Does harmaline cause brain damage (and other astute questions)? (Patreon)

Barry asked a bunch of questions that I thought I'd post responses to here:

1) The Wikipedia article on harmaline describes its neurotoxicity in rats, citing https://www.sciencedirect.com/science/article/abs/pii/030645229390500F.  What are your thought on this?

The first thing you have to understand is that virtually everything causes damage or even death at a high enough dosage.  This is true even for common food ingredients/additives people eat all the time (salt, water, nitrates, iodine, vitamin-C, baking soda, etc).  All medications have what is known as an "LD50" (the lethal dose at which 50% of test animals drop dead).  I read the paper you cited above, they were giving rats mega-doses (overdoses) of ibogaine and harmaline (specifically, they were giving ibogaine (100 mg/kg daily for 3 days) - ibogaine experts say 12mg/kg is a high dose, beyond this and you start seeing cardiac events (arrhythmia), they also say one should NEVER exceed 24mg/kg in a 24 hour period, so you can see how 100mg/kg given 3 times on back to back days might be a problem.  Similarly, for harmaline they were giving 40mg/kg or 25mg/kg on 3 consecutive days.  Even taking the lower dosage, for a 165lb man, that equates to a harmaline dose of 1.87g.  First of all, the only way a human could even get such a ridiculous dose would be by injecting themselves -- if taken orally you would surely vomit this toxic dose out quickly. Also note from the paper itself, they were torturing these poor rats, within minutes of these overdoses they lost all motor control, they began shaking (head and body), occasionally they'd have violent twitching of the limbs sending them flying off the floor of their cage, then they laid loose and motionless like they were dead except they were still shaking (tremor) for 6 to 8 hours!!
If you are interested in how humans react to different dosages of harmaline, please see the notes from Alexander Shulgin on harmaline self tests:

(with 150 mg, orally) "In an hour and a quarter, there was a rapid-onset intoxication and I felt a little unstable. And a little bit numb. There was an unusual shimmering, in my lateral vision when I turned my head to the side. Everything was just a little bit down. Music was pretty much normal but I was missing the higher frequencies. Even light food sat heavily, and I wasn't too hungry (and I was remembering to watch what I eat, with this monoamineoxidase stuff). Sex was difficult -- probably due to some reduced sensations. I feel that this compound is unlikely to be attractive to most people, as its major effects are an intoxication with a clouding of thoughts and some disruption of musical relationships."
(with 175 mg, orally) "After about one hour I found myself becoming relaxed and a bit sloppy. By the end of the second hour, I had peaked, and was pretty much at baseline after five hours. At the peak, three areas of disturbance were obvious. There were obvious tracers -- when looking at a bright object, and moving your eyes to the side, the image of the object lags in its leaving the visual field, and it leaves in the opposite direction. As to the auditory, it seemed as if the higher frequencies of music were attenuated, and the lower frequencies amplified. And as to touch, there is a definite numbing. I had no appetite, and the little I ate didn't taste particularly good."
(with 200 mg, orally) "At about the two hour point I remember three things. The first was the effort to bring into reality the visual image of a face that was playing with my eyes-closed imagery. I got the mouth and, after a bit of work, I got the eyes. So I concentrated on the nose and it came into view, finally, but it was upside down. The second and third things were more easily defined. Nausea and diarrhea. Fortunately they alternated. This is not my trip of choice."
(with 300 mg, orally) "I was in a psychotherapy environment, so there was some suggestions and leading that influenced my responses. But I have great difficulty reliving my experience, in fact I don't remember anything. I have only disconnected images. There is a girl -- me -- in front of a church on a dusty road, myself at communion, receiving the Host from an invisible hand at a grandiose alter. I feel that I am going crazy. Something inside. It is not anxiety. It is not depression. It is some of each, plus irritation and disorientation. I am dead but still have to come back to life. I am facing a reality of mine that I cannot accept."
(with 400 mg, orally) "This is Fluka material, and has a nasty taste. I felt completely immobilized and sick to my stomach. Closed eyed visuals yielded native women, 'organic' colors and shapes, and a black panther! I would like to do DMT and Harmaline together, but am put off by the nausea."
(with 500 mg, orally) "I took a half gram of pure synthetic harmaline after fasting for over a day. The resulting nausea was greatly attenuated after I vomited. At this dose there were intense and annoying visual disturbances, and complete collapse of motor co-ordination. I could barely stagger to the bathroom, and for safety's sake locomoted by crawling. Tracers and weird visual ripplings disturbed my sight with open eyes. With eyes closed, there was eidetic imagery. It had no symbolic significance, just bothersome disjointed sequences that lacked a relevant theme. They proceeded to transform so slowly (in comparison to the speed of my thought) that they were predictable and boring. Throughout the experience I just lay hoping it would end soon. It did not seem as though I had encountered intrapsychic material which was being expressed through somatic symptoms. Rather, I felt that I was struggling to metabolize a chemical disruption of my physiological functions. Although the session was not enjoyable, I was satisfied at having educated myself about the effect produced by a penalty dose of this compound."

Note how a 500mg dose was barely tolerable, caused him to vomit, even at 400mg there was complete immobilization, inability to walk, collapse of motor co-ordination...
Now contrast all of this with the dosages I recommend via the 2:1:1 blend, at the upper end of my range (170mg) that comes to 85mg THH, 42.5mg Harmine, 42.5mg Harmaline (for a 165lb person that's just  0.567mg/kg compared to the 25mg/kg they gave the rats even in their small dose - a whopping 44 times my recommended human oral dose). And for vaped DMT I recommend half that, so just 21.25mg harmaline (0.284mg/kg).  At the sublingual dose for vaping, the effects are so mild that some people may not notice anything at all, at the higher dose, you mostly just feel relaxed and have mild visual effects like occasional tracers.
Sadly, those researchers did some pretty shoddy work - don't get me wrong, I'm all for testing things for toxicity, but these guys should have also tested "normal" dosages to look for the same types of brain damage!  Thankfully, it seems they inspired other researchers to do just that! 3 years later, these guys were able to reproduce the original results, but found that at 40mg/kg there was no damage.  More recently, another study (https://www.ncbi.nlm.nih.gov/pubmed/10966515 ) showed:

Here, we treated rats (n = 6 per group) with either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons. All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected; despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls, indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).

(Note: the ibogaine dose that was considered to have no observable adverse effect was still about twice the recommended high dose for a human). I haven't found similar studies with harmaline but I'm confident the outcome will match the above especially since both compounds are structurally similar and exhibit similar side effects in the rats.  

Also note that we are comparing oral or sublingual doses (for humans) vs. injected doses for the rats in these experiments.  The bioavailability is likely to be significantly lower with the oral/sublingual routes compared to injection.

2) The 2:1:1 THH:harmine:harmaline blend you recommend is different than traditional ayahuasca proportions, as the table shows at https://www.youtube.com/watch?v=i0PYGDuMOBU&t=19m11s. Notably that shows much lower harmaline. Is your higher harmaline recommendation mainly to induce drowsiness?

I'm not sure "drowsiness" is the right word - but yes, the goal is to lower anxiety and induce a calm, peaceful state of mind with lower blood pressure.

3) The Callaway et al paper you cited says "THH possibly contributes neuroactivity by weakly inhibiting the uptake of serotonin". Does this mean it is SSRI? Would this interact badly with MAOI if too high proportion in the blend? There is a relevant nexus thread at https://www.dmt-nexus.me/forum/default.aspx?g=posts&t=18410

Not a concern, due to the fact that it only weakly acts as an SSRI, and also the MAOI is RIMA type.  

4) What is your thought on spitting vs swallowing the sublingual dose?

I wish someone would study/test this with blood results.  You should give this a try, maybe if 80% is absorbed sublingually that's good enough? I have no idea what the actual percentage would be, and I am not aware of any published studies on this.  I would love to see people's experience reports on that.

-Gordo