Treatment-resistant depression, end of life anxiety due to terminal illness, alcohol and tobacco addiction and obsessive-compulsive disorder are all mental illness that cause large amounts of suffering and contribute to significant health care cost in our communities. The WHO list depression as one of the leading causes of disability in the world (Murray and Lopez, 1996) and in a report from 2003 Depression was the reason for the loss of 225,000 years of healthy life in the Australian community (Australian Institute of Health and Welfare, 2003). Mental illness is also complex and difficult to treat. Many current treatments have varying rates of success and some have serious side effects (Martínez-Amorós et al., 2012).
Imagine if there was a naturally occurring drug that was safe when used appropriately, had minimal side effects, was non-addictive and had the potential to be a long term effective treatment for Treatment-resistant depression, end of life anxiety due to terminal illness, alcohol and tobacco addiction and obsessive-compulsive disorder after only one or two doses?
Recent research suggests one may no longer have to imagine… Psilocybin, a psychedelic compound produced by several mushrooms in the genus Psilocybe, has excellent potential to meet this need (Studerus et al., 2011)(Johnson et al., 2018). This preliminary research is extremely promising with regard to depression showing substantial and persistent improvement of symptoms beyond that seen in any current treatments. Future research and treatment will require a cost-effective and reliable supply of psilocybin that could be met by in vivo synthesis in E. coli.
Psilocybin is a psychotropic compound derived from tryptophan that is a product of mushrooms of the genus Psilocybe also known as “magic mushrooms”. The enzymatic pathway for biosynthesis involves four enzymes: PsiD an l-tryptophan decarboxylase, PsiK which catalyses phosphate transfer, PsiM which iteratively catalyses n-methyl transfer and PsiH which is a monooxygenase (Fricke et al., 2017).
The increasing interest and research into psilocybin as a therapeutic agent are likely to increase demand for high quality and affordable supply. Currently, the demand for pure psilocybin for clinical trials is met by current organic synthesis and is estimated to cost more than 2000 USD per gram to produce (Fricke et al., 2019). If this promising drug is to be developed and become a recognised treatment large scale and cost-effective production methods will need to be found, in particular, biosynthesis.
The enzymatic pathway for biosynthesis within the mushroom involves four enzymes: PsiD an l-tryptophan decarboxylase, PsiK which catalyses phosphate transfer, PsiM which iteratively catalyses n-methyl transfer and PsiH which is a monooxygenase (Fricke et al., 2017).
Biosynthesis Pathway of Psilocybin
In nature psilocybin is produced from tryptophan via a pathway that uses four different enzymes. Our aim is to clone this pathway into E. coli to demonstrate psilocybin can be produced in sufficient quantity and purity to meet research and future treatment needs in a cost-effective way.
Depression and anxiety in advanced stage cancer
Cluster Headaches and Obsessive Compulsive Disorder
Obsessive Compulsive Disorder
Major depressive illness is the leading cause of disability in the world (Murray and Lopez, 1996). The current gold standard treatment for treatment-resistant depression is electroconvulsive therapy which is very effective in the short term but associated with side effects including persistent memory loss and requires general anaesthesia (Martínez-Amorós et al., 2012). A recent small study using a single moderate dose of psilocybin in patients with TRD and anxiety showed that at 3 months, 8 of 12 participants met the criteria for complete remission and 5 of 12 at 6 months (Carhart-Harris et al., 2016).
A recent small double-blinded study demonstrated a significant reduction in depression and anxiety at 3 and 6 months after treatment. An additional larger study with higher doses showed 80% of participants had clinically significant improvement in mood and anxiety symptoms 6 months after a single treatment. None of the patients experienced any serious adverse effects of the treatment (Grob et al., 2011).
Two psilocybin sessions accompanied by four therapy sessions resulted in the self-reported reduction of drinking at 36 weeks follow up in all patients. A large randomised trial is currently being conducted (Bogenschutz et al., 2015).
A small preliminary study resulted in 80% of patients maintaining smoking cessation at 6 months follow up and 75% at 2.5 years after 2-3 treatment sessions. This is a very high rate of abstinence compared to existing medications and a larger randomised trial is currently being conducted (Johnson et al., 2014).
A small sample of psilocybin users reported that psilocybin successfully halted their cluster headaches suggesting further investigation as a treatment may be worthwhile (Sewell et al., 2006).
A small preliminary partially blinded study found that patients with OCD who were treated with psilocybin experienced significant relief from symptoms and that psilocybin was well tolerated with no serious side effects (Moreno et al., 2006).
In a review of current literature Johnson et al demonstrate that based on the major factors considered for the classification of drugs as controlled substances, psilocybin has a very low potential for abuse (Johnson et al., 2018). Animal studies and human studies indicate that psilocybin is not an addictive drug and potential for harm is small (dos Santos, 2014) and participants in clinical trials report a low desire for repeat use (Johnson et al., 2018). In the context of therapeutic treatment of mental illness and addiction in a supervised and controlled setting risks to patients appear to be very low while the potential for benefit is high.
Psilocybin is a prohibited drug in most countries, as explained above current research suggests that potential for abuse is not strong and in particular that when used in a therapeutic setting is unlikely. Current models of treatment using psilocybin are as in-patient procedures under close medical supervision in combination with therapeutic debriefing and counselling. In this context, patients have reported no desire for further use of the drug (Johnson et al., 2018).
As an open source technology, there is potential for unauthorised production using our method. Appropriate controls will need to being investigated in order to minimise this possibility but given the low potential for addiction and abuse, this risk does not outweigh the potential benefits of a low cost and reliable supply for therapeutic use.
- Murray C, Lopez A (1996) The Global Burden of Disease: a comprehensive assessment of mortality & disability from diseases, injuries & risk factors in 1990 & projected to 2020, Volume 1, Global Burden of Disease & Injury Series, Harvard: Harvard School of Public Health.
- Australian Institute of Health and Welfare (2003) Health Expenditure, Australia, 2001–2002, Australian Institute of Health and Welfare, Cat No HWE 24, Health and Welfare Expenditure Series No 17. - (2005) Health system expenditure on disease and injury in Australia 2000-01, second edition, AIHW cat. no. HWE 28 - (2006) Australia’s Health 2006 Canberra, AIHW cat. No. AUS 73. - (2007a) Statistics on Drug Use in Australia, 2006. - (2007b) Mental Health Services in Australia, 2004-05.
- Martínez-Amorós, E., Cardoner, N., Soria, V., Gálvez, V., Menchón, J.M. and Urretavizcaya, M., 2012. Long-term treatment strategies in major depression: a 2-year prospective naturalistic follow-up after successful electroconvulsive therapy. The journal of ECT, 28(2), pp.92-97.
- Studerus E., Kometer M., Hasler F., Vollenweider F.X. (2011) Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology. 25(11), pp. 1434-1452.
- Johnson, M.W., Griffiths, R.R., Hendricks, P.S. and Henningfield, J.E., 2018. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology, 142, pp.143-166.
- Carhart-Harris, R.L., Bolstridge, M., Rucker, J., Day, C.M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J.A., Forbes, B., Feilding, A. and Taylor, D., 2016. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry, 3(7), pp.619-627.
- Grob C..S, Danforth A.L., Chopra G.S., Hagerty M., McKay C.R., Halberstadt A.L., Greer G.R. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry. 68(1). pp. 71-8.
- Bogenschutz, M.P., Forcehimes, A.A., Pommy, J.A., Wilcox, C.E., Barbosa, P.C.R. and Strassman, R.J., 2015. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of psychopharmacology, 29(3), pp.289-299.
- Johnson, M.W., Garcia-Romeu, A., Cosimano, M.P. and Griffiths, R.R., 2014. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of psychopharmacology, 28(11), pp.983-992.
- Sewell, R.A., Halpern, J.H. and Pope, H.G., 2006. Response of cluster headache to psilocybin and LSD. Neurology, 66(12), pp.1920-1922.
- Moreno, F.A., Wiegand, C.B., Taitano, E.K. and Delgado, P.L., 2006. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. Journal of Clinical Psychiatry, 67(11), pp.1735-1740
- Fricke, J., Blei, F. and Hoffmeister, D., 2017. Enzymatic synthesis of psilocybin. Angewandte Chemie International Edition, 56(40), pp.12352-12355.
- Fricke, J., Lenz, C., Wick, J., Blei, F. and Hoffmeister, D., 2019. Production Options for Psilocybin: Making of the Magic. Chemistry–A European Journal, 25(4), pp.897-903.
- Hoefgen, S., Lin, J., Fricke, J., Stroe, M.C., Mattern, D.J., Kufs, J.E., Hortschansky, P., Brakhage, A.A., Hoffmeister, D. and Valiante, V., 2018. Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi. Metabolic engineering, 48, pp.44-51.
- dos Santos, R.G., 2014. Potential therapeutic effects of psilocybin/psilocin are minimized while possible adverse reactions are overrated. Therapeutic drug monitoring, 36(1), pp.131-132.