This review article (2020) argues that mindfulness meditation (MM) and psilocybin may work through similar mechanisms and may be complementary.
Abstract
“Depression is a major public health problem that affects approximately 4.4% of the global population. Since conventional pharmacotherapies and psychotherapies are only partially effective, as demonstrated by the number of patients failing to achieve remission, alternative treatments are needed. Mindfulness meditation (MM) and psilocybin represent two promising novel treatments that might even have complementary therapeutic effects when combined. Since the current literature is limited to theoretical and empirical underpinnings of either treatment alone, the present review aimed to identify possible complementary effects that may be relevant to the treatment of depression. To that end, the individual effects of MM and psilocybin, and their underlying working mechanisms, were compared on a non-exhaustive selection of six prominent psychological and biological processes that are well known to show impairments in patients suffering from major depression disorder, that is mood, executive functioning, social skills, neuroplasticity, core neural networks, and neuroendocrine and neuroimmunological levels. Based on predefined search strings used in two online databases (PubMed and Google Scholar) 1129 articles were identified. After screening title and abstract for relevance related to the question, 82 articles were retained and 11 were added after reference list search, resulting in 93 articles included in the review. Findings show that MM and psilocybin exert similar effects on mood, social skills, and neuroplasticity; different effects were found on executive functioning, neural core networks, and neuroendocrine and neuroimmune system markers. Potential mechanisms of MM’s effects are enhanced affective self-regulation through mental strategies, optimization of stress reactivity, and structural and functional adjustments of prefrontal and limbic areas; psilocybin’s effects might be established via attenuation of cognitive associations through deep personal insights, cognitive disinhibition, and global neural network disintegration. It is suggested that, when used in combination, MM and psilocybin could exert complementary effects by potentiating or prolonging mutual positive effects, for example, MM potentially facilitating psilocybin-induced peak experiences. Future placebo-controlled double-blind randomized trials focusing on psilocybin-assisted mindfulness-based therapy will provide knowledge about whether the proposed combination of therapies maximizes their efficacy in the treatment of depression or depressive symptomatology.“
Authors: Kristin Heuschkel & Kim P. C. Kuypers
Notes
The topic of this paper has been recently studied in a double-blind, placebo controlled study by Smigielski and colleagues (2020), which found positive long-term (four month) changes.
Summary
INTRODUCTION
Depression or major depressive disorder (MDD) is a common mood disorder and major cause of disability worldwide. It is thought to originate from a complex interplay of psychological and biological factors.
Depressive mood is characterized by negative thinking patterns, inadequate emotion regulation, and excessive rumination. These psychological processes promote cognitive rigidity, as evident from underperformance in executive functioning tests.
Depressed people show poor interpersonal skills, such as an inanimate body language and bias toward negative facial expressions and conversational contents, which contribute to the perpetuation of depressive symptoms.
MDD is characterized by neural imbalances and signaling dysregulations, partly grounded in genetic predispositions. BDNF levels are abnormally low in individuals with depression, and might originate from epigenetic factors, such as stress exposure.
MDD is associated with hyper-connectivity within the default mode network (DMN), a system of brain areas engaged during rumination, and with hypo-connectivity between the salience network (SN) and central executive network (CEN), which could further contribute to the maintenance of negative and rigid thinking patterns.
MDD features dysregulations within the hypothalamic-pituitary-adrenal (HPA) axis, which are characterized by chronically elevated cortisol levels, a diminished cortisol awakening response (CAR), and abnormally high levels of pro-inflammatory cytokines, such as interleukin 6 (IL-6).
The six factors involved in depression can be categorized into six non-exhaustive broad factors, including mood, executive functioning, social skills, neuroplasticity, neural core networks, and neuroendocrine and neuroimmunological factors.
Deficits within these factors have been shown to result in profound impairments in daily functioning, a reduced quality of life, an increased risk of suicide, and a substantial lack of productivity.
Conventional Treatments of Depression
Many different biological and psychological treatment options exist for depression, targeting different elements that are thought to be the underlying pathological cause in their specifi c theoretical framework. However, antidepressants may cause severe adverse effects.
Psychotherapy includes cognitive-behavioral therapy (CBT) and interpersonal therapy, both based on different psychosocial theories, and aims to reduce depressive symptoms. Despite large effects, relapse and drop-out rates are considerable high.
Alternative Treatments of Depression
In response to the profound limitations of conventional treatments of depression, several alternatives have been proposed. Psilocybin has received the “breakthrough therapy for treatment-resistant depression” designation from the FDA, which means that it is likely to be used to treat a serious or life threatening disease or condition.
Mindfulness Meditation
MM is a form of meditation that emphasizes present moment awareness and remaining in a relaxed state. It has been linked to improvements in self-regulation and subjective well-being.
Different forms of meditation may be applied, depending on the meditator’s expertise and personal goals. Focused attention meditation (FAM) is a common variant, while open-monitoring meditation (OMM) is more advanced.
MM can be used as a supplement in psychotherapy, constituting mindfulness-based interventions (MBIs). MBSR and MBCT are the most common MBIs, and they are effective in reducing symptoms in a variety of psychiatric and medical conditions, such as depression, social anxiety, drug-resistant epilepsy, and mental fatigue following brain damage.
Psilocybin
Psilocybin, a tryptamine hallucinogen, can be derived from a variety of Psilocybe mushroom species. It can cause perceptual, cognitive, and emotional alterations that may resemble psychosis.
Psilocybin, a psychedelic drug, is metabolized into psilocin, which acts as a 5-HT agonist. Psilocin has been shown to have positive effects on well-being, attitude, and personality, and may be used to treat depression, anxiety in terminal illness, obsessive – compulsive disorder, and substance dependence.
AIM AND OUTLINE
MM is a psychologically focused approach, similar to other trainings or exercises, and has effects on neurobiological processes. Psilocybin is a pharmacological agent, acutely affecting neurobiological processes and inducing psychological effects.
Clinical psychedelic patient trials often include multiple integration sessions after the experience, and include meditative elements such as inward-directed attention and relaxation practices. The inclusion of MM in the psychedelic-assisted psychotherapy might yield larger or longer positive effects than either treatment on its own.
The present review aims to compare the acute and long-term effects of MM and psilocybin on psychological and biological factors associated with depression, and to provide a theoretical understanding of the potential benefit when used in combination in the treatment of MDD.
METHODS
In order to gain information on the effects of mindfulness meditation and psilocybin on six selected factors associated with MDD, empirical articles, textbooks, and review papers were searched using the databases PubMed and Google Scholar.
This review included 95 articles on psilocybin and mindfulness, of which 67 were original research articles, seven were original research articles without an experimental manipulation, three were pooled data analyses, 12 were review papers, and the remaining six included theoretical (3) or editorial (1) pieces and one book.
PSYCHOLOGICAL FACTORS
MDD features a rigid, negatively biased cognitive style that contributes to depressed mood, regulatory difficulties, and social conflict.
Mood
MM has been found to elevate mood in healthy participants, depressed patients and other conditions, and remains apparent up to six months after training.
It has been proposed that mindfulness-based mental strategies improve mood regulation by reducing cognitive reactivity and promoting emotion acceptance. Additionally, non-judgemental awareness of negative thoughts might diminish the association between negative thoughts and negative mood, and prevent the perpetuation of depressive symptoms.
Psilocybin has been shown to acutely enhance mood in healthy participants as well as depressed and cancer patients. The mood-enhancing effect of psilocybin is dose-dependent and may involve a “peak” experience, a blissful sense of sacredness, revelation, transcendence of time and space, or connectedness with the environment.
The combination of the strategy-based approach of MM with the content-based approach of psilocybin may contribute to a potentiation or longer maintenance of induced mood enhancements. Moreover, the positive mood state following personal insights during a psychedelic experience might facilitate the non-judgmental observation of negative thoughts.
Ayahuasca, another psychedelic substance with similar 5-HT2A agonistic action as psilocybin, increased emotion regulation and some aspects of mindfulness in healthy volunteers, but not in participants with borderline personality disorder traits.
Executive Functioning
Studies have demonstrated positive effects of mindfulness meditation (MM) on executive functioning, including improvements in cognitive flexibility (122). Repeated training of mindfulness meditation (MBSR) has been shown to improve attentional and inhibitory capacities (74, 123, 132, 147, 148).
Psilocybin tends to impair some aspects of executive functioning like inhibition, attention, and working memory, while improving others. This may be why some people report experiencing a loss of control over thoughts or perceptions.
Psilocybin impairs cognitive focus and control, while 5-HT2A agonism increases cognitive flexibility and divergent thinking. These effects may be related to decreased executive control and a loosening of associations via neuroplastic changes in core neural networks.
MM practice may enhance the effects of psilocybin therapy by reducing the risk of adverse reactions, or may worsen the effects of psilocybin therapy by reducing attentional capacities.
Social Skills
With regard to social skills, mindfulness has been linked to greater relationship satisfaction. This led to the emergence of variants of mindfulness training that focus on the interpersonal aspects of mindfulness.
Psilocybin has positive effects on empathy, including cognitive empathy, in TRD patients and healthy volunteers.
Pahnke suggested that the afterglow of psychedelic peak experiences may increase the willingness to enter into close interpersonal relationships. This is in agreement with self- and other reports of positive changes in social attitudes and behavior following psychedelic peak experiences.
MM and psilocybin enhance social skills by influencing the way an individual deals emotionally with social encounters, and by enhancing empathic abilities and a changed personality.
BIOLOGICAL FACTORS
Studies have shown that MDD is associated with impaired neuroplasticity, an imbalance in core neural networks, and disturbances in stress responses.
Neuroplasticity
MM may promote BDNF expression by prolonged, repeated practice, frontal activation following active engagement of attention, vagal stimulation or a reduction in stress response.
Psilocybin and related classical psychedelics are hypothesized to promote neuroplasticity through mechanisms involving 5-HT2A agonism. MM, on the other hand, supposedly relies on top-down regulatory efforts and encourages plasticity incrementally throughout the progress of training.
Neural Core Networks
MM engages the insula and anterior cingulate cortex, which are involved in interoceptive processes, whereas the lateral PFC and parietal cortex, which are involved in external awareness, decrease activity during mediation. Moreover, MM promotes the activation of the dorsolateral PFC, which is important for cognitive control.
Psilocybin was proposed to decrease functional neural integrity within networks and increase connectivity between networks, which may explain the experience of hallucinations and cognitive flexibility following its administration. Psilocybin induces widespread cortical activations, particularly in association cortices, where 5-HT2A receptors are most abundant (182). This pattern of activity correlated positively with the measures of psychotic symptoms, especially ego dissolution, and might be explained by an involvement of GABAergic interneurons within psilocybin’s pathway of action.
While jointly working to resolve DMN dominance associated with excessive rumination, MM and psilocybin seem to alter circuits differentially. This may reflect the psychological changes induced by MM and psilocybin, which may contribute to a reduction of negative and rigid thinking patterns.
Neuroendocrine and Neuroimmunological Factors
MM training may attenuate stress responses by promoting regulatory prefrontal pathways, reducing amygdalar projections and HPA axis activity, and reducing subjective psychological stress, but its effect on cortisol secretion varies across populations.
As diseases represent sources of profound stress, the association between MM and cortisol only holds for highly stressful situations. However, MBSR increases the CAR in cancer patients who demonstrate depressive symptoms, which conforms an alternative hypothesis, namely that MM optimizes HPA responsivity.
Psilocybin is associated with an acute increase in cortisol levels and a reduction of subjective stress in terminally ill cancer patients. It might also facilitate top-down control of stress responses in limbic structures.
5-HT2A receptors are integrated in an abundance of cells throughout the immune system and may be involved in anti-inflammatory responses. Psilocybin may be able to reduce inflammatory responses by means of 5-HT2A agonism and consequently reduce the stimulation of the HPA axis through anti-inflammatory cytokines.
DISCUSSION
The present review aimed to identify possible additive or complementary effects of MM and psilocybin on six factors associated with MDD. Results showed that MM and psilocybin exerted similar effects on mood, social skills, neuroplasticity, and neuroendocrine and neuroimmune system markers.
MM employs mental strategies that augment emotional and cognitive self-regulation in the long term, whereas psilocybin induces a state of apparent “flexible cognition” and may lead to personal insights that diminish negative biases.
The biological effects of MM and psilocybin may be combined to promote a two-way reorganization of neural networks, especially those involved in rumination, and downregulation of neuroendocrine and neuroinflammatory responses.
Implications for Future Research
The combination of MM and psilocybin may have larger or longer-lasting effects than either treatment alone in the treatment of MDD. A randomized, double-blind, placebo-controlled trial is needed to test this hypothesis. Primary endpoints would be depressive symptomatology and social skills, with secondary endpoints including neuroplasticity, neuroendocrine and neuroinflammatory factors. Cognitive tests at different time points in the treatment would be useful to clarify potential opposing effects.
No norms regarding the exact procedure, type of psychological support, dose(s) of the psychedelic, or duration of the psychedelic therapy have been agreed upon. MM practice prior to a psilocybin session may have the potential to reduce the risk of adverse effects in depressed patients.
A combination of mindfulness and psilocybin may also bear benefits for MDD patients, and mindfulness training may be a useful asset to psychedelic therapists.
Limitations
The present review features a number of limitations, including the use of diverse assessment methods and the use of different questionnaires to measure similar variables in different populations, which could explain the inconsistent findings across studies.
A significant decrease in immune markers was shown in healthy participants after six weeks of MBSR, but not in university staff and students following an 8-week-long low-dose MBI.
Methodological issues noted in the reviewed MM studies include the general lack of active control groups and the use of gold standard tests.
Methodological issues with studies investigating the effects of psilocybin, such as small samples, open-label designs, and no control group, make it difficult to make firm statements about potential implications. Moreover, there are conceptual issues regarding the definition of mindfulness, such as FAM, MBCT or MBRE.
The discussion largely pertained to 5-HT2A agonism, but psilocybin may also act on other neurotransmitter systems. Further, hypotheses regarding the immunosuppressive action of psilocybin and BDNF-promoting effects of MM were proposed, but have not been subject to sufficient empirical testing.
CONCLUSION
This review provides an extensive overview of the current scientific knowledge on the effects of psilocybin and methanol on depression. It also provides a theoretical ground for future research.