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= **ENTHEOGENS AND THE BRAIN** =

1 Introduction
Psychedelic drugs have been used in religious settings for centuries, as well as for psychological self-enhancement purposes. The neural correlates of entheogens, psychedelic drugs that have been historically used during religious ceremonies to trigger spiritual experiences, have yet to be completely elucidated. These hallucinogens such as psilocybin and DMT are believed to act as agonists of the 5-HT2A serotonin receptor. The beta-carbolines, a major constituent of the Pan-Amazonian entheogen //ayahuasca//, act as monoamine oxidase (MAO) inhibitors. In recent studies, Griffiths et al. (2006-2011) reported that psilocybin induces mystical-type experiences and a sense of well-being. The relevance of systematically studying entheogens lies in the vast therapeutic implications that these drugs hold for disorders such as depression.

2.1 Ayahuasca, MAO Inhibition and Paralimbic/Frontal Cortex Activation
Ayahuasca is composed of the serotonergic psychedelic DMT (N,N-dimethyltryptamine) and beta-carbolines such as harmine, harmaline and tetrahydroharmine (THH). The beta-carbolines act as [|monoamine oxidase (MAO) inhibitors] enabling ingested DMT to reach the central nervous system (CNS) and occasion its hallucinogenic effects. Investigations into the psychotropic effects of ayahuasca emphasize an altered state of consciousness (ASC), altered somatic perceptions/emotional reactions that are frequently accompanied by visual imagery and improved introspection (Barbosa et al. 2005). The neurobiological effects of ayahuasca on the brain are not completely understood. Riba et al. (2006) used **[|single photon emission tomography (SPECT)]** to examine the effects of ayahuasca on cerebral blood flow. Fifteen males were administered 1mg DMT/kg of body weight of freeze-dried //ayahuasca//. Approximately 2 hours following the ingestion of ayahuasca, the cerebral blood flow of participants was measured using SPECT. Analysis of the results revealed that ayahuasca led to significant activations of frontal and paralimbic brain regions. More specifically, increased activation was observed bilaterally in the anterior insula and the anterior cingulate/frontomedial cortex of the right hemisphere, areas associated with physiological awareness and emotional processing. The results implicate a central role of the serotonergic system in ayahuasca’s neurobiological correlates. De Araujo et al. (2011) explored the neural basis of the enhanced visual imagery that characterizes ayahuasca experiences by employing **[|functional magnetic resonance imaging (fMRI)]** scans during a closed-eyes imagery task. Ayahuasca was observed to increase the activation of several occipital, temporal and frontal areas.

2.2 Serotonergic Hallucinogens: The 2AR Receptor
Psilocybin and DMT (a key component of ayahuasca) are potent psychoactive substances that are classified as tryptamine alkaloid hallucinogens. Rodent experiments, neural imaging and pharmacological studies seem to suggest that the hallucinogenic mechanism of action occurs through agonist activity at the 5-HT2A serotonin receptor, alternatively coined the 2AR. The 5-HT2A serotonin receptors are found on both excitatory pyramidal cells and GABA-ergic interneurons (Carhart Harris et al. 2012a). In addition, the 2AR receptor is widely expressed in the central nervous system and especially in areas that have been linked to psychosis, the ventral striatum and ventral tegmental area (Nichols 2004). Ketanserin, a selective 5-HT2A antagonist, was shown to dose-dependently block the hallucinogenic effects of psilocybin in a study that aimed to elucidate the neural substrates of schizophrenia (Vollenweider et al. 1998). Evidence shows that stimulation of the 2AR receptor leads to increased glutamatergic activity of the pyramidal neurons in Layer V of the prefrontal cortex. Findings also suggest that the glutamatergic surge mediated by 2AR receptors in cortical neurons leads to increased expression of AMPA receptors causing the release of brain derived neurotrophic factor (BDNF), suggesting that psychedelics contribute to enhanced neural plasticity.

2.3 Psilocybin and Decreased Functional Connectivity
Psilocybin is a serotonergic indoleamine naturally derived from “magic mushrooms” (Psilocybe fungi). The hallucinogenic effects of psilocybin are caused by its biologically active form, psilocin. The acute psychological effects of psilocybin are characterized by an altered state of consciousness (ASC) with significant changes observed in visionary restructuralization, self-awareness and emotional processing (Studerus et al. 2011). In a study with 110 subjects, Strudeus et al. (2011) reported that in the long-term over 60% of subjects continued to rate the psilocybin experience as “enriching.” Research has suggested that these hallucinogenic effects can be attributed to the fact that psilocybin induces hyperfrontality. Gouzoulis-Mayfrank et al. (1999) examined the neurometabolic effects of psilocybin using [F-18] fluorodeoxyglucose FDG-positron emission tomography (PET). The results showed that psilocybin increased metabolic activity in distinct right hemisphere prefrontal regions (hyperfrontality) such as the anterior cingulated, areas that are important for emotional and cognitive processing. However, Carhart et al. (2012a)challenged the prominent models of hallucinogenic actions that have principally focused on their potential to increase excitatory neurotransmission and brain activity. Carhart et al. (2012a) purported that the 5-HT2A serotonin receptors are found on both excitatory pyramidal cells and GABAergic interneurons, suggesting that psilocybin interacts with both excitatory and inhibitory neurons to cause an overall decrease in brain activity. In an fMRI study, Carhart et al. (2012a) showed that psilocybin was associated with decreased blood flow in the thalamus, anterior and posterior cingulate cortices (ACC and PCC). In addition, the researchers demonstrated marked decreases in “functional connectivity” between the medial prefrontal cortex and the ACC/PCC. An important finding that has therapeutic implications for depression is that the medial prefrontal cortex (mPFC) was consistently deactivated by psilocybin. Hyperactivity of the mPFC is observed in individuals diagnosed with depression(Carhart-Harris et al. 2012a).

3.1 Psilocybin and Mystical-type Experiences
Griffiths et al. (2006) examined the acute and longer-term psychological effects of psilocybin in contrast to methylphenidate hydrochloride in a double-blind study. Thirty-six religious volunteers without prior exposure to hallucinogens received a dosage of 30mg/70kg psilocybin and 40mg/70kg methylphenidate hydrochloride alternatively under comfortable, serene and supportive environments. Participants were encouraged to close their eyes, relax and shift their attention inward in a state of serene contemplation. After psilocybin, the results showed that 61% of the participants reported a full mystical experience as measured by the Mysticism Scale. Furthermore, 31% of subjects experienced significant fear sometime during the psilocybin session. Two months following the initial experiment, 71% of the volunteers described their sessions with psilocybin as among the top five most “spiritually significant” experiences in their lives (Griffiths et al. 2006). In addition, 79 % of volunteers rated that the psilocybin experience had improved their sense of personal well-being or life satisfaction. Griffiths et al. (2008) reported the effects of the initial psilocybin experience in a 14-month follow-up study. During the follow-up, participants continued to rate the psilocybin experience as being one of the most spiritually meaningful and significant in their lives. Griffiths et al. (2008) found that 64% of participants continued to rate the psilocybin experience as increasing well-being or life satisfaction. In addition, 58% of participants maintained that the psilocybin session represented a complete, mystical experience (See Fig. 3). Griffiths et al. (2011) extended their findings about the spiritual effects of psilocybin in a dose-effect, double-blind study. Griffiths et al. (2011) concluded that positive changes in mood and behavior correlated with increasing psilocybin quantity (from 0, 5, 10, 20, 30 mg/70kg). Dosage of 20 and 30mg/70kg psilocybin administered under comfortable conditions facilitated mystical-type experiences with a persisting positive impact. MacLean et al. (2011) reported that a high-dose psilocybin session induced a significant increase in the personality trait of Openness,which remained significantly higher one year after the initial experiment.

4.1 Ayahuasca as Antidepressant
The two major constituents of ayahuasca, DMT (N, N-dimethyltryptamine) and betacarbolines, have been pharmac ologically implicated to exhibit therapeutic potential for the treatment of **[|depression]**. Following oral ingestion of DMT (up to 1000 mg), its hallucinogenic effects are not displayed because the psychoactive agent is most likely degraded by gastrointestinal **MAO**, monoamine oxidase (Santos et al. 2007). The beta-carbolines, such as **harmine**, **harmaline** and **tetrahydroharmine** (THH), act as [|MAO inhibitors], thereby allowing DMT “to reach the central nervous system and produce its effects” (Santos et al. 2007). In addition to MAO inhibition, one of the most common beta-carbolines in ayahuasca, THH, has been shown to inhibit serotonin reuptake (Santos et al. 2007). The inhibitory impact of ayahuasca on MAO and serotonin reuptake leads to elevated levels of serotonin at the synapse, an effect that is replicated by such anti-depressant medication as [|**selective serotonin reuptake inhibitors** (SSRIs)]. Furthermore, 5-HTagonists such as DMT have also been used in the treatment of depression.

4.1a Harmine
Motivated by the neurobiological evidence that underscores the potential therapeutic effects of ayahuasca, a recent study by Santos et al. 2007 used a “double-blind, placebo-controlled procedure” to determine its acute psychological effects. Santos et al. (2007) reported that ayahuasca decreased measures of hopelessness and panic as scored one hour after ingestion of the Amazonian tea by the psychometric tests of the [|**Beck Hopelessness Scale** (BHS)]and Anxiety Sensitivity Index (ASR-I) in nine long-term (minimum 10 successive years) members of a Brazilian ayahuasca-using religion, the //Santo Daime.// In addition, using two classical animal models of learned helplessness, the forced swim and open field tests on rodents, Fortunato et al. (2010) demonstrated the anti-antidepressant effects of harmine, the most abundant beta-carboline in ayahuasca. The study treated mice for fourteen days with harmine before subjecting them to the forced swim and open field tests. Harmine was observant to increase resilient behavior in the mice **(See Fig. 4).** Harmine treatment was also associated with increased levels of brain derived neurotrophic factor (BDNF) in the rodent hippocampus, which has been associated with antidepressant effects.

4.2 Psilocybin
4.2a Treatment of OCD Moreno et al. (2006) investigated the effects of psilocybin in ameliorating the symptoms of Obsessive Compulsive Disorder (OCD) with patients that were resistant to conventional treatments. In a study that spanned three years, nine subjects were administered with four successively escalating doses of psilocybin that ranged from low doses that elicited a non-hallucinogenic response to high hallucinogenic amounts. Following administration of psilocybin (which occurred during sessions that were separated by at least one week) at 0, 4, 8, and 24 hours after consumption, subjects rated their obsessive-compulsive symptom severity as measured by the //Yale-Brown Obsessive Compulsive Scale// (YBOCS). Moreno et al. (2006) reported significant reduction of OCD symptoms for subjects (from 23% to 100%) during one or more of the testing sessions. 4.2b Anxiety in Cancer Patients Grob et al. (2011) evaluated the effectiveness of psilocybin for treating anxiety in patients with terminal cancer. This double blind, placebo-controlled pilot study of patients suffering from late stage cancer and anxiety used the //Beck Depression Inventory, Profile of Mood States// and //State-Trait Anxiety Inventory// to assess the impact of psilocybin for six months after treatment. Grob et al. (2011) found that patients demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. In addition, the //Beck Depression Inventory// revealed that subjects demonstrated a significant improvement of mood at 6 months. The study concluded that a moderate dose of psilocybin is safe to use in clinical research for cancer patients with anxiety. The findings of Grob et al. (2011) on the beneficial effects of psilocybin in psychologically assisting cancer patients have prompted several studies to further investigate the hallucinogen’s therapeutic potential in that regard. Several researchers (among them **[|Griffiths]** and **[|Kalliontzi]**) are currently conducting studies to assess the usefulness of psilocybin in triggering spiritually significant experiences and reducing anxiety/distress for cancer patients. 4.2c Psychedelic-Assisted Psychotherapy In a study published this year, Carhart-Harris et al. (2012b) explored the therapeutic potential of psychedelic-assisted psychotherapy using [|**functional magnetic resonance imaging**(fMRI)]. The experiment examined whether psilocybin improved psychotherapy sessions. Ten participants underwent two fMRI scans on two separate occasions. The first scan was obtained when participants were administered psilocybin. After approximately a week, a second scan was performed when subjects were treated with a placebo, saline. During the scans, the participants viewed two different sets of 15 positive autobiographical memory cues. The subjects were instructed to look at the cue for 6 seconds. Following, subjects closed their eyes for 16 seconds (recollection period) and imagined re-experiencing the incident portrayed by the cue. The recollection period was demarcated into an early (first 8 seconds) and a late phase (last 8 seconds). Examination of the fMRI data revealed activations in response to the memories in the limbic and striatal regions during the early phase and medial prefrontal cortex during the late phase under both psilocybin and the placebo. However, under psilocybin, additional visual and sensory cortical areas were recruited (See Fig. 6). Memories were collectively rated as more vivid, visual, emotional and positive under psilocybin than saline. Furthermore, reports of well being two weeks after each scan were significantly higher after psilocybin. The results that psilocybin leads to an enhancement of positive autobiographical recollections have therapeutic implications for the incorporation of psilocybin with positive memory cues in psychotherapy for depression.



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