Psilocybin: the future of treatment for major depression?
Warning: I do not condone or promote the use of any legal or illegal substances. This article is made for educational and harm reduction purposes only. If you are feeling depressed or suicidal please dial 1–800–273–8255 for the National Suicide Prevention Hotline, available 24 hours; and/or contact a local psychologist or psychiatrist for potential treatment options. Thank you and enjoy the read!
What is psilocybin?
Psilocybin, the active ingredient present in over two hundred species of mushrooms, has been used for it’s mind altering properties by ancient cultures for thousands of years. When psilocybin is ingested orally it is quickly metabolized into psilocin, a psychoactive chemical with a structure similar to serotonin. The user generally experiences a state of heightened awareness and euphoria, accompanied by auditory and visual hallucinations as is common with other entheogens such as LSD, Mescaline or DMT. In recent years the exploration of alternative treatments for major depression has broadened. Psilocybin, accompanied by a therapeutic setting, is being considered as potential treatment and replacement for SSRI’s and other drug therapies used for major depression
How does psilocybin work?
When fully metabolized psilocybin is converted into psilocin and acts acts as a 1A, 2A, and 2C serotonin receptor agonist; meaning psilocin binds to serotonin receptor sites causing the activation of serotonergic systems and the release of serotonin. Studies performed in transgenic rats, and humans have corroborated that psilocybin activates 1A, 2A, and 2C serotonin receptors. But there is convincing evidence that 2A serotonin receptors play a greater role than either the 1A or 2C in regards to the effects of psilocybin. A specific head shaking behavior is characteristic of hallucinogenic effects in rodent. In transgenic mice that have been selectively bred to lack 2A serotonin receptors this head shaking is not observed after a dose of psilocybin, but upon the restoration of individual 2A receptors this characteristic head shaking returns (Wing et al 1990, González-Maeso 2007). When ketanserin, a drug that blocks the activation of serotonin by 2A receptors, is administered in humans after receiving a dose of psilocybin, all subjective effects of the drug cease (Vollenweider, 1998). This supports that the 2A serotonin receptors are mainly responsible for the positive effects of psilocybin.
How does metabolized psilocybin (psilocin) interact with depression and its symptomatology?
One key brain region involved in the serotonergic emotion-processing circuit, is the amygdala. In people with, or at risk for major depression, hyperactivity within in the amygdala in response to negative stimuli, has been shown to be a uniform trait. This is due to a lack of tryptophan, the chemical precursor to serotonin. In one study, twenty five patients, sixteen male and nine female, received either .16 mg/kg psilocybin or a placebo during two sessions conducted fourteen days apart in a double blind procedure. fMRI (functional magnetic resonance imaging) was used to measure brain activity during each session and self report indexes were used to assess mood. fMRI showed that when presented with negative stimuli (Faces emoting negatively) or neutral stimuli under the influence of psilocybin, hyper-reactivity in the right amygdala was significantly lowered. Self report tests showed that psilocybin significantly increased positive affect, but not anxiety or negative affect in comparison to the placebo treatment. The strong association between the effects of psilocybin, the reduction of activity in the amygdala and an increase in positive mood, supports the idea that psilocybin has the potential to help patients in depressed mood states (Kraehenmann et al, 2015).
In another study six men and six women with treatment-resistant major depression, meaning their symptomatology was non-responsive to two or more classes of antidepressants, were given two doses of psilocybin in two sessions separated by seven days. The first dose contained ten milligrams of psilocybin, the second follow up dose containing 25 milligrams of psilocybin. During the experience, patients were placed in a pre decorated room with low lighting and music was played through speakers and earphones. They were asked to recline in a ward bed, accompanied by two psychiatrists that remained bedside throughout the trial. The patients were allowed to, for the most part, experience an “inner journey” with only the occasional supportive interaction with the psychiatrist along with the administration of physiological tests. The Quick Inventory of Depressive Symptoms (QIDS) was used in assessment and compared at baseline, one week, two weeks, three weeks, five weeks, and three months after the high dose session. A score of sixteen to twenty is considered severe depression, eleven through fifteen moderate depression, six to ten mild depression and five or less shows absence of depression.
The mean QIDS reading of the patients at baseline was nineteen, at one week it was reduced to seven, at two weeks to six and by three months had increased to ten. Eight out of the twelve patients had a significant response to psilocybin treatment, and seven of these eight qualified for remission status. On top of this, at the three month mark seven of twelve patients retained their response and five of the twelve remained in remission. Even with positive results such as these, the study itself was fairly limited by sample size and lack of a placebo control group. At very least these results show that in the proper setting and under proper supervision psilocybin can be administered safely to patients willing to undergo the treatment (Carhart-Harris et al, 2016).
How does psilocybin compare with other common treatments for major depression?
SSRI’s, Selective Serotonin Reuptake Inhibitors and other similar antidepressants block the reuptake of serotonin into the presynaptic terminal buttons, temporarily increasing the users serotonin levels and reducing some activity in the amygdala. This is similar to the action of psilocybin, but psilocybin provides several benefits that antidepressant pharmaceuticals do not. Antidepressant pharmaceuticals must be taken on a regular basis, usually daily, and take two to five weeks to build up in a user’s system and start exhibiting effects. Psilocybin, as demonstrated above, can have profound effects in one to two session and the effects can last three months or longer, this is a huge benefit to the user! Psilocybin also has a low toxicity profile and is not associated with “compulsive drug-seeking behavior” in humans or animal analogues. One other unique component of psilocybin is how it interacts with the user’s neurons.
When compared to other chemicals that activate the serotonin 2A receptor, psilocybin regulates intracellular signaling pathways differently, leading to a different expression of signaling proteins in neurons projecting to other parts of the brain (Gonzalez-Maeso et al 2007, Schmid et al, 2008). This difference in expression, correlates with the difference in positive subject effects seen in hallucinogenic 2A receptor agonists, that are not present in non-hallucinogenic 2A receptor agonists. Further study in these differences could lead to new drugs selected for the therapeutic effects of this pathway, but without the hallucinogenic properties. This would significantly lessen the stigma associated with these drugs and allow a whole new group of people, who are willing to try a non-hallucinogenic version of the drug, to experience their positive effects. This could potentially begin a new, more effective class of antidepressants.
Is psilocybin the future of treatment for major depression?
Psilocybin has show potential as a treatment for major depression on both a subjective and objective level. This is seen through the positive subjective effects it has had on users in a controlled setting, as well as the objective data it has allowed scientists to gather on the Serotonin 2A receptors role in the mechanisms of depression and the amygdala. Many people with major depression are not responsive to antidepressants or are put off by the idea of having to take a pill on a daily basis. Psilocybin offers another option that is not only lower in toxicity, but does not have to be used on a daily basis to have a positive effect. As mentioned earlier the remission of major depression can last up to three months for some patients, after only two treatment sessions. As with all treatments psilocybin also has it’s limitations. Some patients are uncomfortable with mild hallucinations or the “high” gained from treatment. But as earlier discussed it may be possible to isolate the chemical elements that cause the psychological benefits of psilocybin while removing the hallucinatory effect, allowing this treatment to be used by a wider range of patients.
In the treatment of mental illness there is no silver bullet that will work for all patients all of the time, relieving them of all their symptoms permanently. Perhaps a combination of psilocybin and talk therapy, or psilocybin used periodically along with antidepressants, will yield life changing results for some patients (although combining antidepressants and psilocybin could be potentially harmful and has not been researched as of yet). Regardless, based on the studies above and many others, it would be wise for psilocybin to be provided as a treatment option for patients with major depression, giving them the best chance at finding a treatment that works for their unique case.
References:
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. (2015). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 78(8), 572–581. doi:10.1016/j.biopsych.2014.04.010
Carhart-Harris, R. L. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry . doi:10.3410/f.726375864.793520560.
Wing, L. L., Tapson, G. S. & Geyer, M. A (1990). 5HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology 100, 417–425.
Gonzalez-Maeso, J. et al (2007). Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53, 439–452.
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A., Vogel, H. & Hell, D (1998). Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9, 3897–3902.
Schmid, C. L., Raehal, K. M. & Bohn, L. M (2008). Agonist-directed signaling of the serotonin 2A receptor depends on b-arrestin-2 interactions in vivo. Proc. Natl Acad. Sci. USA 105, 1079–1084.
