Case Study - The Subjective Clinical, Psychotherapeutic and Spiritual Benefits of Sceletium tortuosum in severe mental illness Sceletium tortuosum as an antidepressant option Mesembrine is a potent serotonin reuptake inhibitor (Ki = 1.4 nM) and to a lesser extent PDE4 inhibitor. Other notable mesembrine-type alkaloids include mesembrenone (also a potent serotonin reuptake inhibitor [Ki = 27 nM] and a more potent PDE4 inhibitor than mesembrine itself), and mesembrenol. Another assay found that Sceletium tortuosum comprising of > 70% (w/w) stabilised mesembrine was a monoamine releasing agent. The actions at VMAT-2 are said to enhance monoamine release. Along with monoaminergic effects, increases in BDNF were noted. The pharmacological properties of mesembrine and it's derivatives are quite diverse, showing anti-inflammatory, cytoprotective, VMAT-2 upregulation, mild inhibition of AChE, mild MAO inhibition, limited reuptake of NE and DA at high concentrations. Mesembrenol and mesembrenone seem to also share the SERT inhibitory and PDE4 inhibitory activity [1]. The PDE4 inhibition has been suggested to be a potential novel therapeutic option for a broad range of neuropsychiatric conditions with cognitive impairment (improving cognitive flexibility, executive function, processing speed etc [2]), including memory impairments and acquired brain injuries [3] Clinically, the Sceletium spp. have shown antidepressant, anxiolytic and cognitive enhancement effects, some case studies demonstrating increased attention, focus, and motivation [1] T.L. Olatunji , F. Siebert et al. Sceletium tortuosum: A review on its phytochemistry, pharmacokinetics, biological and clinical activities Journal of Ethnopharmacology 280 (2021) 114476 https://doi.org/10.1016/j.jep.2021.114476 1 [2] Chiu, S., Gericke, N et al., 2014. Proof of-concept randomized controlled study of cognition effects of the proprietary extract Sceletium tortuosum (Zembrin) targeting phosphodiesterase-4 in cognitively healthy subjects: implications for Alzheimer’s dementia. Evidence-based Complement. Alternative Med. 2014 https://doi.org/10.1155/2014/682014 [3] Arjan Blokland, Pim Heckman et al. Phosphodiesterase Type 4 Inhibition in CNS Diseases. Trends in Pharmacological Sciences Vol. 4 Is. 12 2019 https://doi.org/10.1016/j.tips.2019.10.006 Background The person had a severe complex mental illness comprising multiple dimensions of treatment-resistant MDD, SCHZ/schizoaffective, ASD and significant cognitive impairment. Sleep was significantly impaired with frequent extremely early morning awakenings. Some of the etiology was putatively organic, with significant cognitive complaints (incl. poor sustained attention, working memory, slow cognitive processing speed etc, neuropsychological testing in past revealed cognitive functioning in <0.1% range) potentially stemming from white matter damage from prior suicide attempts. The extremely low moods had been persistent for a long time and zest for life was absent, days were spent catatonic, flapping (stereotyped 'stimming'), collapsing on floor/couch etc with extremely poor quality of life Subjective complaints were extreme depression including dysphoric mood with agitation and cognitive issues and significant negative symptoms of anhedonia, apathy, amotivation and asociality. AVHs were persistently present but he was able to cope with these. Significant catatonic features including posturing were present. Arousal levels were often low (frequent closed eyes) The person was not significantly responsive to conventional antidepressants with a broad range explored including SSRIs, SNRIs etc. Auditory hallucinations remained unresponsive to a broad range of antipsychotics. The person felt a deep connection to plants and hence using them as medicine may have resonated better with personal beliefs and values and encouraged self-empowerment. Exploring S. tortuosum opened up a dimension where it appeared to be a personally effective tool for encouraging psycho-social-spiritual personal growth and deeper self- inquiry . Switching A cold-turkey 5.5 half-life washout of the maximal dose SSRI, straight onto the S. tortuosum, just using plain herb at 1/4 tsp + dried powdered herb. Some of the case-study literature suggests therapeutic benefits in MDD, anxiety, personality disorders etc may be seen in the 10-14 day period. Aripiprazole 10mg was maintained with PRN quietiapine (25-50mg) for sleep. 2 The first few days on the Sceletium were not overly remarkable but slowly an organic contentedness started to build which was solid basis for broadening and building other states from There were a few days of extreme emotional lability on the transition and after a couple of weeks the moods began to not be so volatile. He described a more longer-term leveling out of the effects of the Sceletium where "rather than the more acute robust uplift and transformative effects initially, almost a sort of tolerance to the effect but with improved baseline mental states" was noted Objective improvements were noted on the Sceletium by his support network and friends, with one remark, "whatever you're doing, keep doing it as it seems to be working". Socially, he felt more comfortable and able to converse with friends. His eyes were open during support sessions. Care was required to still not over-do activities to maintain appropriate level of activity, taking into account fatigue management. "In the last few days I've started to have glimpses of feeling free from - or distance from - pain and suffering, the need to hold onto the past and live in that way, to coming home to this place in myself where I'm OK, to recapturing a sense of appreciation of the vast beauty of life in particular the natural world, to being able to sit still (rather than literally flap and scroll all day) and just appreciate beautiful music in the moment and feel this vast depth of inner peace, something that was always hindered by an extreme neurosis and restlessness in my soul, an agitated mind that just couldn't find peace in anything. There's been these super spiritual sublime moments that feel like you're breaking down the negativity, which you do feel to an intensity that moves you to tears) to break through to new places in your body, mind, heart and spirit. There's still lots of negative emotions but the positive mental aspects are amplifying to take a stronger hold on me, despite still in my hermitage. It's been an pushing past of regressive mental stagnation and perpetual breakdown into this new unfolding of uplift of restoration of a sense of the Divine around me. I hesitated to believe that a plant could be truely described as ‘the greatest Clearer of the Spirits, and the noblest Restorative in the World’ as someone described it but I'm seeing theres some validity to that line of thinking, rather than seeing it simply as a phytochemical array of pharmacologically active constituents." --- "Whereas on the maximal SSRI dose it felt like negative emotions were stuck within me, on the kanna I didn't have to hold onto anger, dysphoria, pain and downward negative emotional spirals as me and could now begin to embrace new possibilities despite significant limitations. From the glimmers of contentedness, it felt like new emotions could broaden and build from that but I had to put in the effort to create those states. It wasn't a pushy mania 'high' but an opportunity to grow. For me, that 3 choice was to simply dance with my emotions instead of letting the negative take over me and pin me down. I noticed in switching, contrary to the blocking and blunting of SSRIs, there was a new inner emotional landscape that was opening up. It wasn't the kind of hedonistic happiness that some seek but it was emotional depth of polarity. Some moments would be feeling like I was about to burst into tears (and did) but with that there was a background of greater emotional resilience with the possibility that those states of sadness could be felt for a moment, then transcended into new more positive emotions. I've often felt that psych medicines can be more 'filters' or even constraints to consciousness that lock you into a fixed mental state, which can be useful to taper intensity of suffering but this experience with kanna was one of something positive growing in me, a glimmer of aliveness. A new ability to make a 'choice' other than being miserable. Also, there was a sense of enjoyment that started to build, which had been lacking. Before I was always pushing myself to do things like the runs etc to feel better, now I could simply enjoy going for a run. Music sounded good, whereas before it was simply drowning out woes. Movement, no matter how unco and simple, felt pleasurable. It'll take a while and effort to keep choosing a more positive choice over sadness to build a hedonic baseline of some level of happiness but in deep dark depressions, I think you don't always have that capacity to begin to develop a new more positive choice because nothing feels positive. Something opened in me, I felt more deeply and a gentle activation energy to do positive things opened, on a backdrop of greater contentedness" Several weeks into the switch, the Sceletium was abruptly withdrawn temporarily due to supply issues. Over those days, symptoms rapidly worsened quite intensely (return of diverse symptomatology) hence it seems there was significant symptom reduction being provided by the S. tortuosum day-to-day. Some subjective clinical benefits The person noted that they "have to not expect the kanna to do all the heavy lifting mood wise, it's really a tool that opens a potentiality for better states but without following through with behavioural activation/valued action you rapidly can sink back into the abyss" Simple valued goals were defined as: Aliveness . Embraced through more movement-centric activities, exercise, simple dance, therapeutic drumming Connection. Improving some social engagements particularly deepening already existing ones. 4 Independence. Gaining small steps of growth in self-care and independence doing very simple tasks myself Meaningful Pursuits Growth - currently just trying to be content, happy Noted subjective improvements ⦁ Prosocial and emotional enhancements - encourages a feeling mode, anxiolysis facilitates direct and open communication with others ⦁ Contact with the present moment as 'still', improved cognitive clarity and suppression of mind chatter opens a state more conducive to learning a more meditative state ⦁ Acute mood improvements suppress downward negative emotional spirals of anger, blame, self-hatred etc into a more accepting embrace of peaceful acceptance of the moment Gradual but robust improvement in mood which is once again quite dose dependent. It was possible to push into quasi-manic territory with higher doses but those states were also more conducive to changing outlook and thoughts to more positive ones. At some points he felt like a "butterfly emerging from the chrysalis" Sleep remained significantly impacted with no early signs of improvement Greater cognitive clarity, reductions in cognitive complaints, intrusive lines of thinking and improved time that I can focus on tasks, improved receptiveness to the world around me, rather than being stuck in my own mind A sense of pleasure and enjoyment, currently fairly restricted to very simple activities like movement and dance, 'drumming', feeling rhythm more deeply but very gradually a return to enjoyment of more mundane everyday tasks, cooking, mowing the lawn, cleaning This embrace of the now as more pleasurable, valued and meaningful has somewhat hindered the desire for more goal-directed tasks but I still feel it's personally valuable to have an improved hedonic baseline in the moment that is not so dependent on goal- directed activity Improved emotional tone and states of feeling over obsessive analytical thinking Reductions in sensorimotor stereotypies and aberrant ASD related behavious which are slowly being embraced by a more free flowing way of movement through life. "Whereas I always felt held down by life, I've been able to hold my head higher and put my chin up and be more comfortable in myself and that is slowly reflected in my body posture" Robust anxiolysis and greater inner calm and peacefulness in his mind, rather than being at 5 "war with myself" which is slowly reflecting in his ability to have more positive social relationships. The person was able to feel comfortable and confident doing short bus trips alone, whereas normally support was required Reductions in positive symptoms - AVHs have drastically reduced in intensity (despite resisting conventional antipsychotics) from harsh, persecutory and denigratory to a generally more absent status and slowly less pathological self-talk has become softer, quieter and easier to deal with Reductions in agitation and catatonic posturing, very dependent on current mood and ability to engage on other tasks A sense of stronger healthier self-concept and self-empowerment, the ability to be more in control of my mental state rather than 'driven by pathology' As a tool for Psychotherapeutic and Spiritual Growth The concept that beyond the antidepressant and anxiolytic effects with cognitive enhancement noted in clinical studies, there may be some merits for psychotherapeutic use has been suggested by Nigel Gericke where he states it may have benefits for • facilitating psychotherapy • facilitating meditative and spiritual states Transient states of self-transcendence and spiritual moments were noted, from embracing a more present moment way of thinking to even embracing an all-loving sense of something greater than me in the universe, or higher power particularly within nature. He felt there be this "all-encompassing sense of light in the darkness, the need to pray and hold myself in devotion to such" etc. See: Nigel Gericke Kabbo’s !Kwaiń: The Past, Present and Possible Future of Kanna (2018) https://www.researchgate.net/publication/328942189_Kabbo% 27s_Kwain_The_Past_Present_and_Possible_Future_of_Kanna Feelings of some elements of spirituality, eg embrace of more self-transcendent states, gentle ego-dissolution, positive emotions encourage a more open mental process of appreciating beauty, the uplift of emotions and cognitive fluidity can broaden-and-build mental states of openness to experience, more profound shifts in mental state can encourage consideration of the Divine in one's life It's been interesting simply freeing my way of feeling and thinking a bit, the Kanna seemingly serving as a mild empathogenic ego-dissolution tool that is dose- dependently gentle in action, which has clinical merits over more rapid and robust ego-dissolution seen with 5-HT2AR agonists etc (personally more in line with an empathogenic action), particularly for fragile mental states that may be susceptible to more pathological hallucinations. It's also very emotionally friendly as in it 6 encourages a heart-centred way of thinking, feeling and being He was inspired to create this "Devotion to the Heart and Light" by some of the experiences Downsides: While the Sceletium was significantly effective, real-world issues meant there were challenges using it therapeutically longer-term. One was the lack of standardised material on the market, meaning dosing was a challenge as there was issues ascertaining the potency and potential effects of individual batches and maintaining a steady effect and symptom reduction. Longer-term, there were issues maintaining a steady-state of therapeutic effectiveness due to supply issues and costs involved. Finding a consistent supply of sufficiently effective, affordable Sceletium was very challenging, leading to issues of stability of effect. Subjective final opinions: ...quite often it's our mind's own rigidity and ego barriers that are constraining our consciousness to realms of pain and suffering. A heavily ingrained 'allegiance to pain and suffering' seems to be one of the significant cognitive biases that our brains can be pinned 7 down into low states of consciousness by. By simply loosening those cognitive constraints in a more loving, gentle, kind and spiritualised direction, rigid loops of dysfunctional thinking patterns can slowly be loosened or literally blown away, freeing up new ways of thinking that may be less fear-based, pathological, freer, more loving and kinder to ourselves and others While there is the need to pathologise some aspects of mental functioning, too heavy an ingrained thought pattern of pathology and 'biomedical fixing' constrains you to a dimension where it is always heavy and dark. If you see the beauty, feel the love and peace, cultivate the compassion and kindness towards yourself you can seemingly slowly slay the demons in your mind - I like the line "the monsters in my head are scared of love". It's not an overnight process and it takes lots of repetition to stabilise a more positive growth mentality but it's worth it, and slowly that inner work has the chance to make life more easy to deal with each day 8