschutz MP, Johnson MW. Classic hallucinogens in the treatment of addic-
tions. Prog Neuro-Psychopharmacology Biol Psychiatry 2016.
[32] Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al.
Psilocybin with psychological support for treatment-resistant depression : an open-
label feasibility study. Lancet Psychiatry 2016.
[33] Shelton RC, Hendricks PS. Psilocybin and palliative end-of-life care. J
Psychopharmacol 2016.
[34] Johnson MW, Griths RR. Potential Therapeutic Eects of Psilocybin.
Neurotherapeutics 2017.
[35] dos Santos RG, Osório FL, Crippa JAS, Riba J, Zuardi AW, Hallak JEC.
Antidepressive, anxiolytic, and antiaddictive eects of ayahuasca, psilocybin and
lysergic acid diethylamide (LSD): a systematic review of clinical trials published in
the last 25 years. Ther Adv Psychopharmacol 2016.
[36] De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G. D-Lysergic acid diethylamide,
psilocybin, and other classic hallucinogens: Mechanism of action and potential
therapeutic applications in mood disorders. Prog Brain Res 2018.
[37] Thomas K, Malcolm B, Lastra D. Psilocybin-assisted therapy: a review of a novel
treatment for psychiatric disorders. J Psychoactive Drugs 2017.
[38] Tófoli LF, de Araujo DB. Treating addiction: perspectives from EEG and imaging
on psychedelics. Int. Rev. Neurobiol. 2016;129:15785.
[39] Volkow ND. The reality of comorbidity: Depression and drug abuse. Biol
Psychiatry 2004.
[40] Malan S, Hemmings S, Kidd M, Martin L, Seedat S. Investigation of telomere length
and psychological stress in rape victims. Depress Anxiety 2011.
[41] Smigielski L, Scheidegger M, Kometer M, Vollenweider FX. Psilocybin-assisted
mindfulness training modulates self-consciousness and brain default mode net-
work connectivity with lasting eects. Neuroimage 2019;196:20715. https://doi.
[42] Jylhävä J, Pedersen NL, Hägg S. Biological Age Predictors. EBioMedicine
[43] Banszerus VL, Vetter VM, Salewsky B, König M, Demuth I. Exploring the re-
lationship of relative telomere length and the epigenetic clock in the LipidCardio
Cohort. Int J Mol Sci 2019.
[44] Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock
theory of ageing. Nat Rev Genet 2018;19:37184.
[45] Marioni RE, Harris SE, Shah S, McRae AF, von Zglinicki T, Martin-Ruiz C, et al. The
epigenetic clock and telomere length are independently associated with chron-
ological age and mortality. Int J Epidemiol 2016;45:42432.
[46] Horvath S. DNA methylation age of human tissues and cell types. Genome Biol
[47] Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming:
Resetting the aging clock. Cell 2012.
[48] Wikgren M, Maripuu M, Karlsson T, Nordfjäll K, Bergdahl J, Hultdin J, et al. Short
telomeres in depression and the general population are associated with a hypo-
cortisolemic state. Biol Psychiatry 2012;71:294300.
[49] Wolkowitz OM, Mellon SH, Epel ES, Lin J, Reus VI, Rosser R, et al. Resting leu-
kocyte telomerase activity is elevated in major depression and predicts treatment
response. Mol Psychiatry 2012;17:16472.
[50] Needham BL, Mezuk B, Bareis N, Lin J, Blackburn EH, Epel ES. Depression, anxiety
and telomere length in young adults: Evidence from the National Health and
Nutrition Examination Survey. Mol Psychiatry 2015.
[51] Bin Wei Y, Backlund L, Wegener G, Mathé AA. Lavebratt C. Telomerase dysregu-
lation in the hippocampus of a rat model of depression: Normalization by lithium.
Int J Neuropsychopharmacol 2015.
[52] Okereke OI, Prescott J, Wong JYY, Han J, Rexrode KM, de Vivo I. High phobic
anxiety is related to lower leukocyte Telomere length in women. PLoS One 2012.
[53] Vreeburg SA, Hoogendijk WJG, van Pelt J, Derijk RH, Verhagen JCM, van Dyck R,
et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity:
results from a large cohort study. Arch Gen Psychiatry 2009;66:61726. https://
[54] Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inammation: Depression fans the
ames and feasts on the heat. Am J Psychiatry 2015;172:1075
91. https://doi.
Miller AH, Raison CL. The role of inammation in depression: from evolutionary
imperative to modern treatment target. Nat Rev Immunol 2015;16:2234. https://
[56] Lopresti AL, Maker GL, Hood SD, Drummond PD. A review of peripheral bio-
markers in major depression: The potential of inammatory and oxidative stress
biomarkers. Prog Neuro-Psychopharmacol Biol Psychiatry 2014;48:10211.
[57] Von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci
[58] Boonekamp JJ, Bauch C, Mulder E, Verhulst S. Does oxidative stress shorten tel-
omeres? Biol Lett 2017;13:20170164.
[59] Flanagan TW, Nichols CD. Psychedelics as anti-inammatory agents. Int Rev
Psychiatry 2018.
[60] Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and
anxiety. Nat Neurosci 2007;10:108993.
[61] Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol
Psychiatry 2007;12:107988.
[62] Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: Interactions
C.B. Germann
Medical Hypotheses 134 (2020) 109406
between exercise, depression, and BDNF. Neuroscientist 2012.
[63] Castrén E, Võikar V, Rantamäki T. Role of neurotrophic factors in depression. Curr
Opin Pharmacol 2007.
[64] Fu W, Lu C, Mattson MP. Telomerase Mediates the Cell Survival-Promoting Actions
of Brain-Derived Neurotrophic Factor and Secreted Amyloid Precursor Protein in
Developing Hippocampal Neurons. J Neurosci 2002;22:107109. 22/24/10710
[65] Idell RD, Florova G, Komissarov AA, Shetty S, Girard RBS, Idell S. The brinolytic
system: A new target for treatment of depression with psychedelics. Med
Hypotheses 2017.
[66] Kiecolt-Glaser JK, Glaser R. Psychological stress, telomeres, and telomerase. Brain
Behav Immun 2010;24:52930.
[67] Monaghan P. Organismal stress, telomeres and life histories. J Exp Biol
[68] Lin J, Epel ES, Blackburn EH. Telomeres, telomerase, stress, and aging. Handb.
Neurosci. Behav. Sci. 2009.
[69] Zhang J, Rane G, Dai X, Shanmugam MK, Arfuso F, Samy RP, et al. Ageing and the
telomere connection: An intimate relationship with inammation. Ageing Res Rev
[70] Kotrschal A, Ilmonen P, Penn DJ. Stress impacts telomere dynamics. Biol Lett
[71] Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, et al. Accelerated
telomere shortening in response to life stress. Proc Natl Acad Sci
[72] Blackburn EH, Epel ES. Telomeres and adversity: Too toxic to ignore. Nature
[73] Young AH, Gallagher P, Porter RJ. Elevation of the cortisol-dehydroepian-
drosterone ratio in drug-free depressed patients. Am J Psychiatry
[74] Mahar I, Bambico FR, Mechawar N, Nobrega JN. Stress, serotonin, and hippo-
campal neurogenesis in relation to depression and antidepressant eects. Neurosci
Biobehav Rev 2014.
[75] Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: Opposing eects of
stress and antidepressant treatment. Hippocampus 2006;16:23949. https://doi.
[76] Levone BR, Cryan JF, OLeary OF. Role of adult hippocampal neurogenesis in stress
resilience. Neurobiol Stress 2015.
[77] Schoenfeld TJ, Gould E. Stress, stress hormones, and adult neurogenesis. Exp
Neurol 2012.
[78] Lagace DC, Donovan MH, DeCarolis NA, Farnbauch LA, Malhotra S, Berton O,
et al. Adult hippocampal neurogenesis is functionally important for stress-induced
social avoidance. Proc Natl Acad Sci 2010.
Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sucient to
reduce anxiety and depression-like behaviors. Neuropsychopharmacology 2015.
[80] Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Eects of psilocybin
on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain
Res 2013;228:48191.
[81] Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci
[82] Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression
and in antidepressant treatment. Psychiatry Investig 2010;7:2315. https://doi.
[83] Bouchard TJ, Lykken DT, McGue M, Segal NL, Tellegen A. Sources of human
psychological dierences: the Minnesota Study of Twins Reared Apart. Science
[84] Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter
variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of
genetic moderation. Arch Gen Psychiatry 2011;68:44454.
[85] Moore LD, Le T, Fan G. DNA Methylation and Its Basic Function.
Neuropsychopharmacology 2013;38:2338.
[86] Choudhuri S. From Waddingtons epigenetic landscape to small noncoding RNA:
some important milestones in the history of epigenetics research. Toxicol Mech
Methods 2011;21:25274.
[87] Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, et al.
Serotonin transporter promoter polymorphism, peripheral indexes of serotonin
function, and personality measures in families with alcoholism. Am J Med Genet
[88] Tylš F, Páleníček T, Horáček J. Psilocybin - Summary of knowledge and new
perspectives. Eur Neuropsychopharmacol 2014;24:34256.
[89] Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and
sustained symptom reduction following psilocybin treatment for anxiety and de-
pression in patients with life-threatening cancer: A randomized controlled trial. J
Psychopharmacol 2016.
[90] Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al.
Psilocybin with psychological support for treatment-resistant depression: six-
month follow-up. Psychopharmacology 2018.
[91] Cowen P. Altered states: psilocybin for treatment-resistant depression. Lancet
Psychiatry 2016.
[92] Stroud JB, Freeman TP, Leech R, Hindocha C, Lawn W, Nutt DJ, et al. Psilocybin
psychological support improves emotional face recognition in treatment-re-
sistant depression. Psychopharmacology 2018.
[93] Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall
MB, et al. Psilocybin for treatment-resistant depression: FMRI-measured brain
mechanisms. Sci Rep 2017;7:13187.
[94] Berman MG, Peltier S, Nee DE, Kross E, Deldin PJ, Jonides J. Depression, rumi-
nation and the default network. Soc Cogn Aect Neurosci 2011;6:54855. https://
[95] Cooney RE, Joormann J, Eugène F, Dennis EL, Gotlib IH. Neural correlates of
rumination in depression. Cogn Aect Behav Neurosci 2010.
[96] Andrews NP, Fujii H, Goronzy JJ, Weyand CM. Telomeres and immunological
diseases of aging. Gerontology 2010.
[97] Weng ping N. Telomeres and immune competency. Curr Opin Immunol 2012.
[98] Griths RR, Hurwitz ES, Davis AK, Johnson MW, Jesse R. Survey of subjective
God encounter experiences: Comparisons among naturally occurring experiences
and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or
DMT. PLoS One 2019;14:e0214377
[99] Griths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type ex-
periences occasioned by psilocybin mediate the attribution of personal meaning
and spiritual signicance 14 months later. J Psychopharmacol 2008. https://doi.
[100] Crick F. Central dogma of molecular biology. Nature 1970.
[101] Dias BG, Ressler KJ. Parental olfactory experience inuences behavior and neural
structure in subsequent generations. Nat Neurosci 2014;17:8996. https://doi.
[102] Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, et al. Amygdala-
prefrontal coupling depends on a genetic variation of the serotonin transporter.
Nat Neurosci 2005.
[103] Kraehenmann R, Preller KH, Scheidegger M, Pokorny T, Bosch OG, Seifritz E, et al.
Psilocybin-induced decrease in amygdala reactivity correlates with enhanced po-
sitive mood in healthy volunteers. Biol Psychiatry 2015.
[104] Bernasconi F, Schmidt A, Pokorny T, Kometer M, Seifritz E, Vollenweider FX.
Spatiotemporal brain dynamics of emotional face processing modulations induced
by the serotonin 1A/2A receptor agonist psilocybin. Cereb Cortex 2014. https://
[105] Hesse M. Consilience of inductions. Stud Log Found Math 1968;51:23257.
[106] Fisch M. Whewells consilience of inductions an evaluation. Philos Sci
[107] Laudan L. William whewell on the consilience of inductions. Monist
Glimcher PW. Neuroeconomics: the consilience of brain and decision. Science
[109] Bourdieu P. Outline of a Theory of Practice. Cambridge University Press; 1977.
[110] Johansen P-Ø, Krebs TS. Psychedelics not linked to mental health problems or
suicidal behavior: A population study. J Psychopharmacol 2015;29:2709.
[111] Müller K, Püschel K, Iwersen-Bergmann S. Suizid unter Psilocin-Einuss. Arch
Kriminol 2013;231:1938.
[112] LEtang J. The father of spin: Edward L. Bernays and the birth of public relations.
Public Relat Rev 1999;25:1234.
[113] Bernays EL. Propaganda. Horace Liveright 1928.
[114] Douglas A, Pond C. Americas war on drugs and the prison-industrial complex.
Gend Race Justice 2012;417.
[115] Moore LD, Elkavich A. Whos using and whos doing time: Incarceration, the war
on drugs, and public health. Am J Public Health 2008.
[116] Jacob MS, Presti DE. Endogenous psychoactive tryptamines reconsidered: An an-
xiolytic role for dimethyltryptamine. Med Hypotheses 2005.
[117] Monk RA. The logic of discovery. Philos Res Arch 1977.
[118] Sobiecki J-F. An account of healing depression using ayahuasca plant teacher
medicine in a Santo Daime ritual. Indo-Pacic J Phenomenol 2013;13:110.
[119] Dev L. Plant knowledges: indigenous approaches and interspecies listening toward
decolonizing ayahuasca research. Plant Med. Heal. Psychedelic Sci. Cham:
Springer International Publishing; 2018. p. 185204.
[120] Dean JG. Indolethylamine-N-methyltransferase polymorphisms: Genetic and bio-
chemical approaches for study of endogenous N, N,-dimethyltryptamine. Front
Neurosci 2018.
[121] Breggin PR. Antidepressant-induced suicide, violence and mania: Risks for mili-
tary personnel. Int J Risk Saf Med 2010.
[122] Breggin PR. Rational principles of psychopharmacology for therapists, healthcare
providers and clients. J Contemp Psychother 2016;46:113.
C.B. Germann
Medical Hypotheses 134 (2020) 109406
[123] Breggin PR. The rights of children and parents in regard to children receiving
psychiatric diagnoses and drugs. Child Soc 2014.
[124] Husserl E. Philosophie als strenge Wissenschaft (Philosophy as Rigorous Science)
[125] Ellis RD. Phenomenology-friendly neuroscience: The return to Merleau-Ponty as
psychologist. Hum Stud 2006.
[126] Thompson E, Varela FJ. Radical embodiment: neural dynamics and consciousness.
Trends Cogn Sci 2001;5:41825.
[127] Maturana HR. Autopoiesis, Structural Coupling and Cognition : A history of these
and other notions in the biology of cognition. Cybern Hum Knowing 2002. https://
[128] Maturana HR, Varela FJ. Autopoiesis and cognition. Dordrecht: Springer
Netherlands; 1980. doi:10.1007/978-94-009-8947-4.
[129] Luisi PL. Autopoiesis: a review and a reappraisal. Naturwissenschaften 2003.
[130] Browning M, Holmes EA, Harmer CJ. The modication of attentional bias to
emotional information: A review of the techniques, mechanisms, and relevance to
emotional disorders. Cogn Aect Behav Neurosci 2010.
[131] Vogeley K, Kupke C. Disturbances of time consciousness from a phenomenological
and a neuroscientic perspective. Schizophr Bull 2007.
[132] Arstila V, Lloyd D. Subjective time: The philosophy, psychology, and neuroscience
of temporality. 2014.
[133] Petcher TJ, Weber HP. Crystal structures of the teonanácatl hallucinogens. Part II.
Psilocin, C
O. J Chem Soc Perkin Trans 1974;2.
[134] Ruck CAP, Bigwood J, Staples D, Ott J, Wasson G. Entheogens. J Psychoactive
Drugs 1979;11:1456.
[135] Hofmann A. Historical view on ergot alkaloids. Pharmacology 1978. https://doi.
[136] Zimmer Z, Jagger C, Chiu C-T, Ofstedal MB, Rojo F, Saito Y. Spirituality, re-
ligiosity, aging and health in global perspective: A review. SSM - Popul Heal
[137] Quine WV. Main trends in recent philosophy: two dogmas of empiricism. Philos
Rev 1951;60:20.
[138] Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM,
Vinogradova IA. Melatonin as antioxidant, geroprotector and anticarcinogen.
Biochim Biophys Acta - Bioenerg 2006.
[139] Karasek M. Melatonin, human aging, and age-related diseases. Exp Gerontol
[140] Cardinali DP, Esquino AI, Srinivasan V, Pandi-Perumal SR. Melatonin and the
immune system in aging. NeuroImmunoModulation 2008.
[141] Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR. Melatonin and brain
inammaging. Prog Neurobiol 2015;127128:4663.
[142] Mano H, Fukada Y. A median third eye: pineal gland retraces evolution of verte-
brate photoreceptive organs. Photochem Photobiol 2006.
[143] Soler J, Elices M, Franquesa A, Barker S, Friedlander P, Feilding A, et al. Exploring
the therapeutic potential of Ayahuasca: Acute intake increases mindfulness-related
capacities. Psychopharmacology 2016.
[144] MacLean KA, Johnson MW, Griths RR. Mystical experiences occasioned by the
hallucinogen psilocybin lead to increases in the personality domain of openness. J
Psychopharmacol 2011;25(11):145361.
[145] Bouchard TJ, Lykken DT, McGue M, Segal NL. Tellegen a. Sources of human
psychological dierences: the Minnesota Study of Twins Reared Apart. Science
[146] McCrae RR, Costa PT. Personality trait structure as a human universal. Am Psychol
[147] Pickersgill MD. Debating DSM-5: diagnosis and the sociology of critique. J Med
Ethics 2014;40(8):5215.
[148] Germann CB. 5-Methoxy-N,N-dimethyltryptamine: An Ego-Dissolving Endogenous
Neurochemical Catalyst of Creativity. Activ Nerv Super 2019.
[149] Ridout KK, Ridout SJ, Price LH, Sen S, Tyrka AR. Depression and telomere length:
A meta-analysis. J Aective Disorders 2016;191:23747.
[150] dos Santos, Bouso JC, Alcázar-Córcoles M, Hallak JEC. Ecacy, tolerability, and
safety of serotonergic psychedelics for the management of mood, anxiety, and
substance-use disorders: a systematic review of systematic reviews. Expert Rev
Clini Phar 2018;11(9):889902.
C.B. Germann
Medical Hypotheses 134 (2020) 109406