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Medical Hypotheses

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The Psilocybin-Telomere Hypothesis: An empirically falsiﬁable prediction

concerning the beneﬁcial neuropsychopharmacological eﬀects of psilocybin

on genetic aging

☆

Christopher B. Germann

Marie Curie Alumnus, United Kingdom

ARTICLE INFO

Keywords:

Psilocybin

Depression

Rumination

Telomeres

Cellular senescence

Genetic aging

Epigenetic clock

Neurophenomenology

Senotherapy

Rejuvenation

Life extension

ABSTRACT

We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneﬁcial eﬀects

on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantiﬁable

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 scientiﬁc discovery, viz., bold (and

refutable) conjectures form the very foundation of scientiﬁc 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 beneﬁcial eﬀects 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 beneﬁcial eﬀects on genetic aging.

Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically

signiﬁcantly 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 ﬁve 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

quantiﬁable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost eﬀec-

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 scientiﬁc 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 ramiﬁcations 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 identiﬁcation 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.

Introduction

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

https://doi.org/10.1016/j.mehy.2019.109406

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: —https://psilocybin-research.com/psilocybin-telomere-hypothesis-sma/

E-mail address: christopher-germann@marie-curie-alumni.eu.

Medical Hypotheses 134 (2020) 109406

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 inﬂ 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 [16–18], ﬁt-

ness and physical exercise [19,20], exposure to environmental toxins

such as traﬃc 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 ﬀected by

psychological conditions such as chronic stress, depression, and re-

petitive negative thought patterns, viz., chronic rumination [3,24–27]

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 aﬀect telo-

meres. In addition, our hypothesis rests on the minor premise that the

therapeutic utilisation of psilocybin exhibits signiﬁcant beneﬁcial ef-

fects on various aspects of psychological health.

Rapidly accumulation

converging empirical evidence supports this claim [30–34]. Speciﬁ-

cally, a substantial corpus of studies demonstrated that the therapeutic

utilisation of psilocybin reduces depression in various populations

[35–37] 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 signiﬁcantly 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 inﬂuence aging at the genetic level. We

postulate that beneﬁcial 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

quantiﬁable 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.

Syllogism #1

Major premise: Depression is associated with shorter telomeres.

Minor premise: Psilocybin reduces depression.

Conclusion: ∴ Ergo, psilocybin positively eﬀects 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-

pression].

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 eﬀects. Thus, our hypothesis is

directional (one-tailed) in the case of a positively valenced psilocybin

phenomenology, but bidirectional without any additional speciﬁcation

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

traumata.

Ex hypothesi, negative psychological conditions facilitate

telomere attrition [40]. However, from a longitudinal perspective, a

prima vista seemingly negative psilocybin experience can exert bene-

ﬁcial longitudinal psychotherapeutic/cathartic eﬀects which may take

substantial time to unfold (per analogiam to the occurrence of various

negative side-eﬀects that frequently accompany physiological detox-

iﬁcation which can cause the release of deposited toxins that trigger

various seemingly negative side-eﬀects which are in actuality con-

ducive to long-term healing—similarly, 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 diﬀerent 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

medii).

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 exempliﬁes the basis of the deductive-nomolo-

gical model (Popper–Hempel model) of scientiﬁc 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/ﬂexible semantic format as illu-

strated in Syllogism #2. However, for the sake of speciﬁcity (i.e., ex-

perimental operationalism/falsiﬁability) 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 suﬃcient to induce beneﬁcial 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 eﬀectiveness of the intervention? This is an

empirical question which should be investigated in a controlled

manner. Future research should also elucidate the synergistic eﬀec-

tiveness of psilocybin (cf. [41]) when combined with diﬀerent 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 eﬀects 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 scientiﬁc thought (viz., a holistic/integral perspective which

supersedes dogmatic material reductionism and epiphenomenalism).

Syllogism #2

Major pre-

mise:

Beneﬁcial neuropsychological changes positively eﬀect telomere

length.

Minor pre-

mise:

Psilocybin has quantiﬁable beneﬁcial neuropsychological eﬀects.

Conclusion: ∴ Ergo, psilocybin positively eﬀects 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 eﬀects on psychological health and the predicted genetic/

epigenetic eﬀects are thus likely complex and multifactorial and not

exclusively restricted to telomeres. However, telomeres are a con-

venient biomarker which is readily quantiﬁable 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

falsiﬁcation), 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= > eﬀect 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 diﬀerent

biomarkers measure diﬀerent (unrelated) aspects of biological aging

[43].

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 quantiﬁes the “cumulative

eﬀect 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 quantiﬁable eﬀects

on telomeres [48–50] and animal models support this ﬁnding [51].

recent meta-analysis of 83 studies conﬁrmed a signiﬁcant correlation

between depression and telomere length [149]. The pertinent literature

indicates a general pattern: Positive mental psychological states have

beneﬁcial eﬀects 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 hypothalamic–pituitary–adrenal 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. Inﬂammation 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 scientiﬁc 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,

inﬂammatory 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-

ﬂammatory agents is a topic which recently gained attention [59] and

particularly the role of the σ1 receptor in neuroinﬂammation and

neurodegeneration is of interest in the present context.

Alterations in concentrations of various brain growth factors have

been associated with stress and depression. Speciﬁcally, 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 speciﬁc 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 speciﬁc synaptic and dendritic molecular pro-

cesses (e.g., 5-HT

agonism) may turn out to be a naïve reductionist fallacy—a

“Zeitgeist bias” that inﬂuenced 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 coeﬃcient 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

speciﬁcally 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 [61–63]. 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 eﬀects of psilocybin on BDNF

concentrations [65] as this might provide basic insights into inter-

mediary biochemical mechanisms that mediate between psilocybin and

its postulated eﬀects 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 eﬀects which negatively aﬀect telo-

meres [66–68]. Stress magniﬁes various endogenous inﬂammatory 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, neuroinﬂammation, 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 eﬀects of excessively high levels of cortisol. For

example, the endogenous steroid hormone dehydroepiandrosterone

(DHEA) has been shown to possess antiglucocorticoid properties which

oﬀer protection against the deleterious eﬀects of cortisol [73], thereby

reducing neurocognitive deﬁcits in depression. Likewise, BDNF induced

hippocampal neurogenesis has positive protective eﬀects on chronic

stress levels [74–77] and reduces social avoidance [78,79]. Important

for the present hypothesis is the empirical ﬁnding 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 eﬀects 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 inﬂu-

ence the eﬀects 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 speciﬁc

polymorphism of the serotonin transporter promoter (5-HTTLPR)

moderates the correlation between stress and depression [84]. In ad-

dition to genetic diﬀerences, 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 deﬁnition, not the genetic code itself). Epigenetic

changes can be reversible and non-reversible depending on speciﬁc

conditions (also see [86]). We propound that that the psychologically

profound “transformative transcendental experiences" that can be oc-

casioned by psilocybin are accompanied by speciﬁc/characteristical

epigenetic changes. That is, we predict that the qualitative phenom-

enological aspects of psilocybin are reﬂected at the epigenetic level,

viz., we hypothesise a correspondence between phenomenology

and

epigenetics.

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 ﬁnding

is very intriguing because there is broad scientiﬁc 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 eﬀects on genes

related to serotonin dynamics. Speciﬁcally, 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 aﬀected 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-eﬀects”

associated with SSRIs which deserve constant emphasis, speciﬁcally given the

highly biased lobbyism of “Big Pharma” [126–123].

This line of thought is also revealing from a neurophenomenological van-

tage point which connects the 17/18th century Husserlian school of thought

(deﬁned as German transcendental-idealist philosophy) with the methods and

technologies of modern neuroscience [129,125]. This approach emphasises that

phenomenology is subject to scientiﬁc 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 eﬀorts as current research on psychoactive compounds is almost

exclusively brain-centred (i.e., at the level of speciﬁc 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 scientiﬁc problem which has an intrinsic aﬃnity with

research on altered states of consciousness. We suggest that the transdisci-

plinary cybernetic concept of autopoiesis [132–129] 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 modiﬁcations of the

modus operandi in which information is processed, e.g., modiﬁcations 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 eﬀects)

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 beneﬁcial eﬀects on

various aspects of mental health. We will speciﬁcally focus on its pos-

tulated eﬀects on depression.

Evidence in support of the minor premise: Psychotherapeutic utilisation of

psilocybin reduces depression

Psilocybin

has been reliably associated with numerous mental

health beneﬁts (e.g., in the context of anxiety, PTSD, OCD, addiction,

etc., for a systematic review see [150]). Rapidly accumulating evidence

demonstrates that psilocybin signiﬁcantly reduces clinical symptoms in

depressed populations [89–91,93]. Further, it has been reported that

psilocybin improves emotional face recognition in treatment-resistant

patients [92]. This quasi-interpersonal improvement was statistically

signiﬁcantly correlated with a reduction in anhedonia, viz., deﬁcits 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 ﬂow (CBF) in the

temporal cortex and the amygdala. Importantly, reductions in amyg-

dala CBF were statistically signiﬁcantly correlated with a reduction in

depressive symptoms. It should also be noted that the fMRI study (op.

cit.) demonstrated that the acute eﬀects of psilocybin diﬀer from the

longitudinal eﬀects. In the following paragraphs we will primarily

concentrate on the involvement of the DMN and the amygdala in de-

pression.

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 signiﬁcantly debilitating for the individual ("locus of control" and

self-eﬃcacy 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-

fault-mode-network

[94,95]. Experimental studies have demon-

strated that psilocybin signiﬁcantly downregulates DMN activity [93].

Interestingly, a recent experimental study indicated that psilocybin-

assisted mindfulness training modulates DMN connectivity with lasting

eﬀects [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

aﬀect 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 diﬀerent 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 inﬂammatory 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

ﬁve most meaningful and signiﬁcant 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 quantiﬁable genetic counterpart, i.e.,

the psilocybin-occasioned phenomenological apogee produces a unique

quantiﬁable 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 quantiﬁable quasi-Lamarckian epigenetic eﬀects,

then it is predictable (with a high likelihood) that a profound and life-

changing psilocybin experience (cf. Griﬃths et al., 2008) has equally

quantiﬁable eﬀects 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 scientiﬁc literature by

Ruck et al. [134]. Per deﬁnition, 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 ἔνθεος

(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]].

Speciﬁcally, various connectivity density diﬀerences have been demon-

strated which diﬀerentiate 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

neuroinﬂammation [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 ﬁcally in the

context of depression and anxiety). For instance, it has been reported

that individuals with speciﬁc 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

eﬀects of psilocybin on emotional processing are speciﬁcally 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 ﬁght

ﬂight 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

1A/

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 signiﬁcant

beneﬁcial eﬀects on various organismic levels and, speciﬁcally, that the

therapeutic eﬀects 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 eﬀects 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]).

Conclusion

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. Speciﬁcally, we argue that the con-

vergence of evidence indicates scientiﬁc consilience.

According to

this pivotal meta-scientiﬁc 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 ﬀerent research ap-

proaches in support of the conclusion. Furthermore, if equivalent con-

clusions are reached from multiple perspectives (e.g., diﬀerent

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

inﬂuence all research methods equally. That is, resilience “balances-

out” method speciﬁc 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 diﬀerent 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, scientiﬁc experiments which investigate

the eﬀects 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 eﬀects 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-inﬂammatory 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 diﬀerential 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 eﬀects 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 diﬀ erential eﬀects on telomeres of

various cell types should be systematically examined (speciﬁcally 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 signiﬁcantly 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 signiﬁcant

potential to advance and deepen our understanding of the interactions

between psychological, neuronal, and (epi)genetic processes.

Conﬂict of interest

The author declares no conﬂict of interest.

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