Suboxone and St John's Wort (SJW) Potentiation--Summary Study

Probably of little interest except to those dedicate individuals who keep asking: Does SJW potentiate/intensify Buprenorphine (via increased liver metabolism into Norbuprenorphine)? Several forums raised the issue and reported on individual "experiments." But there never was much of a consensus reached (I guess that's impossible), or even much of summary, so here's SWIMine. For what it's worth. SWIMy conclusion: a "real," contagious "placebo effect." Anyone care to add?

(Another hypothesis: SJW + Bup causes long-winded, excessive-compulsive writing. Sorry!)

Caution**** This is not a “real” scientific study (not fake either; it is based on real reports)… just a humorous tabulation of trip reports… Actually doing this combination sounds dangerous: Norbup depresses breathing, potentially lethally, and at least some users experience withdrawal when they combine Bup with SJW….****

This table and the "Results" are what are important:

Experience/Attribution...Number of Individuals...Percent of Total
1. Positively positive......8.................................38 %
2. Possibly positive........5................................. 24%
3. Neutral.....................6..................... ............29%
4. Possibly negative......0................................... 0%
5. Positively negative.....2.................................10%
Total............................21............... .................100%


But just in the interests of full disclosure and killing time:

“An Exploratory Study of User Reports of Subjective Experiences of Concurrent Consumption of Buprenorphine and St. John’s Wort.” (12/13/2009)

Background: A number of opiate-dependent Suboxone and Subutex users have speculated that St. John’s Wort (SJW) may intensify or potentiate the subjective effects of Buprenorphine (Bup) consumption. (See especially: http://forum.opiophile.org/showthread.php?t=14532 )
Other users have reported experiencing withdrawal effects after concomitant consumption. Potentiation with cytochrome P450 enzyme CYP3A4 (responsible for breaking down Bup)-inhibitors (e.g. grapefruit juice, cimetidine) has been reported with other opioids and Bup (i.e. extending the duration of Bup’s half-life, potentially with corresponding subjective effects). However, based on Bup’s curious and sometimes paradoxical psychopharmacology, the hypothesized effects of SJW depend not on increasing plasma levels of Bup itself, but of its major psychoactive metabolite, Norbuprenorphine (NorBup), a drug with potentially greater agonist properties, but which is ordinarily antagonized by Bup. The speculative hypothesis (H1) is as follows: SJW induces the production of CYP3A4, which is responsible for metabolizing Bup into NorBup; by increasing the ratio of NorBup to Bup, pleasurable, agonist effects are purportedly experienced.

Aims: Multiple users have conducted in vivo auto-“experiments” and posted their experiences, but to date these experiences have not been systematically analyzed. The purpose of the present study is to determine, among those who self-report combining SJW with Bup, the proportion of users that report atypical subjective experiences and the proportion that attribute those experiences to SJW’s purported potentiation of NorBup, to SJW alone, or to “placebo effect.”

Method: Searching Google for all (40) two-term combinations of Term 1 ((St. OR Saint) (John’s OR Johns) Wort) OR SJW) AND Term 2 (Subutex OR Suboxone OR Buprenorphine OR Bupe OR Bup OR Norbuprenorphine OR Norbupe OR Norbup), a convenience sample of anecdotal subjective drug experiences (“trip reports”) were collected from online message boards (posted between January 26, 2008 and October 29, 2009). (The first three pages of results were examined after each google search.) Trip reports were tabulated quantitatively according to a parsimonious, deductive coding scheme designed to test H1, and analyzed qualitatively in an inductive fashion in order to develop further hypotheses.

Sample: A total of 21 trip reports from different individuals qualified for inclusion in the study. Cases were included that met three criteria.

First: the user reported FIRST-HAND (including experiences by SWIM, but not the experiences of friends, family, co-experimenters, etc. reported second-hand) consuming any quantity of St. John’s Wort (range: 300mg – 1200mg; 8 unknown) concurrently (range: 1 hour before – 1.5 hour after; 10 unknown) with buprenorphine (range: 1mg – 32mg; 9 unknown), using any route of administration (3 sublingual alone; 2 insufflated alone; 1 IV; 2 mixed ROA; 13 unknown). A number of second-hand reports were excluded (e.g. “my sister says it works…”). Reports in the form of “general information” (e.g. taimapedia, answers.yahoo, etc.) were excluded.
Second: the user reported no other drug-of-abuse use at the time. Based on this criterion, for instance, one case was excluded of a user who reported pleasurable effects of Suboxone in combination with Fioricet, Tramadol, and SJW (Dr_F on bluelight.ru); another for combining Suboxone with SJW and Xanax (CharlesIV on bluelight.ru). Consequently, any combinatory effects of additional drugs-of-abuse are not investigated in the present analysis. However, one “possibly positive” (coded “2,” below) case was included in the dataset in which the user reported consuming SJW and 50mg of diphenhydramine (aka Benadryl), which may confound the potential potentiating effects of antihistamines.
Third: the user reported subjective effects in sufficient detail to code as follows (note: coding of specific cases is somewhat subjective, as it is based on the present author’s interpretation of other authors’ intentions and often based on minimal information, introducing a real threat to validity of the results):

1. Pleasurable effects definitely perceived and strongly attributed to SJW (e.g. “definitely” real, “for sure”);
2. Pleasurable effects possibly or definitely perceived, but not strongly attributed to SJW, attributed to possible placebo effect, or attributed to SJW alone (e.g. “seem to,” “could be placebo”);
3. Neutral—no atypical effects perceived, effects described as insignificant (e.g. “I’ve yawned a few times. That’s about it.”), or effects described as definitely placebo (e.g. “same either way”);
4. Negative effects possibly or definitely perceived, but not strongly attributed to SJW, attributed to possible placebo effect, or attributed to SJW alone;
5. Negative effects definitely perceived and strongly attributed to SJW.

The unit of analysis—the individual “case”—is the trip report. Complicating the analysis, some individuals report multiple cases that meet the criteria for inclusion in the study. However, since including multiple reports from the same individual introduces a considerable risk of endogenous bias (i.e. the likelihood of correlated errors between multiple observations made by the same individual, particularly since those reporting positive effects are like to repeat the “experiment” and continue reporting), only one case was included per individual (as identified by users’ handles when posting, and any other identifying information; assuming single handles across multiple forums). When multiple trip reports were posted, the user’s “summary” or “overall” attribution was used when available; when a summary attribution is not available, the user’s first codable reported experience is included.

Limitations: No attempt was made to collect information on the user’s level of experience with or dependence on opioids, in general, or Bup, specifically. Some have speculated that the effects may vary between opiate naïve, experienced, full agonist-dependent, and Bup-dependent users. This is a major limitation, but unavoidable since detailed biographical information is often missing from trip reports and too time-consuming to investigate. When human subjects are aware of the substances they are consuming, and particularly when they consume them for the purpose of experiencing a specific effect, the likelihood of “false positives” (i.e. “placebo effect”) is exacerbated. Placebo effects are particularly well-documented in studies of the subjective and behavioral consequences of ingesting intoxicating substances (e.g. alcohol; Testa et al., 2006, "Understanding Alcohol Expectancy Effects," Alcoholism: Clinical and Experimental Research). The present analysis makes no attempt to control for placebo effect. Instead, the study only investigates subjective experiences of knowingly combining Bup and SWJ, oftentimes for the explicit purpose of achieving euphoria. More importantly for the present analysis, sample-selection bias is a major threat to the validity of the results. Anecdotal reports of subjective drug experiences are especially vulnerable to “Type 1” error—false positives. Indeed, there is a strong possibility that a large number of users have attempted the combination and experienced no effects, and consequently have not reported the experience. Evidence suggests the possibility is real: numerous users on the relevant opiophile.org forum reported that they had purchased or already taken the SJW, and would report back later, but then never did. In this analysis, there is an added threat of “false positives” in both directions—that is, of reporting both “false” pleasurable experiences and “false” negative experiences (i.e. precipitation of withdrawal). “Type II” error—“false negatives”—in this context would refer to either “true” effects not noticed or “true” effects not reported. The prevalence of such cases is inherently nearly impossible to estimate. Suggestive evidence indicates that some users may experience the effect but attribute it to other drugs: for instance, Dr_F reports an “opiated” feel from adding Fioricet and SJW to Suboxone; he attributes it to Fioricet, however, not SJW. This case is excluded from the quantitative tabulation because of additional drugs (moreover, some barbiturates are also inducers of CYP3A4 enzyme, consistent with H1). Complicating the interpretation of single cases, some users provide mixed reports or ambivalent or changing interpretations over time. Johnny-5, for instance, is coded as a “1” (“positively positive”) based on his reports on opiophile.org, but in a later posting on stopdrugprohibition.org, he describes the effect as minimal and not worth it.

Nonetheless, anecdotal reports and case studies are an important tool in preliminarily identifying medical phenomena and pharmacological effects. Consequently, an inductive, exploratory qualitative analysis of the available trip reports is conducted in order to develop additional, speculative hypotheses.

Quantitative Results (more detailed records available upon request): See table above. The modal result of concomitant SJW and Bup consumption was self-reported pleasurable effects, attributed strongly to SJW. Approximately 38% (8/21) described the effects as pleasurable and attributed them positively to SJW-potentiation/intensification (Tool, Inspektahdek, Frank Zito/spinelli77, n0yd, Johnny-5, lib.sOCialist, valentine4, lovelikeheroin). Another 24% (5/21) described ambiguous pleasurable effects and/or could not confidently attribute the effects to SJW (Suboxstitute, kil092286, oxy kid, nodrover, 30 units). Thus, about 62% (13/21) experienced some pleasurable effects, potentially attributable to SJW. However, the remaining 38% (8/21) described no effect or negative effects. 29% (6/21) reported neutral or no effect, or concluded the experience was due to “placebo effect” (trainwrecker, scarlettt, The_Highwayman, limitless_euphoria, bodytec, JahRed24x). Interestingly, 10% (2/21) of the subjects reported intense withdrawal symptoms, definitely attributed to SJW (Bghead8che, Halo657). Either experience—euphoria or withdrawal—can be explained by candidate pharmacological hypotheses, based on the differential effects of Bup and Norbup. Indeed, it is possible that under different conditions SJW might cause either effect. Or that both are placebo effects, achieved under different conditions of "priming" and social experience.

Qualitative results:
Data on the SJW and Bup dosages are very incomplete except those reporting the most positive effects. However, the size of the Bup dosage does NOT appear to have an automatic or uniform effect on whether SJW is experienced as pleasurable, since the Bup dosages ranged between moderate-low (3mg (IV), 4mg (sublingual)) and very high (32mg (SL and intranasal)) in the “positively positive” category. But, suggestively, the only dosage specified for any of the "no effect" or "negative effect" experiences was 1-2 mg (not specified; ROA unknown). (This might potentially depend also on unmeasured differences in user experience with opioids.)

Data on SJW dosage is also incomplete, but it appears that higher dosages of SJW may be associated with greater likelihood of reporting positive experiences and more strongly associating them with SJW. SJW dosages in the “1” category ranged between 600 and 900 mg; and between 600 and 1,200 mg in the “2” category. For the only two “3”/“Neutral” cases in which SJW dosage was reported, it was 300 mg (Bup dosage “1-2 mg,” ROA unknown, in one case; Bup dosage unknown in the other).

Although the meaning is unclear, one of the strongest findings is that the more positively a user assessed the effects of SJW, the more detailed the trip report. On the principal quantitative measures (SJW dose, Bup dose, timing, ROA), those coded “1” had 94% full records (2/32 missing values); the “2” reports were 40% complete (12/20 missing); the “3” reports were 29% complete (17/24 missing); the “5” reports were 0% complete (8/8 missing). This finding is certainly consistent with the "false positives"/"placebo effect" hypothesis to explain positive experiences, though clearly not definitively so. (Likewise, reporting more consumption of SJW and/or Bup may lead to greater expectancy of effects.) One interpretation is that those who found positive effects were motivated to share as much information as possible to fellow recreational users, or that users who post to such boards (and in the habit of posting detailed trip reports) were more likely to be “primed” for the placebo effect.
Related, there was considerable clustering by website and forum. Quantitatively, this phenomenon suggests endogenous bias and invalid data. Qualitatively, however, it suggests that information about subjective drug effects is, in a sense, contagious. Users who posted in “harm reduction” forums, geared toward sharing knowledge about recreational drug use, were likely to precipitate other positive experiences in fellow users. Moreover, there was considerable “cross-pollination” between forums; the same users who found positive effects frequently shared them across websites, leading to the rapid dissemination of the effects throughout the online recreational opioid community. The two negative experiences were posted on a single forum, the first apparently attracting the second. The forum was found on a “medical” website oriented to the health concerns of the elderly. These findings are consistent with sociological research on the social interpretation of drug-induced bodily states: opiate addicts must learn to recognize withdrawal symptoms and that continued use will alleviate them (Alfred Lindesmith, 1947, Opiate Addiction, Bloomington, IN: Principia Press); both marijuana and cocaine users must learn not only the technique, but to recognize and appreciate the “high” (Howard Becker, 1953, “Becoming a Marihuana User,” American Journal of Sociology; Craig Reinarman et al., 1991, Cocaine Changes, Philadelphia, PA: Temple University Press). (Crack users need only learn the technique; the “high” is apparently unmistakable [Reinarman et al. 1991].) Thus, sharing one's interpretations of SJW-potentiated-Suboxone use may create or spread the effect in a very real way.

SWIPA’s experience is not included in the results above, though the present author would probably code SWIPA a “2,” viewing it as slightly pleasurable. He had been primed to experience positive pleasurable effects, having read other users’ trip reports over the course of several days. His pleasurable experience may have also been attributable to the fact that, in order to acquire the SJW, he had to leave his one-room apartment for the first time in 24 hours, and walk ½ mile each way to a pharmacy. He took 4mg of Suboxone sublingually on the walk over, then immediately consumed 900 mg of SJW. One hour later he took 4 more mg SL, followed by 300 mg of SJW after 30 minutes. His mood became elevated, although he was not euphoric. He was more active than he had been for the past day or two. Over the course of three hours he conducted a study of subjective user experiences of combining Bup and SJW, using a convenience sample of “trip reports” discovered by searching Google. Although he conducted the study in a humorous mood, he attempted to conduct it in a valid fashion and clearly state the basis for his conclusions and methods of gathering evidence. He did not positively attribute the effects to SJW-potentiation of Bup, but felt positive enough effects to try again tomorrow.

 

That's a hell of a first post.

 

Thanks?

Been reading the forum for a while... including a bunch here on the St John's Wort/potentiation of Suboxone issue. Just now felt I had something I would contribute...

Got to wondering if it's possible to summarize experiences on these forums and get a sense of where opinion stands. Seems like there's a valuable opportunity for sharing experiences, but a lot of it ends up getting lost in space... That, and I felt like killing some time and having some fun with it.

 

Good luck.