Table of Contents Introduction The Similarities and Differences Between Psilocybin Mushrooms and Cannabis Which Conditions Could Psilocybin Potentially Treat? Why Does Psilocybin Work? How Does Psychedelic-Assisted Therapy Work? How Long Does It Work For? More About Fungi and Mushrooms What Are Magic Mushrooms or Psilocybin Mushrooms? Psilocybin Pharmacodynamics Psilocybin Pharmacokinetics Psilocybin/Psilocin Effects How Successful is Psychedelic Therapy? What’s the Overall Verdict? Further Reading Introduction Broaching the subject of magic mushrooms as a form of therapy for psychiatric illnesses is not something one usually does in polite company. Yet, perhaps one sometimes should. It is, after all, something we here at Leafwell take a brief look at on our cannabis for addiction page. We in the cannabis industry have a difficult enough time getting people thinking of cannabis as medicine. Start bringing up psilocybin mushrooms (or indeed any psychedelic), and they might start thinking you should put down the peace pipe. Hence, many in the cannabis industry are wary of ever mixing the two, in fear that it may end up diluting the message of cannabis as medicine and turning off people who might otherwise be convinced. From https://www.pxfuel.com/en/free-photo-otfnb The Similarities and Differences between Psilocybin Mushrooms and Cannabis Yet, there is no doubt that cannabis and psilocybin mushrooms share many similarities. Both are natural and from the earth. Both have associations with counterculture movements. Both are illegal. Both tend to instill a strong appreciation of nature, art and music in users. Both can sometimes cause significant shifts in consciousness and personality. Moreover, with the exception of those with psychosis, neither cannabis or psilocybin have the same potential for harm as many other substances. Psilocybin mushrooms has consistently ranked as one of the least harmful psychoactive substances. The two also have very many differences. For one, cannabis hails from the plant kingdom, psilocybin mushrooms fungi. Another is that the two have a different pharmacology: cannabis targets the endocannabinoid receptors; psilocybin is metabolised into psilocin by the liver, which acts on serotonin receptors in the brain. Psilocybin’s chemical formula is C12H17N2O4P (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine, 4-PO-Psilocin, or 4-PO-HO-DMT), whereas CBD’s and THC’s chemical formulas are C21H30O2. Another thing to remember is that both magic mushrooms and cannabis produce a completely different class of compounds that work together, creating an entourage effect that is unique to each one. They are essentially very different, although some may claim that the two are related in a spiritual sense due to the similarities mentioned above. Some are now claiming that psilocybin mushrooms (and other psychedelics) have significant therapeutic value, in particular for depression, PTSD and addiction. Where cannabis’ mechanism of action seems to be returning balance via interaction with the endocannabinoid system (ECS), psilocybin mushrooms’ is providing insight and connection via serotonergic receptors. Psilocin has a high affinity for the 5-HT2A serotonin receptors, and could increase the concentration of dopamine in the basal ganglia. CBD has an affinity for 5HT1A receptors, whilst psilocin does not. Due to its pharmacodynamics, psilocybin treatment is contraindicated for those with schizophrenia or schizoid personality disorders, as well as bipolar disorder. Where CBD could help such conditions, psilocybin/psilocin does not. There are some people who need to escape from a false/negative reality (e.g. depression) or come to terms with a traumatic one (e.g. PTSD). Others, meanwhile, need to be drawn back to reality. The idea of using psychedelics for mental health problems is not new. In fact, psychedelics and mushrooms of various types have been used for their medical and spiritual applications for thousands of years, before even cannabis use. Co-founder of Alcoholics Anonymous Bill Wilson, was a proponent of psychedelic therapy (LSD in his case) for alcoholism. Here’s why Bill Wilson may have been right … Magnetic resonance imaging of areas of the brain in the default mode network. Source: John Graner, Neuroimaging Department, National Intrepid Center of Excellence, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. https://www.frontiersin.org/articles/10.3389/fneur.2013.00016/full Which Conditions Could Psilocybin Potentially Treat? Before we get into the pharmacology of psilocybin, let’s give an idea of why psilocybin or “magic” mushrooms work. There are several mental health conditions psilocybin could be very useful for. These include: Depression Addiction – proponents have argued that psychedelic-assisted therapy is one of the most successful treatments for drug addiction available today. Post-Traumatic Stress Disorder (PTSD) Anxiety Disorders In one study by John Hopkins University on using psilocybin to help tobacco smokers quit: “Johns Hopkins researchers report 15 study participants taking psilocybin achieved an 80 percent abstinence rate over six months, compared to an approximate 35 percent success rate for patients taking varenicline, which is widely considered to be the most effective smoking cessation drug.” As with THC, those who are at risk of psychosis or suffer from schizophrenia, schizotypal personality disorders or bipolar disorder should avoid psilocybin. Why Does Psilocybin Work? There are a few good reasons why psilocybin works for the above conditions. These include: Disruption of the Default Mode Network (DMN) – the DMN is a network of interacting brain regions that is active when a person is not focused on the outside world. In depressed people, the default mode is one of persistent, ruminating negative thoughts. Psilocybin essentially breaks this cycle – it “breaks the script”. For those who are addicted to a particular substance or activity, psilocybin can act as a prompt to start thinking differently and beating negative patterns of behavior. Psilocybin can help one connect and reconnect with nature and others, as well as one’s self. Can help one face and come to terms with past traumas. Increases brain flexibility – neural plasticity. A single dose can have long-lasting effects – this is not the case with antidepressants, which must be taken daily, can come with serious side-effects and sometimes do not even work. The effects of classic hallucinogens like psilocybin on serotonin 2A and 5-HT2C receptors are thought to give them anti-addictive properties. The duration of the trip is between 4 and 8 hours, which is far more tolerable than the 12+ hours of LSD. Other psychedelics, like ibogaine from the iboga root, may be particularly useful for opioid addiction, as ibogaine works on opioid receptors and can even inhibit or block opioids from attaching to the dopamine and opioid receptors! A single dose of ibogaine can increase Glial Cell Derived Neurotrophic Factor (GDNF) expression, which can reduce drug-seeking behavior. Psilocybin, however, is generally much safer than ibogaine. How Does Psychedelic-Assisted Therapy Work? There is still much to be researched in this area, but using psilocybin effectively requires more than the ingestion of a few grams of mushrooms. Effective psychedelic therapy will likely include: Extensive therapy before and after the trip in order to allow the patient to integrate and talk about their experiences into everyday life, including discussions on planning how they intend to use what they have learned. Group therapy and discussion with others about their experiences, if the patient feels they can do so. Having a guide or a trip sitter – someone who is not using psilocybin – keeping watch and providing support is of immense importance. Some would recommend 2 trip-sitters for each patient – ideally one male and one female. Sensory deprivation – headphones with music (usually Western or Indian Classical, jazz or ambient music) and blindfolded – will also be incorporated in many types of psychedelic-assisted therapy sessions. Others involve a group setting and a guide or even a shaman with experience of the process. Some would suggest using a high dose of 3-4 grams is required for the true therapeutic effects. The intensity of the psychedelic experience can be the thing that makes it potentially very useful. Microdosing psilocybin (i.e. using small amounts that do not have psychedelic effects) can be useful for their mood-boosting (and possibly neurogenic) effects. However, it is the large dose/s that are thought to be truly therapeutic. How Long Does It Work For? Psychedelic-assisted therapy’s efficacy depends on the individual, but some would say around 3-6 months on average. Some have reported positive effects for a year or even longer afterwards, others less than 3 months. More About Fungi and Mushrooms Fungi contain chitin, a cellulose-like derivative of glucose that are the building blocks of insect exoskeletons, fish scales, fungi cell walls and more. Fungi seek out food, and do not photosynthesise. Fungi are nature’s decomposers, and are responsible for nutrient cycling and exchange. Fungi form vast mycorrhizal networks under the ground, connecting individual plants together (and, interestingly, allowing plants to communicate with each other). The fruiting bodies of these networks can display as mushrooms that we see above ground. Fungi can contain all sorts of compounds, from the harmful to the innocuous to the extremely useful. Yeast, bread leavening, detergents, natural pesticides, bioremediation, antibiotics and antivirals, and many immune- and brain- boosting properties. Fungi can be symbiotic to plant and animal species, as well as parasitic. Fungi and its fruiting bodies can also produce extremely toxic effects if consumed. The study of fungi is called mycology. Mycology was once a subset of botany, but as the two are entirely different kingdoms (fungi are closer to mammals than plants), they require a different understanding. They could therefore be seen as different areas of study entirely. However, the two areas share some interesting overlaps with regards to how the two kingdoms interact on top of the historical association. From https://www.pxfuel.com/en/free-photo-xwarm What Are Magic Mushrooms or Psilocybin Mushrooms? These are essentially mushrooms that contain the compound psilocybin, which we have mentioned above. There are various kinds of mushrooms that contain psilocybin from across the world. The following genera contain psilocybin: Psilocybe (116 species), Gymnopilus (14), Panaeolus (13), Copelandia (12), Hypholoma (6), Pluteus (6) Inocybe (6), Conocybe (4), Panaeolina (4), Gerronema (2), Agrocybe (1) and Galerina (1). Psilocybe cubensis (“Golden Teacher”), Psilocybe subcubensis and Psilocybe semilanceata (“Liberty Caps”) are the world’s most widely distributed psilocybin mushrooms. Other widely-distributed kinds include Psilocybe azurescens (“Flying Saucers”), Psilocybe cyanescens (“Wavy Caps”), Psilocybe baeocystis (“Knobby Tops”) and Psilocybe mexicana (“teonanacatl”). Panaeolus cyanescens, aka Copelandia cyanescens (“Blue Meanies”), are another potent type of psilocybin mushroom. Psilocybin-containing species are dark-spored, gilled mushrooms that usually grow in meadows and woods of the subtropics and tropics, most often in soils rich in humus and plant debris. There are four main active alkaloids in psilocybin mushrooms: 1. Psilocybin. 2. Psilocin. 3. Baeocystin. 4. Norbaeocystin. The most potent variety of mushroom is thought to be Psilocybe azurescens, but potency can vary amongst different genus and species, and can only be described in generalities rather than specifics. Yes, there is an entourage effect between these different compounds, and synthesized psilocybin will likely have a different effect compared to the mushroom itself. It is thought that about 4 mg of baeocystin produces mild psychedelic effects, and 10 mg effects similar to the same dose of psilocybin. Psilocybin Pharmacodynamics Psilocybin is rapidly dephosphorylated in the body to psilocin by the liver, which is a partial agonist for several serotonin receptors. Psilocin binds with high affinity to 5-HT2A receptors and low affinity to 5-HT1 receptors, including 5-HT1A and 5-HT1D. Effects are also mediated via 5-HT2C receptors. 5-HT2A antagonists like ketanserin block psilocin’s effects. Psilocin is rapidly metabolized by MAO-A and MAO-B. Serotonin receptors are located in numerous parts of the brain, including the cerebral cortex. Serotonin is involved in a wide range of functions, including regulation of mood, motivation, body temperature, appetite and sex. Psilocin also indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia. Some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist. Psilocin antagonizes H1 receptors with moderate affinity, compared to lysergic acid diethylamide (LSD) which has a lower affinity for H1 receptors. Unlike LSD, psilocybin and psilocin have no affinity for dopamine receptor D2. Author: Cacycle (Public Domain Picture) Psilocybin Pharmacokinetics The effects of psilocybin/psilocin begin 10–40 minutes after ingestion, and can last anything between 2 and 12 hours depending on dose, species, and individual metabolism. A typical recreational dosage is 10–50 mg psilocybin, which is roughly equivalent to 10–50 grams of fresh mushrooms, or 1–5 grams of dried mushrooms. A dosage of 4–10 mg, or roughly to 50–300 micrograms per kilogram (µg/kg) of body weight, is required to induce psychedelic effects. A Johns Hopkins study found the ideal dose for long-term positive effects to be 20 mg per 70 kg of body weight. This is usually around 2 – 3 grams of dried magic mushrooms of standard potency, which can last between 4 and 8 hours depending on individual metabolism. Psilocybin/Psilocin Effects Psilocybin is a tryptamine, a monoamine alkaloid. Tryptamine is a neurotransmitter found in trace amounts naturally in mammals. Tryptamine binds to human trace amine-associated receptor 1 (TAAR1) as an agonist. Tryptamine acts as a non-selective serotonin receptor agonist and serotonin-norepinephrine-dopamine releasing agent (SNDRA), with a preference for evoking serotonin and dopamine release over norepinephrine release. Effects of psilocybin – both positive and negative – can include: Euphoria Peacefulness Spiritual awakening Quickly changing emotions Derealization, or the feeling that your surroundings are not real Depersonalization, or a dream-like sense of being disengaged from your surroundings Distorted thinking Visual alteration and distortion, such as halos of light and vivid colors Dilated pupils Dizziness Drowsiness Impaired concentration Muscle weakness Lack of coordination Unusual body sensations Nausea Paranoia Confusion Visual and auditory hallucinations Vomiting Fatigue & “brain fog” – in particular the next day, which may be partially attributable to fatigue and lack of sleep Yawning Psilocybin may induce a psychotic episode in those who are prone to hallucinations. Some have likened the psilocybin experience to one of “temporary psychosis”, but as the experience is often significant for many people and not necessarily harmful in healthy people, it is simplistic to liken the psilocybin experience to psychosis. Tolerance to psilocybin is built rapidly, and is also diminished quickly. Ingesting more than once a week can lead to diminished effects, and tolerance can dissipate after 3-4 days. There is also cross-tolerance to other tryptamines, like LSD, as well as phenethylamines such as mescaline. Psilocybin is not addictive. In fact, many have claimed that psilocybin could be anti-addictive! Due to its spiritual uses, psilocybin is often described as being an “entheogen” in order to differentiate it from other kinds of psychedelics. There are reports of “flashbacks” – the effects of psychedelics being felt or “revisited” months or even years after the initial experience. Such experiences are often triggered by a certain visual pattern or occurence of a type of event. This could be compounded by polydrug use, or could be caused by a shift in pattern processing or recognition. Such experiences are often brief, and for some can be unusual or uncomfortable. From: https://www.pikrepo.com/fcnxt/crazy-psychedelic-vision-walk-in-the-forest (Creative Commons Zero) How Successful Is Psychedelic Therapy? Although most of the studies so far are small in scale, it does seem that psychedelic-assisted therapy is very effective for treating depression, anxiety and addiction. Another issue is that many sessions are usually done in informal, unstructured environments outside of the views of a healthcare professional. A large-scale study had this to say: “Hendricks et al examined the relationship of lifetime psilocybin use and psychological distress in the past month. They also collected past-year suicidal thinking, suicidal planning, and suicide attempts associated with psilocybin use in an adult population in the United States. Data used was from the National Survey on Drug Use and Health (2008-2012) in which 191 831 participants were divided into 1 of 4 groups: psilocybin use only (n = 7550), psilocybin and other psychedelics (n = 12 724), other non-psilocybin psychedelics only (n = 6963), or no psychedelic use in their lifetime (n = 164 595). The odds of all of the outcomes were reduced in the psilocybin-only group compared to the no psychedelic use group. Past-year suicidal thinking and planning were lower in the psilocybin group compared to the psilocybin and other psychedelics group. Finally, the odds of past-month psychological distress were lower in the psilocybin group relative to the other psychedelics-only group. Based on this data, the psilocybin group appeared to fare better than any other group. This further supports the idea that psilocybin may play a role in reducing suicidality and improving mood although these patients did not necessarily have a diagnosis of major depressive disorder. It also highlights the potential safety of the substance in such a large population.” See also: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721603/ What’s the Overall Verdict? We here at Leafwell are always intrigued by the uses of whole-plant (or whole-fungi in this instance) medications as a treatment for all sorts of health problems. When non-toxic, they are generally very well-tolerated by the human body, have low addiction potential, and do not usually cause death via overdose. Psilocybin mushrooms are no different in this regard, and the evidence so far suggests very strongly that they can be used for the treatment of depression and addiction – perhaps in a better way than ever. As to whether or not psychedelic therapy will become more commonplace and become the next cannabis is hard to say. First of all, we ought to be wary of conflating two entirely different genus and species! They both have different psychotropic compounds, and work on different receptor systems. They share some similarities with regards to what they can be used for, but have a different mechanism of action. The endocannabinoid system (ECS) is involved in homeostasis, and could be said to have a broad range therapeutic effect for many different conditions that arise from endocannabinid deficiency. Psilocybin mushrooms, meanwhile, work on a different set of serotonin receptors. The two perhaps share more of a spiritual connection with each other. The cannabis industry is also used to working with an illegal plant, so it would not be surprising to see their skills and expertise transferred to mycology as well! The two worlds, although different in many respects, will likely enmesh and be used in combination for mental health therapy in the future. Further Reading https://maps.org/ https://www.imperial.ac.uk/psychedelic-research-centre/ https://erowid.org/plants/mushrooms/mushrooms.shtml https://www.ncbi.nlm.nih.gov/pubmed/25563446 https://www.ncbi.nlm.nih.gov/pubmed/10506904 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787540/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732823/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277566/ https://www.annualreviews.org/doi/abs/10.1146/annurev-neuro-071013-014030 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/ See a doctor today and get a physician’s recommendation for a medical marijuana card. Feaured image credits: From https://www.flickr.com/photos/[email protected]/28306445805 Author: Kooikkari (CC BY-SA 2.0). Picture taken with an Olympus Digital Camera.