Psychedelics

Figure 1. A 2014 study in the Journal of the Royal Society Interface. The image on the left is of a human brain on a placebo, and the image on the right is of a brain on a psychedelic.

Psychedelics are medicines that induce Pivotal Mental States. Given the correct priming (set), setting and subsequent integration they can have potent psychoplastogen effects on the mind. In some countries, psychedelics are classified as illegal, however, more recently this taboo has been rapidly lifting.

During the psychedelic experience, as shown in the illustrated brain scan to the right (Figure 1) parts of the brain which do not usually communicate with one another start talking, opening subconscious inputs to the conscious mind. The experience is thought to open a neuroplastic window augmenting learning and cognitive and psychological flexibility. Clinically this can be seen as giving users an opportunity to correct ruminating thought patterns thought to be the basis of mental illnesses such as bipolarity, depression and anxiety.

History

There has been a long and diverse history of human psychedelic use, stretching back at least 3,000 years. Historically, they were incorporated into various cultural practices: as Soma in India, Peyote among the Navajo, and Kykeon in the ancient Greek city of Eleusis. However, since the early 1970s, these substances have been mired in taboo. Today, we're witnessing a renewed interest in these compounds, often referred to as "The Psychedelic Renaissance." Current research indicates that they may be among the safest and most potent treatments for a range of mental health issues.

Psychedelic Compounds

Figure 2. The “Classical” Psychedelics are mescaline, LSD, psilocybin, and DMT. Plus the deliriants and dissociatives.

There are 5 classes of psychedelics, which are classified on their effect and chemistry.

Tryptamines

• Psilocybin / psilocin found in magic mushrooms.
• DMT found in acacias and ayahuasca.
• 5-MeO-DMT found in toad venom.

Ergoline

• LSD derived from the rye fungus, ergot.

Phenylethylamines

• Mescaline found in the peyote cactus a Native American entheogen.
• MDMA and 2C-B synthetic compounds made by the chemist Alexander Shulgin.

Deliriants

• Muscimol found in 🍄 - amanita muscaria.
• Ibogaine, an African entheogen.

Dissociatives

• Ketamine a synthetic anaesthesia, which globally, is the most prescribed drug in this class.
• Nitrous oxide can induce mind-altering experiences, including feelings of bliss, spirituality, and the feeling of being outside of one's body.

Short Term Effects

Psychedelics induce a psychedelic experiences which encompass a wide range of sensory distortions, most common include:

Visual

• Increased apophenia
• Diffraction
• Object activation
• Visual acuity enhancement
• Visual agnosia
• Visual exposure to inner mechanics of consciousness

Cognitive

Novel

• Time distortion
• Conceptual thinking
• Thought loops
• Ego Death - Depersonalization

Enhancements

• Creativity enhancement
• Increased suggestibility
• Novelty enhancement

Suppressions

• Addiction suppression
• Personal bias suppression

Long Term Effects

Figure 3. Relative harm of drugs.

Compared to the majority of other medications, the dangers linked with psychedelic use are considerably lower (See Figure 3). Research indicates that certain personality traits such as neuroticism will negatively influence long term outcomes, whereas traits like a willingness to surrender can have a positive impact. Clinically, provided that appropriate priming, setting and integration are in place, there is substantial evidence supporting the safe and effective use of psychedelics in treating various conditions:

• Depression - multiple meta-analyses results suggest that psychedelic-assisted therapy reduces MADRS with minimal adverse effects, relative to a comparable meta analysis of the effects of 21 traditional antidepressant drugs.
• Obsessive compulsive disorder (OCD)
• Post Traumatic Stress Disorder (PTSD)
• Alcoholism - the founder of AA cured his alcoholism using LSD.
• Tobacco Use - small study has shown an 80% cessation rate after 6 months which compare to the industry standard of 35%.
• Alzheimer's Protection - a small study has found that DMT can prevent Alzheimer's in rat studies.
• Hyper-Consumerism - several peer-reviewed studies have shown that psychedelics also work as ecodelics, medicines which can induce ecological concern.

Emotions and brain function are altered up to one month after a single high dose of psilocybin. Psychedelic use correlates to lifetimes without depression. Numerous studies and a systematic review have concluded that guided psychedelic therapy can further improve the above therapeutic effects.

Learning Enhancement

New evidence suggests that psychedelics can enhance a specific type of learning called the reward learning rate which is how quickly an someone updates their knowledge or policy based on the rewards they receive from the environment.

Mechanism of Action

Figure 4. The neurochemical activity of various psychedelics.

Psychedelics induce neuroplastic, pivotal mental states. It is thought psychedelics mediate this effect by activating 5HT2A and tyrosine kinase receptors causing the release of Brain-Derived Neurotrophic Factor (BDNF) receptor TrkB.

Psychedelic Comparison

The most commonly used psychedelics, Psilocybin, DMT and LSD have a very similar effect whilst dissociative psychedelics like ketamine have a more of an Out of Body Experience effect. This is backed up by recent, real world evidence analysis of 2947 publicly available, erowid.org trip reports which concluded:

"MDMA experience reports featured an emotionally intensifying profile accompanied by many cognitive process words and dynamic-personal language. In contrast, Ayahuasca and DMT experience reports involved relatively little emotional language, few cognitive process words, increased analytical thinking-associated language, and the most semantic similarity with psychedelic and mystical experience descriptions. LSD, psilocybin mushroom, and ketamine reports showed only small differences on the emotion-, analytical thinking-, psychedelic, and mystical experience-related language outcomes. Further research has concluded: “Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration”.

Class	Drug	Light High Dose	Normal Dose	Maximum Safe dose	Time to Onset*	Duration of Experience	Duration of Open State
Classic	LSD	10-30 μg	100 μg	1000-3000 μg	0.25-2 hours	6-11 hours	3 weeks
	DMT (inhaled)	10-20 mg	20-30 mg	100 mg	Immediate	15-30 minutes	-
	Psilocybin	5-10 mg	20mg	150 mg	0.5 hours	3-6 hours	2 weeks
	Ibogaine		0.87mg/kg		1-3 hours	Up to 48 hours	>4 weeks
	Mescaline	50-200 mg	400 mg	1000 mg	<30 mins	8-15 hours	-
Empathogen	MDMA	45-75mg	75-125mg, 50% dose 150 mins later.		20-30 min	2-4 hours	2 weeks
	2-CB						-
Dissociative	Ketamine (Intranasal)					<30 minutes	2 days
	Dextromethorphan						-

Figure 5. Psychedelics differ in how long they induce a social reward learning period

Dosage information frequently changes and is dependent on weight and prior medical condition. Before administering check all information with a suitably qualified professional.

A key effect of psychedelics is their ability to open a period of neuroplasticity where old habits can be erased and new habits formed. This period has been found to differ substantially between the various compounds (see Figure 5).

Medicinal Chemistry

All psychedelics are chemically unique and can be categorised into four main types (see Figure 2). There are three main families of chemical compounds: tryptamines, phenethylamines, or lysergamides and many tend to act via serotonin 2A receptor agonism which plays a key role in the regulation of cortical function. Serotonin antagonism has been proposed as the mechanism for the subjective and biological effects of classical psychedelics as these effects are blocked after administering 5HT2AR antagonists such as ketanserin.

Who would be eligible for psychedelics from a doctor?

Psychedelic therapy is not for everyone. There are various inclusion and exclusion criteria for psychedelic therapy, these can vary dependent on which organisation you get access from. Below is a general list compiled from clinical trial data.

Exclusions Criteria

There are a category of patients that have specific conditions or are taking specific medicines that should be excluded from psychedelic therapy. In general these patients have the following characteristics:

• People taking quetiapine, risperidone, and olanzapine (an atypical antipsychotics) as there is some evidence to suggest it can terminate a trip;
• People taking 5HT2AR high affinity antidepressants such as amitriptyline, mirtazapine, and trazodone.
• Presence of high degrees of Psychedelic Anxiety Syndrome;
• Presence or history of psychosis;
• Presence or history of mania or bipolar disorder;
• Presence or history of personality disorder;

Inclusion Criteria

To be able to obtain a psychedelic from a doctor all of the following criteria must be met:

• Over 25, this age is not written in stone and there will be some variability, however, it is thought that psychedelics should not be taken until brain growth is completed which occurs around the mid 20's.
• Diagnosed as having Treatment Resistant Depression, i.e. no adequate response to a course of appropriate antidepressant medication within a certain time.

Adverse effects

Like all medicines, without proper guidance, adverse effects can occur, many of which can be reduced by utilising proper inclusion and exclusion criteria. As shown in Figure 3, relative to other popular medicines psychedelics cause much less harm. However, there have been some adverse psychedelic effects which have been linked to the intensity and duration of the experience. Scientific data suggests that there are two key factors in ensuring a good psychedelic trip include:

1. Being psychologically “well” in the days prior to the experience.

2. Being ready to surrender oneself to the experience.

Microdosing

Figure 6. Psychedelics exert their effect experientially

The medical definition of microdosing is a dose given which is sub therapeutic, i.e. it is the dose doctors recognise as having no discernible effect. However, many claim, mainly via online survey studies, that very low doses of LSD, taken at 3–4-day intervals, improve mood and cognitive function.

In controlled studies, which in mental health are the gold standard, (see critical appraisal) the placebo effect is excluded. In all of these studies microdosing has been shown to have no effect and even in some have shown negative effects such as neuroticism or even the potential to cause valvular heart disease. It has been suggested that this is because the experience of the trip is more important than the underlying chemical-electrical mechanisms (see Figure 6) . By propagating the myth that microdosing does have an effect may cause people from not accessing the correct dose and getting the actual benefit from the medicine.

Oneirogens

An oneirogen, is a substance or experience which enhances dream states, in effect, this could be likened to an unconscious psychedelic state.

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