Classical Psychedelics and Abroad


By Christopher Gunlock

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Psilocybe Mushrooms

Psilocybe Cubensis, Semilanceata, Cyanescens. . .

Exclusively found in a large array of naturally occurring mushrooms, psilocybin is the main psychoactive compound that brings about the intense experience known to many throughout the world as a “magic mushroom trip.” Several other psychoactive compounds exist in the heads, stems and truffles of psilocybe mushrooms as well. Chemically, it is a close relative to Dimethyltriptamine (DMT) [1], but brings with it a distinct experiential flavor and therapeutic potential.

Their legal status is the same high-level restriction of all other classical psychedelics, but are currently considered a “breakthrough therapy” for treatment-resistant depression by the Food and Drug Administration (FDA). This fast-track was given because they have demonstrated the potential to perform better than conventional anti-depressants in early trials [2]. Apparently, scientists aren’t the first ones to find a good use for it either. Psilocybe mushrooms are on record to be part of the sacraments of certain native cultures throughout the world, some of them quite old [3]. 

The experience of psilocybin has been explained by clinical researchers to take 30-60 minutes to become detectable by the user, 2-3 hours to reach the full effects, and at least 6 hours to taper back down to baseline [4]. The classical psychedelic experience of ego-dissolution, visual patterns/distortions, higher ratings of mystical experiences, and dramatic changes in mood are commonly reported [1], [5], [6].

Not only is physical toxicity remarkably low for psilocybin and all other classical psychedelics, but the adverse effects in controlled clinical settings consist primarily of temporary anxiety, confusion, increased blood pressure, and increased heart rate. These effects are reported to subside once the full effects are reached [4], [7], [8].

A sizable chunk of the new wave of psychedelic research has focused on psilocybin, the primary psychoactive compound of these mushrooms.

  • One study using magnetic resonance imaging and memory cues during psilocybin sessions found activation in sensory brain regions and high ratings of memory vividness. They also found these measurements to be correlated with increased subjective well-being for a period after the session. They postulated that this implies a possible psychotherapeutic application for depression and perspective shifting through reliving past events [1].

  • A systematic review in 2016 of these substances concluded that “…the ability of classical hallucinogens to elicit religious, mystical, transcendent, or peak experiences has also been proposed as a possible psychological mechanism associated with the beneficial effects of these drugs” [9].

  • In a 2016 study assessing participants with treatment-resistant depression (TRD), the authors reported significant reductions in depression and anxiety scores 3 months after the intervention. The maximum effect was observed at 2-weeks, but at 3-months, 42% of the subjects reported full remission [4].

  • In several recent clinical studies including  randomized controlled trials, individuals with advanced-stage cancer were given a single dose of psilocybin, which resulted in lasting reductions in anxiety and depression [8], [10]–[12].

  • In the treatment of tobacco addiction, one 2017 study did a 12-month follow up to find that 67% of participants were confirmed to be abstinent from smoking. Additionally, they reported that “…(86.7%) rated their psilocybin experiences among the five most personally meaningful and spiritually significant experiences of their lives.” [5]

The fascinating fact about these early clinical trials is how effective they are compared to conventional treatments and with an extremely low side-effect profile. However, the actual phase-3 trials doing direct comparisons with conventional treatments are still in development. Therefore, even though the FDA has designated it as a “breakthrough therapy,” that doesn’t mean they will approve psilocybin for depression. Fortunately, thanks to a comprehensive review on the evidence for the limited abuse potential and therapeutic benefit [2], they are hastening the normally arduous process of conducting clinical trials. That means it may be sooner than you think that we see this become a medicine.


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LSD

Lysergic-Acid Diethylamide, Blotter, Acid. . .

Serendipitously synthesized by Albert Hoffmann in 1938, LSD came to be one of the most infamous of all psychedelics, in part due to its unparalleled potency and long-lasting psychedelic effects. A single gram of pure LSD can have 10,000 doses in it and taking just one of those will cause dramatic perceptual changes. Its uniqueness is also present in its unintentional creation. It was synthesized while researching a respiratory stimulant drug and then accidentally ingested by its creator, Albert Hofmann, who was the first ever to report on the profound effects [13].

LSD mystified and fascinated researchers prior to its severe restriction in 1971, as evidenced by the 2000+ published papers on it before research was shut down. Pre-prohibition research is not touted as the most rigorous body of scientific work, but it was more than enough to establish LSD could be used safely in controlled settings by people without pre-existing psychoneurotic disorders. Additionally, the efficacy as a treatment for certain psychological ailments was established as well. Despite the support from the scientific community, politically-driven scare-tactics and irresponsible recreational use were enough to bury it behind the world’s strictest drug laws. However, since then a new wave of research has reawakened scientific inquiry [14].

  • In 2006, a study on 53 cluster headache patients found the majority achieved both termination of symptoms and prolonged remission from this debilitating disease. Both psilocybin and LSD achieved these results in just one dose that no other known medication could replicate [15].

  • In 2014, a phase-1 safety and efficacy trial was conducted on subjects with anxiety associated with a life-threatening illness. The randomized, placebo controlled, double-blinded study found no acute or chronic adverse effects and a significant reduction in anxiety during a 12-month follow-up [16].

  • In 2016, British scientists studied fMRI scans on participants listening to music on LSD. Their findings of visual cortex and parahippocampal cortex functional connectivity confirmed subjective reports of mental imagery evoked by music [17].

  • That same year, scientists were able to correlate ego dissolution survey scores with increased global brain connectivity in fMRI scans [18]. Most recently this year, scientists saw dendritic branches and spine growth in neurons dosed with multiple psychedelics. This is of particular interest in relation to the brain atrophy experiences in depression and post-traumatic stress [19], [20].

The inability for scientists to research this drug for so many decades has left many questions about what exactly is happening during the LSD experience. However, given the evidence of its ability to transform perception and potentially heal the mind, uncovering the truth about it carries significant urgency. The concerns about its safety don’t go unnoticed, though. The incredible potency combined with its water-solubility make it very easy for a person to ingest. If put in the wrong hands, dire consequences could result.


Ayahuasca

Banisteriopsis Caapi vine, Psychotria Viridis. Yage, Hoasca, Vegetal . .

This is the traditional brew that takes advantage of a combination of plants involving dimethyltriptamine (DMT) and monoamine oxidase-inhibitors (MAOIs) to make it readily digestible. Commonly, Banisteriopsis Caapi and Psychotria Viridis are used. The latter, which contains DMT compounds, is combined with various harmine alkaloids in B. Caapi that act as monoamine oxidase inhibitors (MAOI), which cause DMT to become orally active. When this mixture is drunk, it induces DMT-like effects for several hours rather than the normally fleeting effects of smoked or intravenous DMT.

Tourists of the world have been flocking to sites in South America in search of local traditions of ayahuasca ceremonies at an exponential rate. This is easier said than done, though, as reports of charlatans and criminal activity have brought warranted alarm. Nonetheless, stories of life-changing experiences involving ayahuasca continue to circulate. Fortunately, the limited research on this concoction has shown promise in addressing some of the world’s most rampant health epidemics. 

  • Since 2014, studies concluded some of the reported effects of ayahuasca to include altered visual perception, increased introspection, creation of worlds within worlds, offerings of love and acceptance, possibility of meeting dark/evil beings, and increased emotional liability. Clinically, anti-depressive, anti-anxiety, and anti-addictive results are common [9], [20]–[24].

  • In 2015, researchers looked at depression scores in recently diagnosed patients after administering ayahuasca in a dry clinical setting. They found an impressive 82% reduction in those scores up to 21 days later and vomiting was the only adverse side effect [9].

  • More recently in 2018, a randomized, placebo-controlled trial confirmed the dramatic anti-depressive effects of a single dose on treatment-resistant depression [24].

In the brain, long term usage was found to modulate frontal, temporal, and occipital networks, which is associated with intention, memory and vision. While under the effects, the default mode network shows a significant decrease in activity, similar to other psychedelics and meditation. Recently, cortisol balance (the stress hormone) was even found to be restored shortly after administering ayahuasca to patients with treatment-resistant depression [25].

The risks of ayahuasca are not always agreed upon, perhaps in part due to the controlled setting and rigorous screening of participants in these studies. However, similarity to psychosis is often mentioned and suggests certain factors may lead to dangerous effects. Recent analyses don’t find strong evidence of psychosis in long term users, though, similar to controlled clinical studies [20].


DMT

N, N-Dimethyltryptamine, Mimosa, Acacia, Psychotria, Delosperma, Anadenanthera, Desmodium, Petalostylis. . .

This chemical compound is one of the most potent of all psychedelics and is also prolific in nature, so much so it agreed upon that humans and other animals can create their own DMT [26]–[29]. However, it is still up for debate how much DMT is created and how it is used [29]. Strassman and colleagues have stated the key enzyme for its production is supplied in the both the pineal gland and the retina, which may say something about the intense visionary nature of experiences reported by test subjects [27]. It is also found in hundreds of plants around the world as well [3].

DMT is particularly dependent on the method of induction. In extracted forms, it is intravenously injected or smoked and the user immediately feels the effects for about 20-30 minutes. In brewed forms of ayahuasca combined with plants containing mono-amine oxidase inhibitors (MAOIs), it becomes orally active and lasts for several hours [9], [25], [30]. In early clinical trials of intravenous DMT, users reported seeing bright moving colors, a loss of control, dissociation, and alternating between feeling euphoria and anxiety [31][32].

Around the 2-minute mark the drug reaches its full potential and in high enough doses the user experiences “a sense of tremendous acceleration and psychic and somatic tension,” then totally dissociates out of waking state consciousness into a world of extremely complex visions. This lasts for only about 20 minutes before gradually returning the traveler to normal waking consciousness [27].

Dr. Rick Strassman and colleagues oversaw dozens of these clinical tests with intravenous DMT, recording detailed accounts of the experiences. According to them, the nature of this dissociated vision-state seems to feel like a world totally autonomous from dreams and waking life, but somehow more real, unlike a hallucination [27].

These researchers reported a similar side-effect profile to other classical psychedelics: minor increase in blood pressure, heart rate, pupil dilation, and body temperature. It should be noted that the volunteers getting injected with DMT were all experienced psychedelic users already, so side-effects in the general population are likely to be further-reaching and less predictable [27], [31]–[34].

Nonetheless, compared to the uncanny psychological and visual effects of DMT, this drug can be administered with relatively few physical risks. Furthermore, because of the unique nature of its tolerance in the body, the low side-effect profile contributes to another unique property among the classical psychedelics, an absence of psychological tolerance [27], [34], [35].

Strassman and colleagues discovered that as the minor physical side effects like blood pressure and pupil dilation do build a tolerance and, thus diminish across repeated doses, the intense visionary and psychological experience does not. This phenomenon is very unusual to classical psychedelics, especially compared to the fast-building tolerance of LSD and psilocybin mushrooms. Strassman and colleagues took advantage of this discovery and successfully infused DMT to the blood using target-controlled intravenous infusion modeling, the same method used to keep surgery patients unconscious with anesthetics. This allowed for subjects to remain in the dissociated visionary state indefinitely with ease [27], [34]. The implications of this discovery have only begun to be speculated about, but it is safe to say there is something profoundly significant about the human body being capable of this feat.


References

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